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UBC Theses and Dissertations

Serotonin and exercise Walsh, Michael Leonard 1983

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SEROTONIN AND EXERCISE by MICHAEL LEONARD WALSH B. P. E. A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF PHYSICAL EDUCATION i n THE FACULTY OF GRADUATE STUDIES S c h o o l Of P h y s i c a l E d u c a t i o n And R e c r e a t i o n We a c c e p t t h i s t h e s i s as co n f o r m i n g t o the r e q u i r e d s t a n d a r d THE UNIVERSITY OF BRITISH COLUMBIA Feb r u a r y 1983 © M i c h a e l Leonard Walsh, 1983 In p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t of the r e q u i r e m e n t s f o r an advanced degree a t the U n i v e r s i t y of B r i t i s h C olumbia, I agree t h a t the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and s t u d y . I f u r t h e r agree t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g of t h i s t h e s i s f o r s c h o l a r l y purposes may be g r a n t e d by the Head of my Department or by h i s or her r e p r e s e n t a t i v e s . I t i s u n d e r s t o o d t h a t c o p y i n g or p u b l i c a t i o n of t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l not be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . Department of P h y s i c a l E d u c a t i o n , F e b r u a r y , 1 9 8 3 The U n i v e r s i t y of B r i t i s h Columbia 2075 Wesbrook P l a c e Vancouver, Canada V6T 1W5 Date: i i A b s t r a c t The e f f e c t s of a l t e r i n g s e r o t o n i n (5-HT) c o n c e n t r a t i o n on p h y s i c a l e x e r c i s e were i n v e s t i g a t e d i n a d u l t , male, hooded r a t s . The r a t s were t r a i n e d t o run on a t r e a d m i l l a t a speed of 40 m/min, then s u b j e c t e d t o an e x h a u s t i v e r u n . S e r o t o n i n l e v e l s were d e c r e a s e d by p a r a - c h l o r o p h e n y l a l a n i n e (300 mg/kg; i n t r a g a s t r i c ) and i n c r e a s e d by 5-HT (50 ug; i n t r a v e n t r i c u l a r ) . R a t s w i t h lowered 5-HT l e v e l s had a 30% i n c r e a s e i n r u n n i n g time t o e x h a u s t i o n whereas t h e i r c o n t r o l s o n l y had a 1% i n c r e a s e . E l e v a t i n g 5-HT l e v e l s d e c r e a s e d r u n n i n g time 44% whereas a p p r o p i a t e c o n t r o l s had a 7% i n c r e a s e i n r u n n i n g t i m e . In some a n i m a l s the e f f e c t of e x e r c i s e on 5-HT l e v e l s i n the c e r e b e l l u m , m e d u l l a o b l o n g a t a , hypothalamus, m i d b r a i n , s t r i a t u m , hippocampus, and c o r t e x were measured. When compared t o yoked, shocked c o n t r o l s , e x e r c i s e d r a t s had no d i f f e r e n c e i n the a b s o l u t e l e v e l s of 5-HT except f o r a l e s s e r amount i n the hypothalamus. These r e s u l t s suggest t h a t a l t h o u g h e x e r c i s e d i d not i n c r e a s e a b s o l u t e 5-HT l e v e l s , changing r e s t i n g l e v e l s of 5-HT can markedly a l t e r subsequent r u n n i n g time t o e x h a u s t i o n . T a b l e of C o n t e n t s A b s t r a c t i i L i s t of T a b l e s . i v L i s t of F i g u r e s v Acknowledgements v i INTRODUCTION 1 METHODS 3 S u b j e c t s 3 Su r g e r y 3 I n j e c t i o n s 3 S e r o t o n i n A n a l y s i s 4 Ap p a r a t u s 4 Pro c e d u r e 5 H i s t o l o g y 7 RESULTS 9 Running Time 9 S e r o t o n i n A n a l y s i s 11 Locomotor A c t i v i t y 13 H i s t o l o g y 13 DISCUSSION 14 REVIEW OF LITERATURE 16 1 I n t r o d u c t i o n 16 2 S e r o t o n i n As A M o d u l a t o r 17 2.1 I n t r o d u c t i o n 17 2.2 A n a t o m i c a l E v i d e n c e 17 2.3 P h y s i o l o g i c a l E v i d e n c e 18 2.4 B e h a v i o u r a l E v i d e n c e 20 3 S e r o t o n i n I n t e r a c t i o n s With Other N e u r o t r a n s m i t t e r s .24 3.1 I n t r o d u c t i o n 24 3.2 S e r o t o n i n I n t e r a c t i o n W i t h N o r a d r a n a l i n e 26 3.2.1 I n t r o d u c t i o n 26 3.2.2 A n a t o m i c a l E v i d e n c e 26 3.2.3 B i o c h e m i c a l And P h y s i o l o g i c a l E v i d e n c e ....27 3.2.4 B e h a v i o u r a l E v i d e n c e 30 3.3 S e r o t o n i n I n t e r a c t i o n W i t h Dopamine 31 3.3.1 I n t r o d u c t i o n 31 3.3.2 A n a t o m i c a l E v i d e n c e 31 3.3.3 B i o c h e m i c a l And P h y s i o l o g i c a l E v i d e n c e ....32 3.3.4 B e h a v i o u r a l E v i d e n c e 34 4 P o s s i b l e L o c i And Mechanisms By Which S e r o t o n i n May I n h i b i t P h y s i c a l A c t i v i t y 37 4.1 I n t r o d u c t i o n 37 4.2 T h e r m o r e g u l a t i o n 37 4.3 I n h i b i t i o n Of C o r t i c a l Neurones 38 4.4 A c t i o n On S p i n a l Motorneurones 41 4.5 A i r I o n i z a t i o n 43 4.6 S e r o t o n i n e r g i c I n h i b i t i o n At Motor E n d p l a t e s ...44 4.7 S e r o t o n i n e r g i c I n h i b i t i o n Of G l u c o c o r t i c o s t e r o i d A c t i o n 45 4.8 S e r o t o n i n e r g i c I n h i b i t i o n Of A d r e n a l T y r o s i n e H y d r o x y l a s e 47 4.9 Other P o s s i b l e L o c i Of I n h i b t i o n 48 5 C o n c l u s i o n s 49 REFERENCES 51 i v L i s t of T a b l e s 1. E x e r c i s e Regime 6 2. Running Times To E x h a u s t i o n 10 3. S e r o t o n i n C o n c e n t r a t i o n s In Rat B r a i n 12 V L i s t of F i g u r e s 1. P e r c e n t Change In Running Time 11 2. Motor A c t i v i t y Spectrum 16 v i Acknowledgement I g r a t e f u l l y acknowledge the encouragement, e x c e l l e n t d i s c u s s i o n s , and t e c h n i c a l a s s i s t a n c e of my committee members: Dr D.J. A l b e r t , Dr S. Brown, Dr K. C o u t t s , and Dr A. Pe a r s o n . F u r t h e r h e l p f u l d i s s c u s s i o n and t e c h n i c a l a s s i s t a n c e o f f e r e d by Dr L. B u r t n i c k , Dr K. G a l l i c a n o , and Dr P. G a l l o was a l s o g r e a t l y a p p r e c i a t e d . I a l s o l i k e t o acknowledge the e x c e l l e n t t e c h n i c a l a s s i s t a n c e o f f e r by Ben C l i f f o r d , Wayne K a r l s s o n , Wendy L o n g l e y , W a l t e r M a r t i n d a l e , J a n i c e P. O ' B r i e n , L i n d a Walsh, and L y l e W h i t t i m o r e . 1 INTRODUCTION Based on a l a r g e number of s t u d i e s , T r u l s o n and Jacobs (1979b) have put f o r w a r d a h y p o t h e s i s t h a t c r a n i a l s e r o t o n i n modulates an a n i m a l ' s a c t i v i t y l e v e l r a n g i n g from s l e e p t o w a k e f u l n e s s t o s i m p l e locomotor a c t i v i t y . They h y p o t h e s i z e t h a t low s e r o t o n i n (5-HT) l e v e l s , which o c c u r d u r i n g s l e e p , promote locomotor a c t i v i t y ; h i g h 5-HT l e v e l s o c c u r r i n g d u r i n g p r o l o n g e d locomotor a c t i v i t y induce r e s t i n g . T h i s h y p o t h e s i s s u g g e s t s t h a t the mo d u l a t o r y e f f e c t s of 5-HT s e r v e as a s a f e t y mechanism a g a i n s t o v e r - s t r e s s i n g the organism w i t h too l i t t l e or too much a c t i v i t y . From a b e h a v i o u r a l p e r s p e c t i v e , t h e r e i s no reason why T r u l s o n and J a c o b s ' h y p o t h e s i s s h o u l d be l i m i t e d t o the range of s l e e p i n g t o w a l k i n g . I t i s r e a s o n a b l e t o i n f e r t h a t the a c t i v i t y spectrum c o u l d be extended beyond w a l k i n g t o i n c l u d e i n t e n s e motor a c t i v i t y ( e x e r c i s e ) . T h i s e x t r a p o l a t i o n of T r u l s o n and Jacobs' h y p o t h e s i s t o i n c l u d e i n t e n s e motor a c t i v i t y has o b v i o u s and r e a d i l y t e s t a b l e i m p l i c a t i o n s . The f i r s t i s t h a t the a l t e r a t i o n of s e r o t o n i n l e v e l s s h o u l d a l t e r e x e r c i s e performance. To d a t e , t h e r e have been no s y s t e m a t i c s t u d i e s which have a l t e r e d s e r o t o n i n l e v e l s and r e c o r d e d subsequent performance of i n t e n s e motor a c t i v i t y . However, F e l d b e r g and Sherwood (1954) d i d make a p e r i p h e r a l o b s e r v a t i o n t h a t s e r o t o n i n ( i n t r a v e n t r i c u l a r ) produced apparent muscular weakness. The second i m p l i c a t i o n of e x t e n d i n g T r u l s o n and Jac o b s ' h y p o t h e s i s i s t h a t e x e r c i s e s h o u l d cause an i n c r e a s e i n c r a n i a l 5-HT l e v e l s . Rats t h a t a re f o r c e d t o e x e r c i s e a r e c o n f r o n t e d 2 w i t h two d i f f e r e n t s t r e s s e s : (1) the motor a c t i v i t y r e q u i r e d and (2) the d e t e r r i n g c o n d i t i o n which augments the performance of the e x e r c i s e (eg. an e l e c t r i c g r i d a t the r e a r of a r u n n i n g chamber or water immersion d u r i n g swimming). Research by T h i e r r y e t a l ( 1 968), d emonstrates tha,t m i l d e l e c t r i c shock i n c r e a s e s 5-HT l e v e l s i n the b r a i n s t e m . A few s t u d i e s have i n d i c a t e d t h a t s e r o t o n i n does i n c r e a s e d u r i n g e x e r c i s e (Barchas and Freedman, 1963; B l i s s , 1973; Romanowski, 1967; Romanowski and G r a b i e c , 1974). These s t u d i e s , however, used o n l y s e d e n t a r y a n i m a l s as c o n t r o l s and hence t h e i r d a t a do not i n d i c a t e whether the i n c r e a s e d 5-HT i s the r e s u l t of the shock, the e x e r c i s e , or b o t h . I t i s the purpose of t h i s study t o lower and r a i s e s e r o t o n i n e r g i c l e v e l s i n the r a t b r a i n and r e c o r d subsequent r u n n i n g time t o e x h a u s t i o n . F u r t h e r m o r e , by d e t e r m i n i n g 5-HT c o n c e n t r a t i o n i n v a r i o u s a r e a s of the b r a i n a f t e r e x e r c i s e and u s i n g n o n - e x e r c i s e d c o n t r o l r a t s t h a t r e c e i v e a shock regime comparable t o the e x e r c i s e d r a t s , i t w i l l be d e t e r m i n e d i f 5-HT l e v e l s do i n d e e d i n c r e a s e d u r i n g e x e r c i s e . 3 METHODS S u b j e c t s The s u b j e c t s were 48 a d u l t male hooded r a t s o b t a i n e d from C h a r l e s R i v e r , Canada. The r a t s weighed 180-200 g a t t h e time of s u r g e r y and 220-240 g by the f i n a l t e s t . The a n i m a l s were housed i n d i v i d u a l l y i n w i r e mesh cages w i t h f r e e a c c e s s t o food and water. The c o l o n y room was m a i n t a i n e d on a normal 12:12 hour l i g h t : d a r k c y c l e . S u r g e r y N i n e t e e n of the 48 a n i m a l s underwent s u r g e r y . S u r g e r y was performed u s i n g a Kopf s t e r e o t a x i c i n s t r u m e n t and sodium p e n t o b a r b i t a l a n a e s t h e s i a (50 mg/kg). B i l a t e r a l 23 gauge s t a i n l e s s s t e e l c a n n u l a s were permanently i m p l a n t e d i n t o the l a t e r a l v e n t r i c l e s . The b e v e l l e d t i p s of the c a n n u l a s were a l i g n e d p o s t e r i o r l y . The c o o r d i n a t e s , based on the a t l a s of P e l l i g r i n o and Cushman (1967), were AP: -0.2, ML: ±1.8, DV: -2.7 mm from the c o r t i c a l s u r f a c e . The upper i n c i s o r bar was s e t 5 mm above the i n t e r a u r a l l i n e . When not i n use the c a n n u l a s were capped w i t h 30 gauge s t a i n l e s s s t e e l . p l u g s . A n i m a l s were a l l o w e d 1 week of p o s t s u r g i c a l r e c o v e r y . I n j e c t i o n s To d e p l e t e s e r o t o n i n , 10 a n i m a l s were g i v e n an i n t r a g a s t r i c i n j e c t i o n of p a r a - c h l o r o p h e n y l a l a n i n e (pCPA; 300 mg/kg; 30 mg/ml) w h i l e , a n a e s t h e t i z e d w i t h e t h e r . The pCPA was p r e p a r e d i m m e d i a t e l y b e f o r e use by a d d i n g 0.1 ml Tween 80 t o the pCPA i n s a l i n e then homogenizing the s o l u t i o n . Ten c o n t r o l s r e c e i v e d an e q u i v a l e n t volume of v e h i c l e . The i n j e c t i o n s were performed 3 4 days prior to the f i n a l exercise session. To increase c r a n i a l serotonin l e v e l s , 9 rats received a b i l a t e r a l intraventicular inj e c t i o n of serotonin creatinine monophosphate (50 ug in 5 ul) through two 30 gauge i n j e c t i o n needles placed in the cannulas. A Sage Instruments pump, f i t t e d with two 50 ul syringes, injected the 5 u l over a period of 3 min 45 sec. Passage of 5-HT solution into the v e n t r i c l e s was confirmed by the movement of a 1 ul bubble in the infusion l i n e . Serotonin creatinine monophosphate was dissolved in saline and adjusted to a pH of 6.5 just prior to use. Nine rats received a s i m i l a r l y administered vehicle solution. Serotonin Analysis After the f i n a l test session, designated animals were quickly s a c r i f i c e d by c e r v i c a l d i s l o c a t i o n . Their brains were excised within 20 sec, cooled in ice water for 40 sec, and divided into seven regions within 3 minutes. The 7 regions were: the cerebellum, medulla oblongata, hypothalamus, striatum, midbrain, hippocampus, and cortex according to the method of Glowinski and Iversen (1966). Each brain region was put into a p l a s t i c bag and frozen in dry ice and acetone, then stored at -20°C for a maximum of 2 weeks. Each region was spectrofluorometrically analyzed (Farand 810) for 5-HT content using a modification of the method of Curzon and Green (1970) as recommended by Dr. A. Pearson (personal communication). Apparatus Locomotor a c t i v i t y was measured in a 60 x 60 x 60 cm grey box with 3 cm of San-i-cel on the f l o o r . The floor was divided into 9 equal squares by marking the San-i-cel with ink. The 5 a c t i v i t y was" r e c o r d e d by an overhead camera and m o n i t o r e d on t e l e v i s i o n s c r e e n i n an a d j a c e n t room. The m o t o r i z e d t r e a d m i l l c o n s i s t e d of 3 r u n n i n g a l l e y s 32 x 10 x 10 cm, w i t h the f o r w a r d 14 cm p a i n t e d b l a c k . The e l e c t r i c g r i d , 12 x 10 cm, l o c a t e d a t the r e a r of each r u n n i n g a l l e y , was 2 cm below the r u n n i n g s u r f a c e . The c o n t r o l shock box was 35 x 13 x 35 cm, the f l o o r b e i n g an e l e c t r i c g r i d . S i m u l t a n e o u s e l e c t r i f i c a t i o n of the c o n t r o l shock box g r i d and t r e a d m i l l g r i d was a t t a i n e d by h a v i n g a low r e s i s t a n c e p h o t o e l e c t r i c r e l a y i n l i n e w i t h the t r e a d m i l l g r i d and p l u g g e d i n t o the e x t e r n a l c o n t r o l of the shock g e n e r a t o r g o i n g t o the c o n t r o l shock box. P r o c e d u r e There were 6 groups of a n i m a l s : the pCPA-^ i n j e c t e d group (N=10), the c o n t r o l group f o r the p C P A - i n j e c t e d r a t s (N=10), the s e r o t o n i n - i n j e c t e d group (N=9), the c o n t r o l s f o r the s e r o t o n i n group (N=8), the yoked, shocked, c o n t r o l group (N=6), and the s e d e n t a r y group (N=3). The f o u r r u n n i n g groups ( p C P A - i n j e c t e d , 5 - H T - i n j e c t e d , and t h e i r r e s p e c t i v e v e h i c l e - i n j e c t e d c o n t r o l s ) r e c e i v e d the same t r a i n i n g regime and f a t i g u e runs ( T a b l e 1 ) . T h i s e n t a i l e d 3 days of t r a i n i n g f o l l o w e d by a p r e t e s t f a t i g u i n g run a t 40 m/min. Four days l a t e r , day 8,- the r a t s performed t h e i r second f a t i g u i n g run ( p o s t t e s t ) . A r a t was c o n s i d e r e d f a t i g u e d i f i t d i s p l a y e d a non-running response e x c e e d i n g 8 seconds. The time t o e x h a u s t i o n was r e c o r d e d . Each yoked, shocked, c o n t r o l r a t was p a i r e d w i t h a r a t from the p C P A - i n j e c t e d c o n t r o l group. Each time a p C P A - i n j e c t e d c o n t r o l r a t was r u n , the p a i r e d r a t i n TABLE 2 RUNNING TIMES TO EXHAUSTION Group F a t i g u e 1 F a t i g u e 2 pCPA 810±109 953189 c o n t r o l 8321132 8711179 5-HT 6201112 4081127 c o n t r o l 6031134 6041128 R e s u l t s a r e g i v e n as mean 1 S.E.M. i n seconds. 7 the yoked, shocked, c o n t r o l group was put i n the c o n t r o l s h o i c k box. On day 5, one day a f t e r the f i r s t f a t i g u e run (F1) the p C P A - i n j e c t e d group and i t s c o n t r o l group r e c e i v e d t h e i r i n j e c t i o n . T w e n t y - f i v e minutes p r i o r t o the second f a t i g u e run (F2) 5 - H T - i n j e c t e d group and i t s c o n t r o l group r e c e i v e d t h e i r i n j e c t i o n . The locomotor a c t i v i t y was r e c o r d e d i n 3 f i v e minute p e r i o d s 20 minutes p r i o r t o F2. To d e t e r m i n e i f c r a n i a l l e v e l s of s e r o t o n i n change d u r i n g e x h a u s t i v e e x e r c i s e , r a t s from the shocked c o n t r o l group and s e l e c t e d r a t s from the c o n t r o l s f o r the p C P A - i n j e c t e d group were i m m e d i a t e l y s a c r i f i c e d a f t e r e x h a u s t i o n . T h e i r b r a i n s were r a p i d l y removed and l a t e r a n a l y z e d f o r s e r o t o n i n . S e r o t o n i n a n a l y s i s was a l s o done on a group of s e d e n t a r y r a t s as a comparison t o the e x e r c i s e d and shock s t r e s s e d r a t s . T h i s d a t a was used f o r comparison t o p r e v i o u s l i t e r a t u r e on the s u b j e c t . H i s t o l o g y A few days a f t e r F2 the r a t s from the 5 - H T - i n j e c t e d group and i t s c o n t r o l group were a n a e s t h e t i z e d w i t h sodium p e n t o b a r b i t o l . The r a t s were then i n j e c t e d w i t h 10 u l of I n d i a i n k over a 7 1/2 min p e r i o d . S h o r t l y a f t e r t h i s t h e i r b r a i n s were removed and f i x e d i n f o r m a l i n s o l u t i o n . A f t e r f i x i n g , the b r a i n s were f r o z e n t o -18°C i n a c r y o s t a t . A n t e r i o r and p o s t e r i o r t o the c a n n u l a e placement, c o r o n a l s e c t i o n s 90 urn t h i c k were t a k e n t o v e r i f y ink d i s t r i b u t i o n throughout the v e n t r i c l e s . At the l e v e l of the 8 p l a c e m e n t 30 urn s e c t i o n s were t a k e n t o f u r t h e r v e r i f y t h e p l a c e m e n t o f t h e c a n n u l a t i p s . 9 RESULTS R u n n i n g T ime F o r a n i m a l s i n j e c t e d w i t h pCPA, t h e r u n n i n g t o e x h a u s t i o n t e n d e d t o be l o n g e r t h a n t h o s e i n j e c t e d w i t h s a l i n e ( s e e T a b l e 2 ) . To compare any c h a n g e t h a t o c c u r e d f r o m F1 t o F 2 , t h e t i m e t o e x h a u s t i o n f o r F2 was e x p r e s s e d as a p e r c e n t a g e o f t h e t i m e t o e x h a u s t i o n f o r F1 ( i . e . , F 2 / F 1 X 1 0 0 ) . The p C P A - i n j e c t e d g r o u p showed an a v e r a g e i n c r e a s e i n r u n n i n g t i m e o f 31% w h e r e a s i t s c o n t r o l g r o u p o n l y i n c r e a s e d 1% ( s e e f i g . 1 ) . A o n e - t a i l e d S t u d e n t ' s t t e s t f o r i n d e p e n d e n t g r o u p s i n d i c a t e s t h e d i f f e r e n c e b e t w e e n t h e i n j e c t e d and c o n t r o l g r o u p b a r e l y m i s s e d s i g n i f i c a n c e ( p < . 0 6 ) . The r u n n i n g p e r f o r m a n c e o f t h e r a t s i n j e c t e d i n t r a v e n t r i c u l a r l y w i t h 5-HT d e c r e a s e d 44% w h e r e a s i t s c o n t r o l g r o u p i n c r e a s e d 7%; t h i s was s i g n i f i c a n t ( p < . 0 0 5 ) . S e r o t o n i n A n a l y s i s S e r o t o n i n c o n c e n t r a t i o n s i n e a c h a r e a o f t h e b r a i n e x a m i n e d a r e g i v e n i n T a b l e 3. The e x e r c i s e g r o u p showed no d i f f e r e n c e when c o m p a r e d t o i t s s h o c k e d c o n t r o l g r o u p e x c e p t i n t h e h y p o t h a l a m u s . F o r t h e e x e r c i s e g r o u p , t h e m e d u l l a o b l o n g a t a and h y p o t h a l a m u s showed i n c r e a s e s when c o m p a r e d t o s e d e n t a r y c o n t r o l s . F o r t h e s h o c k e d c o n t r o l g r o u p , t h e m e d u l l a o b l o n g a t a , h y p o t h a l a m u s a n d m i d b r a i n showed i n c r e a s e s when c o m p a r e d t o c o n t r o l s . Who le b r a i n 5-HT l e v e l s , o b t a i n e d by p o o l i n g t h e i n d i v i d u a l b r a i n a r e a s , were n o t s i g n i f i c a n t l y d i f f e r e n t be tween g r o u p s . l o TABLE 1 EXERCISE REGIME Day Bout 1 2 3 4 8 1 5+18 22 24 24 2 1 ^ 4 0 — 2 1 ( 1 ) ( 2 ) (2) (2) (2) . (2) 2 21 25 30 33 40 (2) (2) (1) (1) ( f a t i g u e ) 3 24 27 33 37 (2) (2) (1) (1) 4 25 29 35 40 (2) (2) (1 ) (1 ) 5 40 ( f a t i g u e ) T a b l e 1 g i v e s the r u n n i n g speed (m/min) f o r each bout of e x e r c i s e . The d u r a t i o n of each bout of e x e r c i s e i s g i v e n i n b r a c k e t s ( m i n ) . There was a 10 min r e s t between each bout of e x e r c i s e except f o r a 30 min r e s t between bout 4 and 5 of day 4. II FIG. 1. P e r c e n t change i n r u n n i n g time from F1 t o F2 (means±SEM). B l a c k column (pCPA g r o u p ) ; s t r i p e d column (5-HT g r o u p ) ; open column ( r e s p e c t i v e c o n t r o l q r o u p ) . *=p<.06; **=p<„005. TABLE 3 SEROTONIN CONCENTRATIONS IN THE RAT BRAIN AFTER EXERCISE, SHOCKED CONTROL, AND SEDENTARY CONTROL CONDITIONS Brain Area Behavioural Medulla Condition Cerebellum Oblongata Hypothalamus Midbrain Striatum Hippocampus Cortex Exerc 1 se .24+.02 .91+. 15a 1 .58+. 25bf 1 .12+. 21 .99+.25 .78+. 17 .45 + .06 (6) (7) (7) ( 7 ) (7) (7) (7) Shocked .27+.03 1.02+. 15d 1 .93+ . 25be 1.18+. . 14c .90+.18 .78+. 10 .47 + .05 Control (5) (6) (6) (6) (6) (6) (6) Sedentary .24+.02 .71+. 05ad 1 .40+. 10ef .95+. 05c .85+.03 .66+ . 02 .43 + .02 (3) (3) (3) (3) (3) (3) (3) Results are given as mean ug/g+S.D. The number of rats used is given in brackets. a,b,c=p<.05; d=p<.01; e.f=p<.001. 13 Locomotor A c t i v i t y The pCPA-injected group averaged 129 crossings over the 15 min period. Its respective control averaged 127. Analysis of variance of the locomotor a c t i v i t y divided into 5 min intervals indicated no difference between groups (p>.80), a s i g n i f i c a n t e f f e c t of time (p<.00l), and no s i g n i f i c a n t interaction of the groups by time (p>.60). The 5-HT-injected group averaged only 80 crossings in 15 min whereas i t s control averaged 157 crossings. Analysis of variance showed a s i g n i f i c a n t group effect (p<.00l), a s i g n i f i c a n t time effect (p<.00l), and a nonsignificant interaction (p>.20). Hi stology In 5 of the 10 placements in the 5-HT-injected group ink injections indicated that both cannula tip s were located in the ve n t r i c l e s . Four other animals in the 5-HT group had u n i l a t e r a l placements in the ventricles and in 1 animal both canula t i p s were located outside of the 3rd v e n t r i c l e . This l a s t animal was not included in the s t a t i s t i c a l analysis. The 4 animals with u n i l a l t e r a l placements were included in the s t a t i s t i c a l analysis because there was no signicicant differences in their running times (t=.64; p>.50) or their locomotor a c t i v i t y (F group=2.52, p>.13; F groupXtime=.27, p>.75) when compared to animals with b i l a t e r a l placements. The controls for the 5-HT-injected group had 6 b i l a t e r a l placements in the v e n t r i c l e s , 2 u n i l a t e r a l placements, and 1 animal that had neither 'cannula located in the v e n t r i c l e s . This animal was discarded from the s t a t i s t i c a l analysis. 14 DISCUSSION The t r e n d of the d a t a does su p p o r t the e x t e n s i o n of T r u l s o n and J a c o b s ' h y p o t h e s i s t h a t lower 5-HT l e v e l s promote an i n c r e a s e i n the d u r a t i o n of f a t i g u i n g e x e r c i s e . pCPA i n j e c t i o n s , which l o w e r e d 5-HT l e v e l s , i n c r e a s e d r u n n i n g time t o e x h a u s t i o n by 30% when compared t o c o n t r o l s . However, t h i s b a r e l y f a i l e d t o r e a c h s i g n i f i c a n c e (p<.06) hence a f i r m c o n c l u s i o n cannot be made. I n c r e a s i n g 5-HT l e v e l s i n the b r a i n caused the o p p o s i t e e f f e c t : a s i g n i f i c a n t d e c r e a s e i n r u n n i n g time of 50% when compared t o c o n t r o l a n i m a l s . Compared t o s e d e n t a r y c o n t r o l s the yoked, shocked c o n t r o l s i n c r e a s e d a b s o l u t e 5-HT l e v e l s i n the m e d u l l a o b l o n g a t a , hypothalamus, and m i d b r a i n . The e x e r c i s e d r a t s o n l y had i n c r e a s e s i n the m e d u l l a o b l o n g a t a and hypothalamus. C o n t r a s t i n g the s e r o t o n i n l e v e l s of e x e r c i s e d r a t s and shocked c o n t r o l s , o n l y the hypothalamus r e v e a l e d a s i g n i f i c a n t d i f f e r e n c e : the c o n c e n t r a t i o n was e l e v a t e d i n the shocked c o n t r o l a n i m a l s . There was no d i f f e r n e c e between any of the groups when whole b r a i n 5-HT l e v e l s were compared. The r e s u l t s of the s e r o t o n i n a n a l y s i s i s i n agreement w i t h the l i t e r a t u r e . T h i e r r y e t a_l (1968), found s m a l l but not always s i g n i f i c a n t i n c r e a s e s i n 5-HT l e v e l s i n the b r a i n stem-mesencephalon and i n the whole b r a i n . S e r o t o n i n l e v e l s may not be h i g h e r d u r i n g e x e r c i s e because c o n c u r r e n t w i t h the a c c e l e r a t i o n of 5-HT s y n t h e s i s t h e r e i s an a c c e l e r a t i o n of 5-HT c a t a b o l i s m . T h i s i s o b s e r v e d d u r i n g m i n i m a l muscular e x e r c i s e ( t r e a d w h e e l a c t i v i t y @3.7m/min) ( E l o and T i r r i , 1972) and d u r i n g f o o t shock ( B l i s s e t a l , 1968). The i n c r e a s e d c a t a b o l i c 15 a c t i v i t y may p r e v e n t a summation of 5-HT l e v e l s d u r i n g compound s t r e s s e s c r e a t i n g a c e i l i n g e f f e c t . The l a c k of summation i s i n agreement w i t h Heym, T r u l s o n , and Jacobs (1982). These a u t h o r s found an e x c i t a t i o n of s e r o t o n i n e r g i c neurones w i t h p h a s i c a u d i t o r y and v i s u a l s t i m u l i but d i d not observe any summation when the s t i m u l i were p r e s e n t e d s i m u l t a n e o u s l y . The e f f e c t s of changing 5-HT l e v e l s on locomotor a c t i v i t y were as e x p e c t e d . A l t h o u g h l o w e r i n g 5-HT l e v e l s does i n c r e a s e locomotor a c t i v i t y , the e f f e c t i s o n l y o b s e r v e d i n f a m i l a r e nvironments and not i n n o v e l s i t u a t i o n s (Mackenzie §_t_ a l , 1978). S i n c e the a n i m a l s were not p r e v i o u s l y exposed t o the t e s t i n g box, the s i m i l a r s c o r e s f o r the p C P A - i n j e c t e d group and i t s c o n t r o l group a r e not c o n t r a d i c t o r y . In accordance w i t h o t h e r s t u d i e s , the 5-HT i n j e c t e d group performed s i g n i f i c a n t l y fewer c r o s s i n g s than did* i t s c o n t r o l group (Green e t a_l, 1976a; Green e t a l , 1976b; Jacobs and Eubanks, 1974; W a r b r i t t o n , 1978). In c o n c l u s i o n , a l t e r a t i o n s of 5-HT can i n c r e a s e and d e c r e a s e the endurance time t o p h y s i c a l e x h a u s t i o n . The e f f e c t can be p r e d i c t e d from e x t e n d i n g T r u l s o n and Jacobs' motor a c t i v i t y spectrum t o i n c l u d e e x e r c i s e . A l i m i t a t i o n of the e v i d e n c e i s the f a i l u r e t o f i n d any o v e r a l l d i f f e r e n c e i n 5-HT l e v e l s when comparing e x e r c i s e d r a t s t o yoked, shocked c o n t r o l s . Thus a l t h o u g h m a n i p u l a t i o n of s e r o t o n i n l e v e l s produce the p r e d i c t e d change i n motor performance, i t c o u l d not be demonstrated t h a t i n v o l u n t a r y e x h a u s t i v e e x e r c i s e w i l l d i r e c t l y produce changes i n ' t h e a b s o l u t e l e v e l s of s e r o t o n i n . 16 REVIEW OF LITERATURE J _ I n t r o d u c t i o n A l t h o u g h most s t u d i e s r e l a t i n g f a t i g u e and e x e r c i s e i n v e s t i g a t e o n l y t he p e r i p h e r a l l o c u s , i . e . , w i t h i n the muscle, t h e r e i s o t h e r r e s e a r c h t o support an i n h i b i t o r y e f f e c t a t the c e n t r a l l e v e l , i . e . w i t h i n the c e n t r a l nervous system. F i g u r e 1 i s an e x t e n s i o n of the h y p o t h e s i s t h a t s e r o t o n i n (5-HT) i s a modulator of a c t i v i t y ( T r u l s o n and J a c o b s , 1979b); the r i g h t end has been extended t o i n c l u d e i n t e n s e locomotor a c t i v i t y . REM SHORT SLEEP WAVE QUIET TONIC (ATONIA) SLEEP DROWSY WAKING AROUSAL EXERCISE 0.1 0.9 1.9 2.3 2.8 4.0 ??? /////////////////////////////////////////////////////?? ????????? /////////////////////////////////////////////////////? ?????????? ////////////////////// ///////////////////? ?????????? //////////////// //////////////? ?????????? /////////// ////////? ?????????? /////// ////??????????? /// ??????????? F i g u r e 2. The motor a c t i v i t y spectrum i n c l u d i n g e x e r c i s e as a proposed e x t e n s i o n . The numbers r e p r e s e n t the f i r i n g f r e q u e n c y ( s p i k e s / s e c ) of s e r o t o n i n - c o n t a i n i n g neurones. See t e x t f o r f u r t h e r e x p l a n a t i o n . B e f o r e t h i s h y p o t h e s i s can be a c c e p t e d , the a n a t o m i c a l , b i o c h e m i c a l , p h a r m a c o l o g i c a l , p h y s i o l o g i c a l , and b e h a v i o u r a l l i t e r a t u r e r e l a t i n g 5-HT t o mod u l a t o r y f u n c t i o n s and locomotor a c t i v i t y must be re v i e w e d . 17 2 S e r o t o n i n as a M o d u l a t o r 2.1 I n t r o d u c t i o n I t i s g e n e r a l l y a c c e p t e d t h a t the m a j o r i t y of s e r o t o n i n ' s e f f e c t s a r e i n h i b i t o r y . Some a u t h o r s have expanded the r o l e of s e r o t o n i n , s u g g e s t i n g i t i s a modulator of b e h a v i o u r a l a r o u s a l (Harvey ejt a l , 1975; T r u l s o n and J a c o b s , 1979b). When b r a i n 5-HT l e v e l s a r e h i g h t h e r e i s a co n c o m i t a n t d e c r e a s e i n motor a c t i v i t y p r e v e n t i n g a h y p e r a c t i v e s t a t e . C o n v e r s e l y , when b e h a v i o u r a l a r o u s a l i s low, 5-HT d e c r e a s e s ; t h i s r e s u l t s i n removal of i n h i b i t i o n of motor a c t i v i t y thus p r e v e n t i n g h y p o a c t i v i t y . T h i s h y p o t h e s i s i m p l i e s t h a t 5-HT a c t s t o m a i n t a i n the organism's a c t i v i t y i n the mi d d l e range of a motor a c t i v i t y spectrum (see F i g . 1) thus a c t i n g as a s a f e g u a r d a g a i n s t d e t r e m e n t a l extremes of a c t i v i t y . For F i g u r e 1, the amount of shaded a r e a (/////) i s p r o p o r t i o n a l t o b e h a v i o u r a l change t h a t would be i n c u r r e d by a maximal a n t a g o n i z i n g change i n the s e r o t o n i n e r g i c system. An e x t e n s i o n t o the r i g h t , t o i n c l u d e e x e r c i s e , has been added t o the motor spectrum. 2.2 A n a t o m i c a l E v i d e n c e The now c l a s s i c a l s t u d i e s of D a h l s t r o m and Fuxe (1964; 1965) e l u c i d a t e d the anatomy of the s e r o t o n i n e r g i c pathways w i t h i n the c e n t r a l nervous system. The s o u r c e s of c r a n i a l s e r o t o n i n a r e d i s c r e t e n u c l e i w i t h i n the c a u d a l b r a i n s t e m . The a u t h o r s l a b e l l e d t h e s e n u c l e i , c a u d a l t o r o s t r a l , B1-B9. The major, though not o n l y , s o u r c e s of the a s c e n d i n g s e r o t o n i n e r g i c system a r e the B7 ( d o r s a l r a p h e ) , B8 (median r a p h e ) , and B9 n u c l e i ( L o r e n s , 1978; U n g e r s t e d t , 1971). The de s c e n d i n g system o r i g i n a t e s m a i n l y from B1 (raphe o b s c u r u s ) , B2 (raphe p a l l i d u s ) , 18 and B3 (raphe magnus) (Dalhstrom and Fuxe, 1965; Loewy and M c k e l l a r , 1981; S a t o h , 1979; Tohyama e t a l , 1979; U n g e r s t e d t , 1971). The a s c e n d i n g s e r o t o n i n e r g i c system i s as much d i f f u s e as i t i s t o p o g r a p h i c a l . I t i s a w i d e l y d i s t r i b u t e d , h i g h l y c o l l a t e r i z e d , u n m y e l i n a t e d system (Moore et a l , 1978). T h i s i s e x e m p l i f i e d by immunohistochemical e v i d e n c e i n d i c a t i n g the a s c e n d i n g s e r o t o n i n e r g i c system may c o n t a c t every c e l l i n the c o r t e x ( L i d o v e t a l , 1980). I t i s v e r y l i k e l y t h a t i n d i v i d u a l s e r o t o n i n e r g i c neurones themselves account f o r the l a r g e a r r a y s of t e r m i n a l s and l i m i t e d topography noted under a u t o r a d i o g r a p h y (Moore e t a l , 1978). 2.3 P h y s i o l o g i c a l E v i d e n c e A l t h o u g h F i g u r e 1 i l l u s t r a t e s o n l y the motor a c t i v i t y s pectrum, o t h e r a c t i v i t y s p e c t r a i n c l u d i n g b i o c h e m i c a l and p h y s i o l o g i c a l phenomena may a l s o be modulated by s e r o t o n i n . Most spontaneous f a s t - f i r i n g somatosensory neurones of the c a t a r e i n h i b i t e d by e l e c t r o p h o r e t i c a l l y a p p l i e d 5-HT. C o n v e r s e l y , most s l o w - f i r i n g neurones a r e e x c i t e d by 5-HT. A v e r y h i g h c o r r e l a t i o n of r=.98 was d e t e r m i n e d between the p e r c e n t a g e of c e l l s d e p r e s s e d by, 5-HT and t h e i r spontaneous f i r i n g r a t e s ( S z a b a d i e t a l , 1977). The a c t i o n p o t e n t i a l s of c a t l a t e r a l g e n i c u l a t e neurones w i t h l a r g e a m p l i t u d e s a r e d e c r e a s e d by 5-HT a d m i n s t r a t i o n , w h i l e s i m u l t a n e o u s l y , the a c t i o n p o t e n t i a l s i n i n d i v i d u a l neurones w i t h low a m p l i t u d e s a r e i n c r e a s e d by 5-HT a d m i n i s t r a t i o n d i r e c t l y i n t o the n u c l e u s ( R i n a l d i e t a l , 1975). W i t h i n the s y s t e m i c system, the v a s c u l a r response of the dog's g r a c i l i s muscle t o 5-HT i s found t o be 19 dependent upon the i n i t i a l l e v e l of v a s c u l a r r e s i s t a n c e (Emerson et a l , 1973). The r e s i s t a n c e of v e s s e l s w i t h a low b a s e l i n e r e s i s t a n c e i s i n c r e a s e d w h i l e the c o n v e r s e i s t r u e f o r v e s s e l s w i t h a h i g h v a s c u l a r r e s i s t a n c e . S e r o t o n i n a d m i n i s t r a t i o n ( i n t o the s o l i t a r y t r a c t n u c l e u s or i . p . ) c auses a t r a n q u i l i z i n g e f f e c t upon c o r t i c a l a c t i v i t y (Key and Mehta, 1977; Monnier and T r i s s o t , 1958). The d o r s a l raphe n u c l e u s (B7) and the median raphe n u c l e u s (B8) may be i n v o l v e d i n t h i s o b s e r v a t i o n . The u n i t a c t i v i t y of the d o r s a l raphe n u c l e u s i s i n v e r s e l y r e l a t e d t o EEG s y n c h r o n i z a t i o n ( T r u l s o n and J a c o b s , 1979a). E l e c t r o l y t i c l e s i o n i n g of the median raphe causes a p e r s i s t e n t a r o u s a l i n EEG p a t t e r n ( K o s t o w s k i et a_l, 1968; 1969). I o n t o p h o r e t i c a d m i n i s t r a t i o n of 5-HT i n t o the deep neurones of the sensomotor c o r t e x or e l e c t r o l y t i c s t i m u l a t i o n of the median raphe i n h i b i t s the c o r t i c a l neurones ( S a s t r y and P h i l l i s , 1977b). These e f f e c t s a r e d i m i n i s h e d by m e t e r g o l i n e (a s e l e c t i v e 5-HT a n t a g o n i s t ( S a s t r y and P h i l l i s , 1977a)) and p r o l o n g e d by f l u o x e t i n e (a s e l e c t i v e 5-HT uptake b l o c k e r (Wong et a_l, 1975)) ( S a s t r y and P h i l l i s , 1977b). Reader (1980), has shown t h a t the i n h i b i t i o n r e s u l t i n g from 5-HT i n j e c t i o n (10" 1 2M) i n t o the c o r t e x l a s t s over a time span of seconds t h r o u g h t o m i n u t e s . T h i s l o n g d u r a t i o n suggest t h a t i n a d d i t i o n t o i o n i c changes, m e t a b o l i c and b i o c h e m i c a l changes are a l s o o c c u r r i n g . F i g u r e 1 i l l u s t r a t e s the p o s i t i v e c o r r e l a t i o n between s e r o t o n i n neurone f i r i n g r a t e and motor a c t i v i t y . I t i s p o s s i b l e t o d i s s o c i a t e a t o n i a and REM s l e e p by l e s i o n i n g by the p o n t i n e tegmentum a t the l e v e l of the l o c u s c o e r u l e u s . When 20 t h i s d i s s o c i a t i o n i s c r e a t e d , raphe u n i i t a c t i v i t y s t i l l remains c o r r e l a t e d t o motor output ( T r u l s o n and J a c o b s , 1981). 2.4 B e h a v i o u r a l E v i d e n c e I n j e c t i o n s ( i . p . or i n t r a v e n t r i c u l a r l y ) of low doses of s e r o t o n i n or i t s p r e c u r s o r s , t r y p t o p h a n and 5- h y d r o x y t r y p t o p h a n (5-HTP), produce a s e d a t i o n e f f e c t and apparent muscular weakness i n r a t s (Green et. a_l, 1976a; Green e t a_l, 1976b; Jacobs and Eubanks, 1974; W a r b r i t t o n , 1978), i n c a t s ( F e l d b e r g and Sherwood, 1954; Monnier and T i s s o t , 1958; P a t k i n a and L a p i n , 1976), and i n monkeys ( R a l e i g h e t a_l, 1980). D e c r e a s i n g s e r o t o n i n e r g i c l e v e l s w i t h i n j e c t i o n s of p a r a -c h l o r o p h e n y l a l a n i n e (pCPA), a s p e c i f i c i n h i b i t o r of s e r o t o n i n s y n t h e s i s (Koe and Weissman, 1966), produces the r e v e r s e e f f e c t , i . e . , insomnia and i n c r e a s e d locomotor a c t i v i t y i n mice ( C h r u s c i e l and Herman, 1969; H u t c h i n s and Rogers, 1973), i n r a t s ( F i b i g e r and Campb e l l , 1971; Jacobs et aJ., 1975; Kayser and H i l d w e i n , 1977; Mackenzie e t a l , 1978), and i n monkeys ( R a l e i g h e t §_1, 1980). P a r a - c h l o r o p h e n y l a l a n i n e b l o c k s the c o n v e r s i o n of t r y p t o p h a n t o 5-HTP but does not e f f e c t the c o n v e r s i o n of 5-HTP t o 5-HT (Koe and Weissman, 1966). One would t h e r e f o r e e xpect 5-HTP a d m i n i s t r a t i o n t o r e v e r s e the e f f e c t of pCPA whereas t r y p t o p h a n a d m i n i s t r a t i o n would have no • e f f e c t . P u j o l et. al (1971), d i d f i n d t h a t 5-HTP a n t a g o n i z e d the pCPA-induced i n c r e a s e i n locomotor a c t i v i t y and R a l e i g h e t a l (1980) found t h a t t r y p t o p h a n d i d not a f f e c t pCPA-induced b e h a v i o u r a l e f f e c t s . In r a t s , e l e c t r o l y t i c l e s i o n s ( C o s t a l l e t §_1, 1976; Geyer, 1978; Gulmulka et a l , 1970; .Jacobs et a l , 1974; 1975; Jacobs and Cohen, 1976; K o s t o w s k i e t a l , 1968; 1976; Mackenzie et a l , 1978; 21 S r e b r o and L o r e n s , 1975) or 5,7-dihydroxytryptamine(5,7-DHT; a s e r o t o n i n n e u r o t o x i n ) l e s i o n s (Deakin et a l , 1979; Mackenzie e t a l , 1978) of the median raphe n u c l e u s e l i c i t an i n c r e a s e i n spontaneous motor a c t i v i t y . Some a u t h o r s (Hole et. a_l, 1 976; Lorens e_t a l , 1976) have c o n c l u d e d t h a t c e n t r a l s e r o t o n i n e r g i c f i b r e s a r e not i n v o l v e d i n l e s i o n - i n d u c e d i n c r e a s e s i n spontaneous a c t i v i t y . A l t h o u g h e l e c t r o l y t i c l e s i o n s i n c r e a s e a c t i v i t y , more e f f e c t i v e and s p e c i f i c 5,7-DHT l e s i o n s do n o t . These a u t h o r s t e s t e d a c t i v i t y i n the open f i e l d and not i n the home cage. Mackenzie e t a_l (1978), u s i n g both environments when measuring locomotor a c t i v i t y found the 5,7-DHT l e s i o n s i n c r e a s e a c t i v i t y o n l y i n the home s e t t i n g . The a u t h o r s c o n c l u d e d t h a t the home cage and n o v e l environment s e t t i n g s are not measuring the same type of l o c o m o t i o n . T h i s f i n d i n g i s not s u r p r i s i n g s i n c e the b e h a v i o u r of r a t s i n an u n f a m i l i a r environment i s the r e s u l t of a complex i n t e r a c t i o n between f e a r and c u r i o s i t y ( B l a n c h a r d e_t a l , 1974). Semenova et. a_l (1981), took a d i f f e r e n t approach t o i n v e s t i g a t i n g 5-HT and locomotor a c t i v i t y . I n s t e a d of a l t e r i n g 5-HT l e v e l s and r e c o r d i n g subsequent motor a c t i v i t y , t h e s e a u t h o r s grouped r a t s a c c o r d i n g t o t h e i r a c t i v i t y l e v e l and measured c r a n i a l 5-HT i n each group. T h e i r r e s u l t s i n d i c a t e the l a r g e r the r a t i o of c o r t i c a l t o c a u d a l b r a i n s t e m 5-HT c o n c e n t r a t i o n the more p a s s i v e a r a t would be. There a r e o n l y a few s t u d i e s t h a t have a l t e r e d 5-HT l e v e l s i n human s u b j e c t s and have r e c o r d e d some a s p e c t of muscular performance. The s u b j e c t s used i n the s e s t u d i e s a r e u s u a l l y p r i s o n e r s ' or peopl e w i t h n e u r o l o g i c a l d i s o r d e r s . Myoclonus i s a 22 movement d i s o r d e r c h a r a c t e r i z e d by i n v o l u n t a r y , i r r e g u l a r c o n t r a c t i o n of muscl e s . When 5 - h y d r o x y i n d o l a c e t i c a c i d (5-HIAA; s e r o t o n i n ' s major m e t a b o l i t e ) i s measured the c e r e b r a l s p i n a l f l u i d of p e o p l e w i t h myoclonus, the l e v e l s a r e found t o be reduced. Treatment of t h i s d i s o r d e r w i t h 5-HTP p l u s a d e c a r b o x y l a s e i n h i b i t o r d r a m a t i c a l l y d e c r e a s e s the frequ e n c y and i n t e n s i t y of m y o c l o n i c c o n t r a c t i o n s (Van Woert and Sethy, 1975). W i t h r e f e r e n c e t o human motor a c t i v i t y , one study i n d i c a t e d t h a t 22 out of 25 c h i l d r e n t h a t were h y p e r a c t i v e had low l e v e l s of b l o o d 5-HT (Coleman, 1971). As n o t e d above t h e r e a r e many s t u d i e s r e l a t i n g changes i n c r a n i a l s e r o t o n i n l e v e l s t o locomotor a c t i v i t y . These s t u d i e s have g e n e r a l l y found t h a t low c r a n i a l s e r o t o n i n e r g i c l e v e l s i n c r e a s e locomotor a c t i v i t y w h i l e h i g h s e r o t o n i n e r g i c l e v e l s i n h i b i t l ocomotor a c t i v i t y . However, ve r y few s t u d i e s have i n v e s t i g a t e d the r o l e of s e r o t o n i n under a c t i v i t y c o n d i t i o n s more i n t e n s e than g e n e r a l w a l k i n g b e h a v i o u r . The f i r s t s t udy of the r e l a t i o n between 5-HT l e v e l and e x e r c i s e r e p o r t e d v e r y s i g n i f i c a n t i n c r e a s e s (P<.001) i n c r a n i a l 5-HT, i n the r a t , i m m e d i a t e l y f o l l o w i n g 15-30 min of swimming (Barchas and Freedman, 1963). S i g n i f i c a n t i n c r e a s e s (p<.05) i n 5-HT a f t e r l o n g e r d u r a t i o n s of swimming or r u n n i n g wheel a c t i v i t y were a l s o r e c o r d e d . The most s i g n i f i c a n t work i n r e l a t i n g 5-HT t o the s t r e s s of p h y s i c a l e x e r c i s e has been performed by Romanowski and co-w o r k e r s . Romanowski and co-workers b u i l t t h e i r s t u d i e s upon the f i n d i n g of a s u b s t a n c e , e x t r a c t e d from the b r a i n s of r e s t i n g r a t s , which i n h i b i t s a c e t y l c h o l i n e a c t i o n s (Pataky and P f e i f e r , 23 1955; P f e i f e r and P a t a k y , 1955). S i m i l a r b r a i n e x t r a c t s from e x e r c i s e d r a t s i n h i b i t a c e t y l c h o l i n e - s t i m u l a t e d f r o g r e c t u s t r u n c i muscle and, when i n j e c t e d i n t r a p e r i t o n e a l l y , make r a t s drowsy and immobile (Romanowski and Janota-Lukaszewska, 1967). I t was s u b s e q u e n t l y found t h a t the b r a i n 5-HT c o n c e n t r a t i o n i n c r e a s e s i n the e x e r c i s e d r a t , and t h a t 5-HT mimics the e f f e c t of the e x t r a c t on f r o g r e c t u s t r u n c i muscle a t c o n c e n t r a t i o n s comparable t o those found i n the b r a i n (Romanowski, 1967; Romanowski and G r a b i e c , -1974). R u l e d out as b i o c h e m i c a l bases f o r the e f f e c t s of the i n h i b i t o r y e x t r a c t a r e l a c t a t e , sodium, c a l c i u m , p o t a s s i u m , a s p a r t i c a c i d , e t h a n o l a m i n e , s e r i n e , g l y c i n e , a l a n i n e , l y s i n e , t h r e o n i n e , l e u c i n e , i s o l e u c i n e , v a l i n e , a c e t y l c h o l i n e , l i p i d s , a n u e r i n , AMP, ADP, ATP, h i s t a m i n e , a d r e n a l i n e , s u b s t a n c e P, and c h o l i n e ( P f e i f e r and P a t a k y , 1955; Romanowski, 1967; Romanowski and J a n o t a -Lukaszewska, 1967). E x p l o r i n g p o s s i b l e mechanisms of s e r o t o n i n ' s i n h i b i t o r y a c t i o n , Romanowski and G r a b i e c (1979) found t h a t 5-HT and the e x t r a c t i n h i b i t an in v i t r o o x i d a t i v e r e a c t i o n and t h a t 5-HT h y p e r p o l a r i z e s b r a i n c e l l s u r f a c e p o t e n t i a l s . R e l a t i v e t o r e s t , spontaneous a c t i v i t y i n c r e a s e s the c r a n i a l l e v e l of dopamine's major m e t a b o l i t e , h o m o v a n i l l i c a c i d (HVA), i n mice. There i s no change i n the c r a n i a l l e v e l s of s e r o t o n i n ' s major m e t a b o l i t e , 5 - h y d r o x y i n d o l a c e t i c a c i d (HIAA). Under the more p h a s i c c o n d i t i o n of swimming (1 h r ) t h e r e i s an i n c r e a s e i n both HVA and HIAA l e v e l s , i n d i c a t i n g an i n c r e a s e i n the t u r n o v e r of dopamine and 5-HT r e s p e c t i v e l y ( B l i s s , 1973). 24 3 S e r o t o n i n I n t e r a c t i o n s W i t h Other N e u r o t r a n s m i t t e r s  3.1 I n t r o d u c t i o n The r o l e of 5-HT i n b e h a v i o u r a l a r o u s a l has a l s o been approached by i n t e g r a t i n g the s e r o t o n i n e r g i c system w i t h the c a t e c h o l a m i n e r g i c system. In 1954, Hess p o s t u l a t e d two competing systems: (1) an e r g o t r o p i c system "which i s c o u p l e d w i t h energy e x p e n d i t u r e " and (2) a t r o p h o t r o p i c system which i s f o r " p r o t e c t i o n and r e s t i t u t i o n " (Hess, 1954; p60). L a t e r n o r a d r e n a l i n e (NA) was p o s t u l a t e d t o be the c h e m i c a l m e d i a t i n g the e r g o t r o p i c r esponses and 5-HT t o be the c h e m i c a l m e d i a t i n g t r o p h o t r o p i c responses ( B r o d i e and Shore, 1957). Numerous e x p e r i m e n t s have i n v e s t i g a t e d the e r g o t r o p i c and t r o p h o t r o p i c systems i n d i v i d u a l l y and these s u p p o r t e d B r o d i e and Shore's h y p o t h e s i s . Review a r t i c l e s c o n c l u d e t h a t any e x p e r i m e n t a l t o o l t h a t i n c r e a s e s the c r a n i a l a c t i v i t y of n o r a d r e n a l i n e or dopamine (DA) or both t y p i c a l l y enhances b e h a v i o u r a l a r o u s a l , of which locomotor a c t i v i t y was one i n d e x . C o n v e r s e l y , any method t h a t d i m i n i s h e s the f u n c t i o n of t h e s e c a t e c h o l a m i n e s produces a d e c r e a s e i n l o comotor a c t i v i t y ( S c h i l d k r a u t and K e t y , 1967; Weiss and L a t i e s , 1969). E v i d e n c e f o r s e r o t o n i n ' s r o l e i n the t r o p h o t r o p i c system has a l r e a d y been d i s c u s s e d (see s e c t i o n 2 i n c l u s i v e ) . A s e r o t o n i n e r g i c system t h a t i n h i b i t s c a t e c h o l a m i n e a r o u s a l (dopamine and n o r a d r e n a l i n e were not i n v e s t i g a t e d i n d i v i d u a l l y ) i s i n f e r r e d from the o b s e r v a t i o n s t h a t (1) 5-HT d e p l e t i o n v i a pCPA i n c r e a s e s b e h a v i o u r a l a r o u s a l , (2) pCPA p o t e n t i a t e s a r o u s a l i n d u c e d by amphetamines ( c a t e c h o l a m i n e s t i m u l a n t s ) , (3) 5-HTP r e v e r s e s the i n c r e a s e i n b e h a v i o u r a l a r o u s a l i n d u c e d by pCPA, 25 (4) 5-HTP e l i m i n a t e s the p o t e n t i a t i o n of amphetamine-induced a r o u s a l by pCPA, and (5) pCPA t r e a t m e n t augments b e h a v i o u r a l a r o u s a l i n d uced by r e s e r p i n e (a p o t e n t d e p l e t o r of b i o g e n i c amines) (Mabry and Campbell, 1973). I n c r e a s i n g 5-HT l e v e l s by 5-HT i n f u s i o n t o the l a t e r a l v e n t r i c l e ( W a r b r i t t o n , 1978), a d m i n i s t e r i n g 1 - tryptophan ( i . p . ) ( H o l l i s t e r e t a_l, 1976), t r e a t m e n t w i t h p a r g y l i n e (an i n h i b i t o r of monoamine o x i d a t i o n ) ( H o l l i s t e r e t a_l, 1974) or d e c r e a s i n g 5-HT l e v e l s by l e s i o n i n g of the median and d o r s a l raphe n u c l e i (Carey, 1976; N e i l l et. a l , 1972), u s i n g a t r y p t o p h a n f r e e d i e t ( H o l l i s t e r e_t a l , 1976), and a d m i n i s t r a t i o n of pCPA ( H o l l i s t e r e t a l , 1974; H o l l i s t e r e_t a l , 1976) support Mabry and Campbell's f i n d i n g s t h a t t h e r e i s a s e r o t o n i n e r g i c system t h a t i n h i b i t s amphetamine-induced a r o u s a l . S i m i l a r e f f e c t s a r e a l s o o b t a i n e d u s i n g 5 , 6 - d i h y d r o x y t r y p t a m i n e (75ug; i n t r a c i s t e r n a l ) (a p o t e n t and s p e c i f i c s e r o t o n i n e r g i c n e u r o t o x i n w i t h the e f f e c t d e l i m i t e d t o the CNS when a d m i n i s t e r e d i n t h i s manner (Baumgarten e_t a_l, 1971)) which f u r t h e r i n d i c a t e s t h a t the l o c u s of s e r o t o n i n e r g i c i n h i b i t i o n of amphetamine-induced a r o u s a l i s p r o b a b l y c e n t r a l (Breese et a l , 1974) . A c o m b i n a t i o n of harmine and apomorphine induces an extreme c a t e c h o l a m i n e r g i c a r o u s a l . T h i s a r o u s a l , t y p i f i e d by v i o l e n t jumping, can be p o t e n t i a t e d by pCPA or m e t h y s e r g i d e (a s e r o t o n i n b l o c k e r ) and reduced by 5-HT t r e a t m e n t ( T a k a s h i and Kuga, 1981). C l i n i c a l s t u d i e s a l s o i n d i c a t e a s e r o t o n i n - c a t e c h o l a m i n e i n t e r a c t i o n . M i n i m a l b r a i n d y s f u n c t i o n i s symptomized i n p a r t by h y p e r k i n e t i c b e h a v i o u r , o u t b u r s t s of a g g r e s s i v e a c t s , and f a i l u r e t o respond t o reprimand or punishment. A r e v i e w by 26 Brase and Loh (1975), r e l a t i n g 5-HT and c a t e c h o l a m i n e s t o m i n i m a l b r a i n d y s f u n c t i o n ( e s p e c i a l l y the symptom of h y p e r a c t i v i t y ) c o n c l u d e s t h e r e i s an i n h i b i t o r y s e r o t o n i n e r g i c system c o n t r o l l i n g c a t e c h o l a m i n e r g i c a r o u s a l . W i t h r e g a r d s t o o t h e r symptoms of m i n i m a l b r a i n d y s f u n c t i o n s e r o t o n i n i s thought t o (1) subserve a punishment f u n c t i o n by i n h i b i t i n g normal c a t e c h o l a m i n e g o a l - d i r e c t e d reward systems ( S t e i n and Wise, 1974; Wise e t a l , 1973) and (2) i n h i b i t a g g r e s s i v e b e h a v i o u r ( A l b e r t and Walsh, 1982). In mice t r e a t e d w i t h pCPA, a g g r e s s i v e b e h a v i o u r has been s i g n i f i c a n t l y c o r r e l a t e d w i t h g r o s s motor b e h a v i o u r (Matte and Tornow, 1978). 3.2 S e r o t o n i n I n t e r a c t i o n w i t h N o r a d r e n a l i n e 3.2.1 I n t r o d u c t i o n Gromova et a l , (1976; p149), p o i n t e d out t h a t t h e r e i s a "remarkable s i m i l a r i t y i n the d i s t r i b u t i o n of the t e r m i n a l s and axons which proceed from s e r o t o n i n e r g i c and n o r a d r e n e r g i c neurones and g i v e r i s e t o t r a c t s both a s c e n d i n g t o the f o r e b r a i n and d e s c e n d i n g t o the s p i n a l c o r d . . . . a l s o some common e n z y m e s . . . p a r t i c i p a t e i n the metabolism of s e r o t o n i n and n o r a d r e n a l i n . " From t h i s the a u t h o r s c o n c l u d e d t h e r e must be a f u n c t i o n a l i n t e r r e l a t i o n s h i p between these two monoamines. 3.2.2 A n a t o m i c a l E v i d e n c e A n a t o m i c a l s t u d i e s s u p p l y p h y s i c a l e v i d e n c e f o r the c o n n e c t i o n s between the l o c u s c o e r u l e u s (the main s o u r c e of n o r a d r e n e r g i c p e r i k a r y a ) and s e r o t o n i n e r g i c n u c l e i . The use of h o r s e r a d i s h p e r o x i d a s e , d e g e n e r a t i o n , and a u t o r a d i o g r a p h y i n d i c a t e the l o c u s c o e r u l e u s r e c e i v e s a f f e r e n t i n p u t from s e r o t o n i n e r g i c n u c l e i ( B o b i l l i e r e t a l , 1976; 1 979; Conrad e_t a l 27 , 1974; Morgane and J a c o b s , 1979; S a k a i e t a l , 1976). A l s o , 5-HT c o n t a i n i n g t e r m i n a l s (l0 7/mm 3) have been i n d e n t i f i e d i n the l o c u s c o e r u l e u s (Leger and D e c a r r i e s , 1978; P i c k e l e t a l , 1977). The r e v e r s e , c a t e c h o l a m i n e t e r m i n a l s c o n t a c t i n g s e r o t o n i n e r g i c neurones i n raphe n u c l e i , has been demonstrated v i a f l u o r e s c e n c e ( D a l h s t r o m and Fuxe, 1964; Fuxe, 1965). 3.2.3 B i o c h e m i c a l and P h y s i o l o g i c a l E v i d e n c e B i o c h e m i c a l a n a l y s i s has demonstrated h i g h l e v e l s of n o r a d r e n a l i n e i n the source n u c l e i of 5-HT as w e l l as h i g h l e v e l s of 5-HT i n the sour c e n u c l e i of n o r a d r e n a l i n e (Saaverda et a l , 1976). L e s i o n i n g of the d o r s a l raphe n u c l e u s d e c r e a s e s 5-HT l e v e l s i n the l o c u s c o e r u l e u s (McRae-Degueurce et a_l, 1982; P a l k o l v i t s e t a l , 1977). D e p l e t i o n of 5-HT by pCPA ( C r e s p i e t a l , 1980; McRae-Degueurce e t a l , 1982), by 5,6-DHT (McRae-Degueurce e t a l , 1982; P u j o l e t a l , 1979; Renaud e t a l , 1975), or by e l e c t r o l y t i c l e s i o n i n g of the d o r s a l raphe (DR) or median raphe (MR) n u c l e i (Lewis et a_l, 1976; McRae-Degueurce e t a l , 1982), i n c r e a s e s the a c t i v i t y of the NA s y n t h e s i s enzymes, t y r o s i n e h y d r o x y l a s e and dopamine-b-hydroxylase, i n the l o c u s c o e r u l e u s . The i n c r e a s e d e nzymatic a c t i v i t y i s g r e a t l y reduced i f 5-HTP i s s i m u l t a n e o u s l y a d m i n i s t e r e d w i t h pCPA, s u g g e s t i n g an antagonism of the c a t e c h o l a m i n e r g i c system by 5-HT ( C r e s p i e t . a l , 1980). The r e v e r s e has a l s o been i n d i c a t e d , i . e . , c a t e c h o l a m i n e r g i c antagonism of the s e r o t o n i n e r g i c system, by the o b s e r v a t i o n t h a t 5-HT s y n t h e s i s and u t i l i z a t i o n i n c r e a s e s i n the c o r t e x , b r a i n s t e m , mesencephalon, and c e r e b e l l u m a f t e r an i n t r a c i s t e r n a l i n j e c t i o n of the c a t e c h o l a m i n e n e u r o t o x i n 6-hydroxydopamine (6-28 OHDA) (Blondaux e t a l , 1973). A l s o , the i n f u s i o n of the c a t e c h o l a m i n e p r e c u r s o r 3 , 4 - d i h y d r o x y p h e n y l a l a n i n e (1-DOPA; 20mg i . p . ) causes an i n c r e a s e i n n o r a d r e n a l i n e l e v e l s and a d e c r e a s e i n 5-HT l e v e l s i n the c o r t e x and hypothalamus (Gromova e t a l , 1976). The r e c i p r o c a l i n t e r a c t i o n between 5-HT and NA i s f u r t h e r s u p p o r t e d by (1) n o t i n g an i n c r e a s e i n the NA m e t a b o l i t e 3 - m e t h o x y - 4 - h y d r o x y - p h e n y l g l y c o l s u l p h a t e a f t e r e l e c t r o l y t i c l e s i o n i n g of the m i d b r a i n raphe n u c l e i and (2) o b s e r v i n g an i n c r e a s e 5-HIAA a f t e r b i l a t e r a l l e s i o n i n g of the l o c u s c o e r u l e u s ( K o s t o w s k i e_t a l , 1974). I n j e c t i o n s ( i . p . ) of the p o w e r f u l dopamine-b-hydroxylase i n h i b i t o r , 1 - p h e n l y - 3 - ( 2 - t h i a z o l y l ) - 2 -t h i o u r e a , caused a 79-98% d e p l e t i o n of n o r a d r e n a l i n e l e v e l s i n the b r a i n , i n c l u d i n g the s e r o t o n i n e r g i c raphe n u c l e i . C o n c u r r e n t w i t h the n o r a d r e n a l i n e d e p l e t i o n t h e r e was an i n c r e a s e i n s e r o t o n i n l e v e l s i n the m e d i a l raphe n u c l e u s and the raphe magnus (Saaverda et. a l , 1976) and i n the whole b r a i n (Johnson e_t a_l, 1972). No change i n 5-HT l e v e l s were o b s e r v e d i n the d o r s a l raphe (Saaverda e t a_l, 1976). In r a t hippocampal s l i c e s , NA i n h i b i t s the d e p o l a r i z a t i o n - i n d u c e d 5-HT r e l e a s e . T h i s p r o c e s s i s thought t o oc c u r d i r e c t l y v i a o c - r e c e p t o r s (Frankhuyzen and M u l d e r , 1980). At the s p i n a l l e v e l , f l u o r e s c e n c e t e c h n i q u e s have i n d i c a t e d a c o n c e n t r a t i o n of 5-HT t e r m i n a l s i n the s y m p a t h e t i c l a t e r a l column ( C a r l s s o n e t a l , 1964). S t i m u l a t i n g the raphe p a l l i d u s or raphe o b s c u r u s and r e c o r d i n g the e f f e c t on s y m p a t h e t i c o u t f l o w a t the t h o r a c i c l e v e l i n d i c a t e s the f u n c t i o n of t h e s e s e r o t o n i n e r g i c t e r m i n a l s i s one of i n h i b i t i o n ( G i l b e y e t a l , 1981). Coote and Macleod (1974), found t h a t a l t h o u g h 5-HTP 29 ( i n t r a v e n o u s ) had no e f f e c t on spontaneous s y m p a t h e t i c r e n a l nerve a c t i v i t y , 5-HTP d i d de p r e s s r e f l e x a c t i v i t y of the ner v e . T h i s o b s e r v a t i o n i l l u s t r a t e s the p h a s i c n a t u r e of s e r o t o n i n m o d u l a t i o n i n many i n s t a n c e s . A change i n the s t a t e of the system t o be modulated had t o oc c u r b e f o r e an a n t a g o n i s t i c change i n the s e r o t o n i n e r g i c system c o u l d have a s i g n i f i c a n t e f f e c t . There a r e s t u d i e s t h a t i n d i c a t e the s e r o t o n i n - n o r a d r e n a l i n e i n t e r a c t i o n i s not r e c i p r o c a l . N o r a d r e n a l i n e t e r m i n a l s p r e s e n t i n the d o r s a l raphe mediate a t o n i c a l l y a c t i v e a d r e n e r g i c i n f l u e n c e upon which the f i r i n g of s e r o t o n i n e r g i c c e l l s depend. The impairment of n o r a d r e n e r g i c t r a n s m i s s i o n by r e s e r p i n e (Baraban e t a l , 1978) or low doses (30ug/kg) of c l o n i d i n e (Svensson e t a l , 1975) reduces s e r o t o n i n e r g i c c e l l f i r i n g and n o r a d r e n e r g i c c e l l f i r i n g . S e r o t o n i n e r g i c c e l l a c t i v i t y i s a l s o s u p p r e s s e d by the s y s t e m i c a d m i n i s t r a t i o n of drugs which b l o c k a d r e n e r g i c a c t i v i t y (Baraban and A g h a j a n i a n , 1980; G a l l a g e r and A g h a j a n i a n , 1976). Furthermore m i c r o i o n t o p h o r e t i c a l l y a p p l i e d a d r e n e r g i c a g o n i s t s can reduce the s u p p r e s s i o n caused by a l p h a a d r e n e r g i c a n t a g o n i s t s (Baraban e t a l , 1978; Baraban and A g h a j a n i a n , 1980; Svensson ejt a_l, 1975). T h i s d a t a , r e c o r d e d from a n a e s t h e t i z e d a n i m a l s , l e d A g h a j a n i a n and co-workers t o c o n c l u d e t h e r e i s a t o n i c n o r a d r e n e r g i c i n p u t ( i n the d o r s a l raphe) which d r i v e s 5-HT c e l l f i r i n g . However, Heym e t a_l (1980), have shown t h a t even w i t h n o r a d r e n e r g i c t r a n s m i s s i o n i m p a i r e d , the s e r o t o n i n e r g i c system s t i l l f u n c t i o n s i n a s t a t e dependent manner. 30 3.2.4 B e h a v i o u r a l E v i d e n c e As noted e a r l i e r i n s e c t i o n 2.4, i n c r e a s i n g 5-HT l e v e l s a t t e n u a t e motor a c t i v i t y and d e c r e a s i n g 5-HT l e v e l s promote motor a c t i v i t y . The r e v e r s e i s t r u e f o r n o r a d r e n l i n e . D e p l e t i o n of n o r a d r e n a l i n e l e v e l s w i t h d i s u l f i r a m ( G o l d s t e i n e t a l , 1964) or 6-OHDA ( L a v e r t y and T a y l o r , 1970) de c r e a s e motor a c t i v i t y . I n c r e a s i n g c r a n i a l n o r a d r e n a l i n e l e v e l s by i n j e c t i o n of the n e u r o t r a n s m i t t e r (50ug-3mg) i n t o the t h i r d v e n t r i c l e or c i s t e r n a magna produces w a k e f u l n e s s and e x c i t a t i o n (Cordeau e_t a l , 1971). I n t r a v e n t i c u l a r i n j e c t i o n s of 6-OHDA (200ug) d e c r e a s e NA l e v e l s by 70-80% i n the d o r s a l raphe, median raphe, and raphe magnus (Saaverda e t a_l, 1976). Six-hydroxydopamine a d m i n i s t e r e d i n t h i s manner a l s o d e c r e a s e s l o c o m o t o r a c t i v i t y , y e t 5,6-DHT i n j e c t i o n s ( i n t r a v e n t r i c u l a r l y ) do not cause the o p p o s i t e e f f e c t . I f the two n e u r o t o x i n s a r e a d m i n i s t e r e d s i m u l t a n e o u s l y t h e r e i s no change i n locomotor a c t i v i t y . These r e s u l t s l e d R i c h a r d s o n e t a l , (1974) t o c o n c l u d e the de c r e a s e d motor a c t i v i t y caused by 6-OHDA i s due t o an i n c r e a s e i n 5-HT l e v e l s and not the de c r e a s e i n NA l e v e l s . The above o b s e r v a t i o n s once more i n d i c a t e a p h a s i c n a t u r e of s e r o t o n i n . M i l l e r and M a i c k e l (1969), a l t e r e d 5THT and NA l e v e l s i n r a t s and obs e r v e d the e f f e c t s on a c o n t i n u o u s a v o i d a n c e response. The b e n z o q u i n o l i z i n e , Ro 4-1284 (a drug t h a t r e l e a s e s both 5-HT and NA, 5-HT b e i n g r e l e a s e d i n g r e a t e r q u a n t i t i e s ) , c auses b e h a v i o u r a l d e p r e s s i o n of the avoi d a n c e t a s k . pCPA had no e f f e c t on the t a s k . However, pCPA tre a t m e n t p r i o r t o Ro 4-1284 r e v e r s e d the e f f e c t s of Ro 4-1284 t r e a t m e n t . The a u t h o r s 31 c o n c l u d e d i t i s the b a l a n c e of f r e e 5-HT/NA t h a t i s the d e c i d i n g f a c t o r i n the b e h a v i o u r a l d e p r e s s i o n induced by b e n z o g u i n o l i z i n e s . I t s h o u l d a g a i n be noted t h a t a c t i v a t i o n of the n o r a d r e n e r g i c system was r e q u i r e d b e f o r e a l t e r a t i o n of the s e r o t o n i n e r g i c system c o u l d have an e f f e c t . 3.3 S e r o t o n i n I n t e r a c t i o n w i t h Dopamine 3.3.1 I n t r o d u c t i o n The r e l a t i o n s h i p t h a t Gromova et a l (1976) i n d i c a t e d between s e r o t o n i n and n o r a d r e n a l i n e (see 4.3.2.1) i s a l s o t r u e f o r s e r o t o n i n and dopamine i n the b r a i n . A s c e n d i n g t r a c t s of s e r o t o n i n e r g i c and dop a m i n e r g i c neurones t e r m i n a t e i n the n e o s t r i a t u m and l i m b i c f o r e b r a i n . Monoamine o x i d a s e i s r e s p o n s i b l e f o r the o x i d a t i o n of 5-HT and DA. H i g h c o n c e n t r a t i o n s of both monoamines a r e found i n the sour c e n u c l e i of 5-HT and DA. Hence one must a c c e p t the p o s s i b i l i t y of a f u n c t i o n a l i n t e r r e l a t i o n s h i p between s e r o t o n i n and dopamine. 3.3.2 A n a t o m i c a l E v i d e n c e There a r e two major a s c e n d i n g d o p aminergic pathways: the n i g r o - n e o s t r i a t a l pathway ( i n c l u d i n g the s u b s t a n t i a n i g r a and s u p e r i o r c o l l i c u l s ) and the me s o l i m b i c dopamine system ( i n c l u d i n g the m e d i a l accumbens and tu b e r c u l u m o l f a c t o r i u m ) (Anden e_t a l , 1 966; U n g e r s t e d t , 1971). E a r l y s t u d i e s of the anatomy of s e r o t o n i n e r g i c and dopaminergic systems i n d i c a t e common a r e a s of t e r m i n a t i o n i n c l u d i n g the n e o s t r i a t u m and l i m b i c f o r e b r a i n (Anden e_t a_l, 1966). L o c a l i z e d i n j e c t i o n s of h o r s e r a d i s h p e r o x i d a s e and 3 H - l e u c i n e p r o v i d e s t r o n g e v i d e n c e f o r a d o r s a l raphe n u c l e u s p r o j e c t i o n ( F i b i g e r and M i l l e r , 1977; Moore et a_l, 1 978) and a median raphe n u c l e u s p r o j e c t i o n 32 ( B o b i l l i e r et a l , 1979; Dray et a l , 1976; Moore e t a l , 1978) t o the s u b s t a n t i a n i g r a (SN; a major source of c r a n i a l dopamine). T h i s c o i n c i d e s w i t h the o b s e r v a t i o n of l a r g e number of s e r o t o n i n e r g i c f i b r e s f o r m i n g a x o - d e n d r i t i c synapses w i t h i n the SN ( P a r i z e k et. §_1, 1971). A l a r g e number of c a t e c h o l a m i n e t e r m i n a l s can a l s o be seen on the s u r f a c e of 5-HT p r o d u c i n g n e u r o n a l p e r i k a r y a ( D a l h s t r o m and Fuxe, 1964; Fuxe, 1965). 3.3.3 B i o c h e m i c a l and p h y s i o l o g i c a l e v i d e n c e B i o c h e m i c a l and p h y s i o l o g i c a l t e c h n i q u e s a r e used t o s u b s t a n t i a t e an i n t e r a c t i o n between the s o u r c e n u c l e i of DA and 5-HT. W i t h i n the SN t h e r e a r e s u b s t a n t i a l c o n c e n t r a t i o n s of 5-HT ( P a l k o v i t s e t a l , 1974; P a l k o v i t s e t a l , 1977) and h i g h t r y p t o p h a n h y d r o x y l a s e a c t i v i t y ( B r o w n s t e i n et a l , 1975). • In the s e r o t o n i n e r g i c raphe n u c l e i (B1-B9) dopamine c o n c e n t r a t i o n s a r e h i g h and l e v e l s of t y r o s i n e h y d r o x y l a s e a r e of the same o r d e r of magnitude as t r y p t o p h a n h y d r o x l a s e (Saaverda et a l , 1976). E l e c t r o l y t i c ' ( F i b i g e r and M i l l e r , 1977) or 5,7-DHT (Deakin et a l , 1979) l e s i o n i n g of the DR d e c r e a s e s n i g r a l and s t r i a t a l 5-HT c o n t e n t . S t i m u l a t i o n of the DR i n h i b i t s u n i t a c t i v i t y i n the SN; t h i s e f f e c t i s b l o c k e d by pCPA p r e t r e a t m e n t ( F i b i g e r and M i l l e r , 1977) and mimicked by 5-HT a p p l i c a t i o n i n t o the s t r i a t u m ( D a v i e s and Tongroach, 1978). However, pCPA t r e a t m e n t a l o n e does not a l t e r DA u t i l i z a t i o n i n the m e s o l i m b i c nor n i g r o - s t r i a t a l systems ( F i b i g e r and M i l l e r , 1977). These o b s e r v a t i o n s l e d the a u t h o r s t o c o n c l u d e the i n h i b i t o r y s e r o t o n i n e r g i c p r o j e c t i o n from the DR i n f l u e n c e s dopaminergic c e l l s i n the SN i n a p h a s i c but not a t o n i c manner. T h i s p h a s i c n a t u r e of s e r o t o n i n e r g i c i n f l u e n c e on dopamine 33 may e x p l a i n the n e g a t i v e f i d n i n g s of Gumulka e_t a l (1970) and Rommelspacher and S t r a u s s , (1980). These a u t h o r s found t h a t e l e c t r o l y t i c l e s i o n s i n the DR or MR do not a l t e r t he s t r i a t a l dopamine c o n t e n t . Serotonin-dopamine i n t e r a c t i o n has a l s o been obse r v e d under more t o n i c c o n d i t i o n s . S e r o t o n i n uptake i n h i b i t o r s p o t e n t i a t e and 5-HT r e c e p t o r b l o c k e r s a n t a g o n i z e the i n c r e a s e d dopamine met a b o l i s m induced by h a l o p e r i d o l (Waldmeier e t a l , 1979). U n i l a t e r a l i n j e c t i o n s of 5,7-DHT i n t o the SN cause an i p s i l a t e r a l i n c r e a s e i n s t r i a t a l DA t u r n o v e r (Giambalvo and Snodgrass, 1978). C h r o n i c t r e a t m e n t w i t h pCPA or m e t e r g o l i n e (Roberge, 1979) or e l e c t r o l y t i c l e s i o n i n g of the d o r s a l and median raphe n u c l e i (Herve e t a_l, 1 979; 1981) enhance dopamine u t i l i z a t i o n i n the n u c l e u s accumbens. E l e c t r i c a l s t i m u l a t i o n of the MR c a u s e s , m a i n l y , the d e p r e s s i o n of s i n g l e neurone a c t i v i t y i n t he SN (Dray e t a_l, 1976). M i c r o i o n t o p h o r e t i c a l l y a p p l i e d 5-HT t o the SN produces m a i n l y i n h i b i t i o n of n e u r o n a l a c t i v i t y (Dray e t §_1, 1 976). D i s c r e t e e l e c t r o l y t i c l e s i o n s of the MR de c r e a s e 5-HT i n the SN and i n c r e a s e ' s t r i a t a l dopamine l e v e l s (Dray e_t a_l, 1976).. 5,7-DHT i n j e c t i o n s i n t o the MR d e c r e a s e 5-HT uptake i n the SN (Giambalvo and Snodgrass, 1978). The d a t a c o l l e c t e d by t h e s e a u t h o r s s t r o n g l y suggest a d i r e c t i n h i b i t o r y pathway from the MR t o the SN t h a t i n f l u e n c e s n i g r o - s t r i a t a l d o p a m i n e r g i c a c t i v i t y . U n i l a t e r a l l e s i o n s of the DR d e c r e a s e 5-HT and 5-HIAA and i n c r e a s e dopamine metabolism i n the i p s i l a t e r a l SN ( N i c o l a o u e_t a_l, 1979). U n i l a t e r a l l e s i o n s of the MR produced s i m i l a r e f f e c t s i n . t h e c o r p us s t r i a t u m ( N i c o l a o u et a l , 1979). The a u t h o r s c o n c l u d e d t h a t the DR and MR send 34 p r o j e c t i o n s d i f f e r e n t i a l l y t o the SN and corpus s t r i a t u m , r e s p e c t i v e l y , which e x e r t t o n i c i n h i b i t i o n of DA metabolism. N i g r a l dopamine a d m i n i s t r a t i o n (10" 7M) d e c r e a s e s 5-HT i n the caudate putamen and SN and s i m i l a r a p p l i c a t i o n of a l p h a -m e t h y l p a r a t y r o s i n e (a dopamine d e p l e t o r ) has the o p p o s i t e e f f e c t (Hery e t a_l, 1980). In an i n v i t r o s t r i a t a l synaptosome p r e p a r a t i o n , 3uM 5-HT d e p r e s s e s dopamine s y n t h e s i s from t y r o s i n e (Andrews e t a l , 1978). Somewhat c o n t r a r y t o the above r e s u l t s , e v i d e n c e p r e s e n t e d by Lyness and Moore (1981) does not su p p o r t a 5-HT-DA i n t e r a c t i o n . These a u t h o r s r e c o r d e d an i n c r e a s e i n d-amphetamine- and apomorphine-induced locomotor a c t i v i t y a f t e r 5,7-DHT i n j e c t i o n s i n t o the l a t e r a l c e r e b r a l v e n t r i c l e or the n u c l e u s accumbens s e p t i but d i d not f i n d a c o n c u r r e n t change i n dopa m i n e r g i c neurone a c t i v i t y as i n d i c a t e d the DOPAC c o n c e n t r a t i o n or 1-DOPA a c c u m u l a t i o n . 3.3.4 B e h a v i o u r a l E v i d e n c e Motor a c t i v i t y i s reduced by e l e c t r o l y t i c l e s i o n s of the SN (Gumulka e_t a_l, 1 970) and by b i l a t e r a l 6-OHDA l e s i o n s i n dopamine's m e s o l i m b i c system (Koob and R o b i n s , 1979). S t i m u l a t i o n of c e n t r a l dopamine r e c e p t o r s by apomorphine ( i . p . ) i n d u c e s h y p e r a c t i v i t y i n r a t s (Grabowska and M i c h a l u k , 1974; Westermann e t a_l, 1976). S e r o t o n i n e r g i c d e p l e t i o n by pCPA ( i . p . ) or 5,6-DHT ( i n j e c t e d i n t o the MR) enhances the h y p e r a c t i v i t y . S e r o t o n i n e r g i c e l e v a t i o n w i t h harmine (a monoamine o x i d a s e i n h i b i t o r ) p r e t r e a t m e n t reduces the apomorphine-induced h y p e r m o t i 1 i t y and the e x t r a enhancement caused by pCPA or 5,6-DHT (Westermann et. a l , 1976). An 35 enhancement of apomorphine- and "d-amphetamine-induced l o c o m o t i o n i s a l s o o b s e r v e d a f t e r i n j e c t i o n s of 5,7-DHT i n t o the l a t e r a l v e n t r i c l e or b i l a t e r a l l y i n t o the n u c l e u s accumbens s e p t i (Lyness and Moore, 1981). The a u t h o r s a l s o c o n c l u d e d the enhanced a c t i v i t y was not due t o a change i n dopaminergic a c t i v i t y as de t e r m i n e d by 3 , 4 - d i h y d r o x y p h e n y l a c e t i c a c i d c o n c e n t r a t i o n s and 1-DOPA a c c u m u l a t i o n . A dose-dependent i n c r e a s e i n locomotor a c t i v i t y i s produced by i n j e c t i o n s of dopamine i n t o the n u c l e u s accumbens ( C a r t e r and Pycock, 1979; C o s t a l l e t a l , 1976; C o s t a l l e t a l , 1980; P i j n e n b u r g e t a_l, 1976). S e r o t o n i n i n j e c t i o n s , a t the same s i t e , reduce locomotor a c t i v i t y ( C a r t e r and Pycock, 1979; C o s t a l l et a l , 1976; Jones et_ a l 1981; P i j n e n b u r g e t a l , 1976). E l e c t r o l y t i c median raphe l e s i o n s enhance dopamine-induced h y p e r a c t i v i t y and markedly d e c r e a s e the t h r e s h o l d and maximal doses of dopamine ( C o s t a l l e_t a_l, 1976). S e r o t o n i n i n j e c t i o n s i n t o the n u c l e u s accumbens, of r a t s p r e t r e a t e d w i t h dopamine i n t o the same s i t e , causes an immediate r e d u c t i o n i n motor a c t i v i t y ( C o s t a l l et_ a l , 1976). S e r o t o n i n a l s o i n t e r a c t s w i t h dopamine s t i m u l a t e d a c t i v i t y i n the n i g r o - s t r i a t a l system. 6-OHDA l e s i o n s of the SN (the o r i g i n of DA p e r i k a r y a f o r the n i g r o - s t r i a t a l s y s t e m ) , a l t h o u g h not a f f e c t i n g apomorphine-induced h y p e r l o c o m o t i o n , does p r e v e n t f u r t h e r augmentation of the h y p e r a c t i v i t y induced by 5,6-DHT l e s i o n s (Westermann e t aJL, 1976). L e s i o n i n g of the s u p e r i o r c o l l i c u l u s ( p a r t of the n i g r o -s t r i a t a l system) and o b s e r v i n g the e f f e c t s upon amphetamine-induced locomotor a c t i v i t y , Pope et a l (1980) c o n c l u d e d the 36 nigro-striatal system is not necessary for the increased locomotor behaviour induced by amphetamine. However, a review by Cole (1978) concludes that both the mesolimbic and nigro-striatal dopamine systems are involved in amphetamine-induced locomotor activity and that inhibition of these systems inhibits the amphetamine-induced locomotion. 37 4 P o s s i b l e L o c i and Mechanisms by Which S e r o t o n i n May I n h i b i t  P h y s i c a l A c t i v i t y 4.1 I n t r o d u c t i o n The p o s s i b l e mechanisms d i s c u s s e d , by which s e r o t o n i n may i n h i b i t p h y s i c a l a c t i v i t y , a r e those i n the l i t e r a t u r e t h a t have a r e a s o n a b l e documented b a s i s . I t s h o u l d not be assumed t h a t any of the p o s s i b l e l o c i and mechanisms are m u t u a l l y e x c l u s i v e . 4.2 T h e r m o r e g u l a t i o n The i n t e g r i t y of the monoamine system i s v i t a l f o r c o r r e c t f u n c t i o n i n g of the hypothalamus i n temperature r e g u l a t i o n ( C r o n i n and Baker, 1977; Jacob and G i r a u l t , 1979; Woolf e_t a l , 1975). Many a s p e c t s of the r o l e of 5-HT i n t h e r m o r e g u l a t i o n remain t o be e l u c i d a t e d . C o n f l i c t i n g o b s e r v a t i o n s due t o s p e c i e s , drug dosage, and s i t e of i n j e c t i o n have been r e p o r t e d (see C l a r k and C l a r k (1980) and Jacob and G i r a u l t (1979) f o r an e x t e n s i v e r e v i e w ) . The c o n f l i c t i n g d a t a may, i n p a r t , be e l u c i d a t e d by the p r o p o s i t i o n t h a t 5-HT synapses i n the r o s t r a l and c a u d a l p o r t i o n s of the hypothalamus of c a t s mediate f u n c t i o n a l l y o p p o s i n g t h e r m o r e g u l a t o r y e f f e c t s (Komiskey and Rudy, 1977). T h i s may e x p l a i n the f i n d i n g t h a t DR l e s i o n s d e c r e a s e c a t e c h o l a m i n e a c t i v i t y i n the hypothalamus whereas MR l e s i o n s i n c r e a s e c a t e c h o l a m i n e a c t i v i t y i n the hypothalamus (Rommelspacher and S t r a u s s , 1980). C e r t a i n 5-HT pathways do a c t t o i n c r e a s e heat l o s s and de c r e a s e heat p r o d u c t i o n ( B l i g h e_t a l , 1971). I t i s known t h a t , i n the r a t , an i n c r e a s e i n ambient te m p e r a t u r e causes an i n c r e a s e i n 5-HT t u r n o v e r and i n t r a v e n t r i c u l a r i n j e c t i o n s of 5-HT cause a d e c r e a s e i n c o r e 38 temperature ( F e l d b e r g and L o t t i , 1967; Jacob and G i r a u l t , 1979; Weiss and A g h a j a n i a n , 1971). In a n e s t h e t i z e d c a t s , most neurones i n and around c a u d a l m i d b r a i n raphe n u c l e i i n c r e a s e d t h e r e f i r i n g f requency w i t h i n 30 sec when the temperature was i n c r e a s e d 5°C by water thermodes ( C r o n i n and Baker, 1977) D u r i n g h i g h i n t e n s i t y e x e r c i s e the f a s t t w i t c h f i b r e s of the a c t i v e muscle ' are p r e f e r e n t i a l l y r e c r u i t e d (Essen and K a y s e r , 1976; G i l l e s p i e e t a l , 1974; G o l l n i c k e t a l , 1974; K a r l s s o n and Komi, 1976). I f the e x e r c i s e i s not of h i g h i n t e n s i t y or e x h a u s t i v e , f a s t t w i t c h f i b r e s w i l l not be a c t i v a t e d . These f a s t t w i t c h , g l y c o l i t i c f i b r e s a r e r e s p o n s i b l e f o r the major p o r t i o n of muscle temperature i n c r e a s e ( B o l s t a d and E r s l a n d , 1978). Here 5-HT, p o t e n t i a l l y , can f u n c t i o n as d u a l s a f e t y mechanism f o r an a n i m a l p e r f o r m i n g h i g h i n t e n s i t y e x e r c i s e . F i r s t l y , 5-HT can i n h i b i t the motor a c t i v i t y thus r e d u c i n g the organism's heat p r o d u c t i o n . S e c o n d l y , 5-HT can s t i m u l a t e heat l o s s , r e d u c i n g the organism's c o r e t e m p e r a t u r e . 4.3 I n h i b i t i o n of C o r t i c a l Neurones L i d o v e t a_l (1980) i n v e s t i g a t e d the a s c e n d i n g s e r o t o n i n e r g i c pathways of the B7-B9 n u c l e i u s i n g a new and v e r y s e n s i t i v e i m m u n o h i s t o l o g i c a l p r o c e d u r e . These r e s e a r c h e r s found such a u b i q u i t o u s a r r a y of 5-HT t e r m i n a l s i n the c e r e b r a l c o r t e x as t o s t a t e "the raphe neurones may c o n t a c t every c e l l i n the c o r t e x " (p.207). O n t o l o g i c a l l y , h i g h c o n c e n t r a t i o n s of s e r o t o n i n a r e p r e s e n t i n the motor c o r t e x a t b i r t h and i n the e a r l y s t a g e s of p o s t n a t a l development i n the r a t . These l e v e l s s l o w l y d e c r e a s e t o a d u l t l e v e l s (Uzbekov et a l , 1979). S t i m u l a t i o n of the DR, i n a n a e s t h e t i z e d r a t s , causes a 39 frequency-dependent r e l e a s e of 5-HT i n the p a r i e t a l c o r t e x ( F u j i w a r a , 1981). E l e c t r o p h o r e t i c , i o n t o p h o r e t i c , a r t e r i a l i n j e c t i o n , and d o r s a l and median raphe s t i m u l a t i o n s t u d i e s i n d i c a t e s e r o t o n i n has i n h i b i t o r y (Bloom et a l , 1973; F r e d e r i c k s o n et. a_l, 1972; Huang and M a r r a z z i , 1973; Johnson et a l , 1970; O l p e , 1981; P h i l l i s ejt a l , 1968a; Reader et a l , 1979; Reader, 1980; S a s t r y and P h i l l i s , 1977b; Sharma, 1977) or both e x c i t a t o r y and i n h i b i t o r y e f f e c t s ( S z a b a d i et. a_l, 1977) upon c o r t i c a l neurones. A l t h o u g h the e x a c t l o c a t i o n of the c o r t i c a l neurones were not always s t a t e d , the i n h i b i t o r y e f f e c t s of 5-HT were obse r v e d i n the p o s t e r i o r c r u c i a t e c o r t e x ( F r e d e r i c k s o n e t a l , 1972), the deep neurones of the sensomotor c o r t e x ( S a s t r y and P h i l l i s , 1977b; Szabadi et a l , 1977) and p y r a m i d a l , p e r i c r u c i a t e c o r t e x c e l l s (Huang and M a r r a z z i , 1973). K o s t o w s k i e t a l , (1968) showed t h a t e l e c t r o l y t i c l e s i o n i n g of the MR n u c l e u s causes (1) a d e c r e a s e of f o r e b r a i n 5-HT and 5-HIAA l e v e l s , (2) an i n c r e a s e d i n g e n e r a l , a c t i v i t y , (3) the e s t a b l i s h m e n t of a p e r s i s t e n t EEG a r o u s a l p a t t e r n , and (4) an i n c r e a s e i n spontaneous motor a c t i v i t y . More r e c e n t l e s i o n s t u d i e s have c o n f i r m e d t h a t the MR n u c l e u s i s r e s p o n s i b l e f o r the i n c r e a s e d l o comotor a c t i v i t y o bserved i n r a t s when the a s c e n d i n g pathways are l e s i o n e d (Geyer, 1978; Jacobs e_t a l , 1974; J acobs and Cohen, 1976; L o r e n s , 1978). The hippocampus i s thought t o p l a y a major r o l e i n m e d i a t i n g the e f f e c t s of median raphe l e s i o n s . A n a t o m i c a l d a t a i n d i c a t e s t h a t t h e r e are two d i s t i c t pathways of median raphe f i b r e s t o the hippocampus: one pathway i s s u p r a c a l l o s a l t r a v e l l i n g w i t h the c i n g u l u m bundle and the o t h e r i s 40 i n f r a c a l l o s a l a s s o c i a t i n g w i t h the f o r n i x - f i m b r i a system ( A z m i t i a and S e g a l , 1978). L a t e r , A z m i t i a (1981) used h o r s e r a d i s h p e r o x i d a s e and 3H-5-HT i n a double l a b e l l i n g t e c h n i q u e t o show t h a t the DR a l s o has an e f f e r e n t pathway t o the hippocampus. R e s e a r c h by P a s q u i e r and Rein o s o - S u a r e z (1977) i n d i c a t e s the d o r s a l raphe e f f e r e n t s t e r m i n a t e p r i m a r i l y i n the d o r s a l hippocampus whereas the median raphe p r o j e c t s neurones throughout the e n t i r e hippocampus. A comparison of DR and MR l e s i o n s i n d i c a t e t h a t o n l y MR l e s i o n s s i g n i f i c a n t l y d e c r e a s e hippocampal s e r o t o n i n (Geyer, 1978; Geyer et a l , 1976; H e r r and Roth, 1976; Jacobs e t a l , 1974; K e l l e r e t a l , 1977; L o r e n s and G u l d b e r g , 1974; Trimbach as i n d i c a t e d by Mabry and Campb e l l , 1973; Van de Kar and L o r e n s , 1979) whereas DR l e s i o n s have l i t t l e e f f e c t on hippocampal 5-HT l e v e l s (Geyer, 1978; Jacobs e t a l , 1974; K e l l e r e t a l , 1977; Lor e n s and G u l d b e r g , 1974; Trimbach a c c o r d i n g t o Mabry and Ca m p b e l l , 1973; Van de Kar and L o r e n s , 1979). C o n t r a r i l y , D e a k i n e t a l (1979) showed t h a t 5,7-DHT l e s i o n s of the DR and MR produced s i m i l a r d e c r e a s e s i n hippocampal 5-HT l e v e l s and Rommelspacher and S t r a u s s , (1980) found t h e r m a l l e s i o n s of DR a l s o d e c r e a s e hippocampal 5-HT a l t h o u g h not n e a r l y t o e x t e n t as MR l e s i o n s . A p p r o x i m a t e l y n i n e t y p e r c e n t of hippocampal p y r a m i d a l c e l l s a r e i n h i b i t e d by i o n t o p h o r e t i c a d m i n i s t r a t i o n of 5-HT and 40% of hippocampal p y r a m i d a l c e l l s a r e i n h i b i t e d by median raphe s t i m u l a t i o n ( S e g a l , 1975; 1980; 1981). In v i t r o s t u d i e s a l s o s u p p o r t 5-HT i n h i b i t i o n of hippocampal c e l l s . S e r o t o n i n caused h y p e r p o l a r i z a t i o n of a l l r a t CA1 hippocampal c e l l s s t u d i e d i_n 41 v i t r o (Cobbett and C o t t r e l l , 1980). The h y p e r p o l a r i z a t i o n i s b e l i e v e d caused by a c t i v a t i o n of p o t a s s i u m c h a n n e l s ( S e g a l , 1980) . C o n t r a r i l y , Hole e t a l (1977) found t h a t l e s i o n i n g the mes e n c e p h a l i c m e d i a l s e r o t o n i n e r g i c bundle (the major a s c e n d i n g s e r o t o n i n e r g i c system) w i t h 5,7-DHT had no e f f e c t on motor a c t i v i t y . However, the motor a c t i v i t y was measured 20 days a f t e r l e s i o n i n g and by t h i s time r e g e n e r a t i o n of some 5-HT neurones (Svendgaard e_t a l , 1975; W i k l u n d e t a l , 1978) or i n c r e a s e s i n 5-HT s e n s i t i v i t y ( B l a c k b u r n e_t a l , 1981; Seeman e t a l , 1980; Stewart e t a l , 1976; T r u l s o n and J a c o b s , 1978), or b o t h , c o u l d have o c c u r r e d . The locomotor a c t i v i t y was a l s o measured i n the open f i e l d — a n environment not c o n d u c i v e t o measuring a c t i v i t y i n 5-HT d e p l e t e d a n i m a l s (see s e c t i o n 2.4). The o b s e r v a t i o n s t h a t p r i o r hippocampectomy b l o c k s t h e a b i l i t y of pCPA or e l e c t r o l y t i c l e s i o n s t o produce h y p e r a c t i v i t y ( Jacobs e t a l , 1975) p r o v i d e s s t r o n g e v i d e n c e f o r hippocampal i n v o l v e m e n t i n s e r o t o n i n e r g i c m o d u l a t i o n of a c t i v i t y . 4.4 Act i o n on S p i n a l Motorneurones The p o s t e r i o r raphe n u c l e i (B1-B3) a r e the major source of d e s c e n d i n g s e r o t o n i n e r g i c t r a c t s which t e r m i n a t e i n the s p i n a l c o r d . Minor c o n t r i b u t i o n s of d e s c e n d i n g 5-HT neurones come from B5, B7, B8, and B9 (Bowker e t a l , 1981; Satoh, 1979; S h i m i z u e t a l , 1981; Tohyama e t a l , 1979). S e r o t o n i n c o n c e n t r a t i o n s a r e h i g h e s t i n s p i n a l segments t h a t c o n t a i n motorneurones which i n n e r v a t e the l i m b s (Anderson, 1972). Moreover, u s i n g m i c r o a s s a y , m i c r o d i s s e c t i o n , and f l u o r e s c e n c e t e c h n i q u e s i t was d e t e r m i n e d t h a t the v e n t r a l 42 h o r n s , the l o c a t i o n of motorneurone p e r i k a r y a , have the h i g h e s t 5-HT c o n c e n t r a t i o n i n the s p i n a l c o r d (Anderson and H o l g e r s o n , 1966; C a r l s s o n e t a l , 1964; O l i v e r a s e t a l , 1977; Segu and C a l a s , 1978). I t i s p o s t u l a t e d t h a t the source of the h i g h 5-HT l e v e l s i n the v e n t r a l horn i s from d e s c e n d i n g s e r o t o n i n e r g i c neurone t e r m i n a l s d i r e c t l y c o n t a c t i n g a l p h a motorneurones ( D a l h s t r o m and Fuxe, 1965; N a f t c h i e_t a_l, 1972; Torskaya and Goloborodo'ko, 1977; U n g e r s t e d t , 1971). S p i n a l c o r d t r a n s e c t i o n produces d i m i n i s h e d amounts of 5-HT below the t r a n s e c t i o n i n d i c a t i n g the sour c e of 5-HT t o be of b r a i n o r i g i n (Anderson, 1972; N a f t c h i e t a l , 1972; O l i v e r a s e t a l , 1977). Only a few s t u d i e s have a t t e m p t e d t o e l u c i d a t e the e f f e c t s of 5-HT on motorneurones and the r e s u l t s a r e c o n f l i c t i n g . E x t r a c e l l u l a r a p p l i c a t i o n of 5-HT (l50nA; i o n t o p h o r e t i c ) or n o r a d r e n a l i n e (lOOnA) t o s p i n a l motorneurones causes membrane p o l a r i z a t i o n s u g g e s t i n g both t r a n s m i t t e r s a c t as i n h i b i t o r y a g e nts ( P h i l l i s e t a l , 1968b). The s e r o t o n i n a n t a g o n i s t s c i n a n s e r i n and me t h y s e r g i d e a b o l i s h l o n g l a t e n c i e s of v e n t r a l r o o t p o t e n t i a l s evoked by b r a i n s t e m s t i m u l a t i o n i n d i c a t i n g a t o n i c i n h i b i t i o n of motorneurone p o t e n t i a l s ( P r o u d f i t and Anderson, 1973). C o n t r a r i l y , i t has been noted t h a t 5-HTP (75mg/kg; i . v . ) ( M y s l i n s k i and Anderson, 1978) or 5-HT (.16M; i o n t o p h o r e t i c ) ( B a r a s i and R o b e r t s , 1974; White and Neuman, 1980) i n c r e a s e s the e x c i t a b i l i t y of s p i n a l motorneurones. Perhaps e l u c i d a t i n g these c o n t r a d i c t o r y r e s u l t s Komissarov and Abramets (1980) r e p o r t e d t h a t low c o n c e n t r a t i o n s of 5-HT (10~ 5M) d e p o l a r i z e s p i n a l motorneurones whereas h i g h c o n c e n t r a t i o n s (10""-10" 3M) h y p e r p o l a r i z e motorneurones. 43 4.5 A i r I o n i z a t i o n Another p o s s i b l e mechanism of 5-HT a c t i o n i s a i r i o n i z a t i o n . W i t h a h i g h barometer t h e r e i s a decrease of p o s i t i v e i o n s i n the a i r ( S c h r e i b e r , 1967). P o s i t i v e i o n i z a t i o n of ambient a i r i n c r e a s e s b l o o d and c r a n i a l 5-HT and, l i k e w i s e , n e g a t i v e i o n i z a t i o n d e c r e a s e s b l o o d and c r a n i a l 5-HT (Krueger e_t a_ l , l 9 6 6 ; Krueger and K o t a k a , 1969). N e g a t i v e i o n i z a t i o n a l s o d e c r e a s e s c o r t i c a l 5-HT l e v e l s (Diamond et a l , 1980). With r e g a r d t o these o b s e r v a t i o n s , one would e x p e c t a r i s i n g barometer t o i n c r e a s e spontaneous a c t i v i t y and a f a l l i n g barometer t o decrease spontaneous a c t i v i t y . T h i s i s what happens a c c o r d i n g t o Krueger and Smith (1960). In r a t s , t h e r e i s an i n c r e a s e i n 5-HIAA e x c r e t i o n a f t e r n e g a t i v e i o n i z a t i o n t r e a t m e n t ( O l i v e r e a u , 1971). I t i s p o s t u l a t e d t h a t n e g a t i v e i o n i z a t i o n a c c e l e r a t e s enzymatic o x i d a t i o n of 5-HT thus d e c r e a s i n g b o d i l y 5-HT l e v e l s ( O l i v e r e a u , 1971). The mechanism by which p o s i t i v e i o n s i n c r e a s e b l o o d 5-HT i s b e l i e v e d v i a a c a t i o n exchange. The r e l e a s e of 5-HT from b l o o d c e l l s such as mast c e l l s and p l a t e l e t s i s v i a a d i s p l a c e m e n t of p o s i t i v e i o n s i n t o the c e l l s c a u s i n g 5-HT t o be r e l e a s e d from the c e l l s i n t o the b l o o d stream (Unvas, 1978). F u r t h e r e v i d e n c e s u p p o r t i n g a r e l a t i o n s h i p between a i r i o n i z a t i o n and 5-HT i s as f o l l o w s : (1) n e g a t i v e i o n s have been shown t o decrease a l p h a wave f r e q u e n c y 2-4Hz, i n c r e a s e EEG a m p l i t u d e , i n c r e a s e s p r e a d of a l p h a waves, i n c r e a s e s y n c h r o n i z a t i o n of EEG between hemispheres, i n c r e a s e a l e r t n e s s , and i n c r e a s e w o r k i n g c a p a c i t y ( A s s a e l et a l , 1974). 44 (2) n e g a t i v e i o n s have been shown, i s some c a s e s , t o i n c r e a s e muscular endurance i n r a t s ( O l i v e r e a u , 1973). (3) weather c o n d i t i o n s t h a t augment p o s i t i v e i o n i z a t i o n and i n c r e a s e 5-HT cause the S e r o t o n i n I r r i t a t i o n Syndrome i n about one t h i r d of the human p o p u l a t i o n (Sulman et a l , 1975). T h i s syndrome, as m a n i f e s t e d by headaches, d i z z i n e s s , and i r r i t a t i o n of the r e s p i r a t o r y pathways, i s r e l i e v e d by t r e a t m e n t w i t h n e g a t i v e a i r i o n i z a t i o n . T h i s syndrome can be i n d u c e d , i n humans, by t r e a t m e n t w i t h p o s i t i v e i o n s (Winsor and B e c h e t t , 1958). (4) n e g a t i v e i o n s i n c r e a s e oxygen uptake of i s o l a t e d mouse l i v e r c e l l s (Bhartendu and Menon, 1978). I t i s a p o s s i b i l i t y t h a t the i n c r e a s e d p r e s s u r e and temperature t h a t take p l a c e i n the l u n g s and muscles d u r i n g e x e r c i s e w i l l i n c r e a s e b l o o d 5-HT enough t o cause a s i g n i f i c a n t p h y s i o l o g i c a l e f f e c t on muscular performance. 4.6 S e r o t o n i n e r g i c I n h i b i t i o n a t Motor E n d p l a t e s S e r o t o n i n d e c r e a s e s the e l e c t r o p h y s i o l o g i c a l and a s s o c i a t e d m e c h a n i c a l responses of a c e t y l c h o l i n e a p p l i e d t o the f r o g neuromuscular j u n c t i o n (Akasu et a l , 1981; Colomo e t a l , 1968; H i r a i et a_l, 1981; Magazanik e_t a l , 1976 a c c o r d i n g t o Akopyan et a l , 1980; Romanowski, 1967). S e r o t o n i n , i n i t s e l f , does not a l t e r the p o s t s y n a p t i c membrane conductance but i s a b l e t o i m p a i r the a c e t y l c h o l i n e - a c t i v a t i o n of i o n i c c h a n n e l s (Magazanik e t a l , 1976) by r e d u c i n g the a f f i n i t y of a c e t y l c h o l i n e t o the r e c o g n i t i o n s i t e of a c e t y l c h o l i n e r e c e p t o r s ( H i r a i e t a l , 1981). The c o n c e n t r a t i o n of 5-HT r e q u i r e d i s the same as found i n the b r a i n e x t r a c t s of e x e r c i s e d r a t s (Romanowski, 1967). 45 4.7 S e r o t o n i n e r g i c I n h i b i t i o n of G l u c o c o r t i c o s t e r o i d A c t i o n Adrenalectomy d e c r e a s e s r u n n i n g wheel t i m e . S y n t h e t i c c o r t i c o s t e r o n e t r e a t m e n t of a d r e n a l e c t o m i z e d r a t s r e s u l t s i n an immediate i n c r e a s e i n r u n n i n g wheel a c t i v i t y (Moberg and C l a r k , 1976; P e d e r s e n - B j e r g a a r d and Tonnesen, 1954). The r i s e i n g l u c o c o r t i c o s t e r i o d s e c r e t i o n d u r i n g the l a t e r e s t i n g phase r e s u l t s i n an i n c r e a s e i n g l y c o g e n c a t a b o l i s m - — y i e l d i n g f u e l f o r the subsequent a c t i v i t y phase. E l i m i n a t i o n of the s e r o t o n i n e r g i c i n n e r v a t i o n t o the s u p r a c h i a s m a t i c n u c l e i (SCN) of the hypothalamus e i t h e r v i a e l e c t r o l y t i c l e s i o n of B7 and B8 n u c l e i or d e s t r u c t i o n of 5-HT neurones i n the SCN by 5,7-DHT ( l u g i n 1ul) t r e a t m e n t , d e c r e a s e s a d r e n o c o r t i c o t r o p i c hormone (ACTH) a m p l i t u d e s and l e v e l s and i n c r e a s e s c o r t i c o s t e r o n e a m p l i t u d e s and l e v e l s ( S z a f a r c z y k e_t a l , 1980). C o n c u r r e n t w i t h the i n c r e a s e i n c o r t i c o s t e r o n e above c o n t r o l l e v e l s , the locomotor a c t i v i t y of the a n i m a l was a l s o e l e v a t e d r e l a t i v e t o c o n t r o l s f o r b o t h l e s i o n p r o c e d u r e s . There was no change i n e i t h e r the phase r e l a t i o n s h i p of the c o r t i c o s t e r o i d or the ACTH c i r c a d i a n rhythm t o the l i g h t - d a r k c y c l e ( B a l e s t r e r y and Moberg, 1976; S z a f a r c z y k e t a l , 1980). E l e c t r i c a l s t i m u l a t i o n of m i d b r a i n raphe n u c l e i reduces the s t r e s s i n d u c e d i n c r e a s e of plasma c o r t i c o s t e r o n e — a n e f f e c t t h a t i s b l o c k e d by m e t h y s e r g i d e (a 5-HT a n t a g o n i s t ) (Kovacs e t a l , 1976). These o b s e r v a t i o n s l e d Kovacs e t a l (1976), t o s p e c u l a t e the e x i s t e n c e of s e r o t o n i n e r g i c i n h i b i t i o n of h y p o t h a l a m o - p i t u i t a r y -a d r e n c o r t i c a l a c t i v a t i o n i n r a t s . The 5 - H T - c o r t i c o s t e r o n e i n t e r a c t i o n may a l s o e x i s t i n the r e v e r s e d i r e c t i o n . N o r m a l l y , i t appears c o r t i c o s t e r o n e mediates 46 a n e g a t i v e feedback mechanism on s e r o t o n i n . B i l a t e r a l a d r e n a lectomy and c o n c u r r e n t d e c r e a s e s i n c o r t i c o s t e r o n e l e v e l s e l e v a t e s b r a i n t r y p t o p h a n l e v e l s but d e c r e a s e s the c o n c e n t r a t i o n s of c r a n i a l 5-HT and 5-HIAA ( M i l l e r e t a l , 1980; Sze, 1976). The l o c u s of a c t i o n f o r t h i s e f f e c t i s p r o b a b l y t r y p t o p h a n h y d r o x y l a s e , f o r b i l a t e r a l a d r e n a l e c t o m y a l s o d e c r e a s e s t r y p t o p h a n h y d r o x y l a s e a c t i v i t y and 5-HT uptake. T h i s e f f e c t i s r e v e r s e d w i t h c o r t i c o s t e r i o d t r e a t m e n t ( A z m i t i a e t a l , 1970; D e k l o e t e t a l , 1982; Sze, 1976; Vermes, 1976). I n c r e a s e s i n c o r t i c o s t e r o i d s augment t r y p t o p h a n uptake and i t s subsequent me t a b o l i s m t o 5-HT (Sze, 1976). Sze (1976), c o n c l u d e s t h a t c o r t i c o s t e r i o d s have a f a s t a c t i o n upon 5-HT by r e g u l a t i n g t r y p t o p h a n uptake and a slow a c t i o n on 5-HT by r e g u l a t i o n of t r y p t o p h a n h y d r o x y l a s e a c t i v i t y . Vermes et a l (1976), goes even f u r t h e r , s u g g e s t i n g t h a t c o r t i c o s t e r o i d hormones might p l a y a modulatory r o l e i n m a i n t a i n i n g a c e r t a i n f u n c t i o n a l a c t i v i t y l e v e l of c e n t r a l s e r o t o n i n e r g i c neurones. The l o c u s of the n e g a t i v e feedback of c o r t i c o s t e r o i d s upon the s e r o t o n i n e r g i c system may o c c u r i n the raphe n u c l e i , or even the hippocampus. Twenty t o t h i r t y p e r c e n t of the s m a l l b l o o d v e s s e l s i n the DR and MR have d i r e c t a p p o s i t i o n w i t h s e r o t o n i n e r g i c p e r i k a r y a and d e n d r i t e s ( F e l t e n and C r u t c h e r , 1979). H i s t o c h e m i c a l f l u o r e s c e n c e and p h a r m a c o l o g i c a l m a n i p u l a t i o n p r o v i d e s t r o n g s u p p o r t f o r the e x i s t e n c e of 5-HT t e r m i n a l s i n the supra-ependymal l a y e r of. the l a t e r a l c e r e b r a l v e n t r i c l e s ( R i c h a r d s e t a l , 1973). The hippocampus, which b o r d e r s the v e n t r a l s u r f a c e of the l a t e r a l v e n t r i c l e s , has the h i g h e s t c o r t i c o s t e r i o d uptake and b i n d i n g c a p a c i t y of any 47 s t r u c t u r e i n the b r a i n ( G r o s s e r e t a_l, 1973; McEwen et a l , 1969) . The p o s s i b i l i t y of a 5 - H T - c o r t i c o s t e r o n e i n t e r a c t i o n i n f l u e n c i n g motor a c t i v i t y i s s t r o n g l y documented. 4.8 S e r o t o n i n e r g i c I n h i b i t i o n of A d r e n a l T y r o s i n e H y d r o x y l a s e L e s i o n i n g of the a d r e n a l m e d u l l a reduces the time t o e x h a u s t i o n i n l o n g d u r a t i o n e x e r c i s e ( R i c h t e r e_t a_l, 1981). P r i o r t o and d u r i n g e x e r c i s e , s y m p a t h e t i c a c t i v i t y r e l e a s e s a d r e n a l i n e and n o r a d r e n a l i n e from the a d r e n a l g l a n d s i n t o the b l o o d stream. These c a t e c h o l a m i n e s markedly enhance g l y c o g e n o l y s i s mediated by motor nerve a c t i v i t y ( R i c h t e r e l a l , 1981). T h i s enhancement can come about v i a s t i m u l a t i n g g l y c o g e n o l y s i s (Mayer, 1970), s t i m u l a t i n g c a l c i u m r e l e a s e from the s a r c o p l a s m i c r e t i c u l u m (Mayer et a l , 1970), s t i m u l a t i n g l i p o l y s i s ( C a r l s o n , 1965; Newsholme and S t a r t , 1973; F i z a c k , 1965; Schimmel, 1976), s t i m u l a t i n g muscle (Na+,K+)-ATPase (Cheng et a l , 1977; Flatman and C l a u s e n , 1978), s t i m u l a t i n g s u b s t r a t e c y c l i n g i n the muscle (Newsholme, 1976) and i n h i b i t i n g g l y c o g e n s y n t h e s i s (Mayer, 1970). The f o r c e of c o n t r a c t i o n i s a l s o f a c i l i t a t e d by c a t e c h o l a m i n e s , but o n l y i n f a s t t w i t c h f i b r e s and o n l y by b e t a a d r e n e r g i c s t i m u l a t i o n (Holmberg et a l , 1979). The key r e g u l a t o r y enzyme f o r s y n t h e s i z i n g t h e s e s y m p a t h e t i c hormones i s t y r o s i n e h y d r o x y l a s e (TOH) (Nagatsu et a l , 1964). There i s a s l i g h t ( 1 8 % ) , though s i g n i f i c a n t , i n c r e a s e i n a d r e n a l TOH a c t i v i t y f o l l o w i n g 5-HT d e p l e t i o n w i t h pCPA (Breese e t a l , 1974). I f the TOH a c t i v i t y i s i n c r e a s e d v i a c h r o n i c amphetamine a d m i n i s t r a t i o n p r i o r t o pCPA t r e a t m e n t , t h e r e i s a v e r y l a r g e i n c r e a s e (100%) i n TOH a c t i v i t y (Breese e t 48 a l , 1974; H o l l i s t e r e t aJL, 1974). These o b s e r v a t i o n s i n d i c a t e t h a t 5-HT i n h i b i t i o n of c a t e c h o l a m i n e s y n t h e s i s i n the a d r e n a l s i s much g r e a t e r when t h e c a t e c h o l a m i n e system i s a c t i v a t e d . Most l i k e l y , the c e n t r a l nervous system mediates the e f f e c t s of pCPA. C e n t r a l s e r o t o n i n e r g i c neurones i n h i b i t s y m p a t h e t i c o u t f l o w from the s p i n a l c o r d (Coote and Macleod, 1974) and a d r e n a l TOH a c t i v i t y ( Q u i r k and Sour k e s , 1977). F u r t h e r m o r e , 5-HT has been l o c a l i z e d i n the c y t o p l a s m and n u c l e u s of a d r e n a l m e d u l l a c e l l s (Csaba and Sudar, 1978). The a u t h o r s e l u c i d a t i n g the s e r o t o n i n e r g i c a c t i o n on the a d r e n a l m e d u l l a used a time s c a l e of days f o r t h e i r o b s e r v a t i o n s . On a s h o r t e r time s c a l e , i . e . d u r i n g e x e r c i s e of a l o n g d u r a t i o n , a d r e n a l p r o d u c t i o n of c a t e c h o l a m i n e s i s i n h i b i t e d ( M a t l i n a , 1976). The p o s s i b l i t y t h a t 5-HT may i n h i b i t a d r e n a l t y r o s i n e h y d r o x y l a s e d u r i n g e x e r c i s e must be c o n s i d e r e d . 4.9 Other P o s s i b l e L o c i of I n h i b i t i o n Other p o s s i b l e l o c i where 5-HT may have i t s i n h i b i t o r y e f f e c t on locomotor a c t i v i t y have a l r e a d y been d i s c u s s e d i n s e c t i o n 3. The l o c i i n c l u d e the do p a m i n e r g i c n i g r o - s t r i a t a l and me s o l i m b i c systems and the l o c u s c o e r u l e u s . 49 5 C o n c l u s i o n s Numerous i n v e s t i g a t i v e p r o c e d u r e s have documented s e r o t o n i n as a m o d u l a t o r . A n a t o m i c a l l y , 5-HT neurones a r e u n m y l e i n a t e d , h i g h l y c o l l a t e r a l i z e d , and have a l a r g e number of t e r m i n a l a b o r a t i o n s . Many d i r e c t c o n t a c t s a r e made between 5-HT c e l l b o d i e s and the c i r c u l a t o r y system. There i s a v a s t a r r a y of 5-HT t e r m i n a l s l i n i n g the v e n t r i c l e s . B i o c h e m i c a l l y , 5-HT and t r y p t o p h a n h y d r o x y l a s e a r e found w i t h i n the e r g o t r o p i c system; c o n t r a r i l y NA, DA, and t h e i r s y n t h e s i s enzymes a r e found w i t h i n the t r o p h o t r o p i c system. P h y s i o l o g i c a l l y , the t o n i c low f i r i n g r a t e of 5-HT neurones and t h e i r l o n g t e m p o r a l e f f e c t s are not c o n d u c i v e t o an o n - o f f system. P h a r m a c o l o g i c a l l y , the many drugs t h a t have been used t o a l t e r the s t a t e of the e r g o t r o p i c and t r o p h o t r o p i c systems support the modulatory i n f l u e n c e t h a t 5-HT has upon the e r g o t r o p i c system. B e h a v i o u r a l l y , i n c r e a s e s or d e c r e a s e s i n s e r o t o n i n e r g i c f u n c t i o n i n g cause the r e c i p r o c a l e f f e c t i n locomotor a c t i v i t y . C o n s i d e r i n g the above, i t appears the s e r o t o n i n e r g i c system i s b e t t e r s u i t e d f o r f u n c t i o n i n g i n m o d u a l t o r y c a p a c i t y — s e t t i n g the response l e v e l s of i n n e r v a t e d neurones t o modify i n p u t from o t h e r neurones, r a t h e r than an on-o f f system of i n f o r m a t i o n p r o c e s s i n g . One can s p e c u l a t e t h a t a modulator t h a t opposses e i t h e r extreme of a c t i v i t y (be the a c t i v i t y b i o c h e m i c a l , p h y s i o l o g i c a l , or b e h a v i o u r a l i n n a t u r e ) t o have a s t r o n g e r modulatory i n f l u e n c e a t the extremes of an a c t i v i t y continuum. The numerous i n s t a n c e s of s e r o t o n i n m o d u l a t i o n under p h a s i c c o n d i t i o n s o n l y (Breese e t a l , 1974; Coote and Macleod, 1974; F i b i g e r and M i l l e r , 1977; M i l l e r and M a i c k e l , 1969; R i c h a r d s o n 50 e t a l , 1974), support t h i s h y p o t h e s i s . The s t u d i e s mentioned i n t h i s r e v i e w l e a d me t o a s i m i l a r c o n c l u s i o n as Heym, T r u l s o n , and J a c o b s (1982): s i n c e the a c t i v i t y of 5-HT neurones i s i n f l u e n c e d by- and i n f l u e n c e s the o u t p u t of c e n t r a l motor systems and t h a t t h e s e c e l l s a r e a l s o r e s p o n s i v e t o sensory i n p u t suggest 5-HT p l a y s a m o d ulatory r o l e i n sensomotor i n t e g r a t i o n . 51 REFERENCES Akasu, T., K. H i r a i , and K. K o k e t s u . 5-Hydroxytryptamine c o n t r o l s A c h - r e c e p t o r s e n s i t i v i t y of b u l l f r o g s y m p a t h e t i c g a n g l i o n c e l l s . B r a i n Res. 211: 217-220, 1981. Akopyan, A.R., N.K. Chemeris, V . I . I l j i n t a n d , and B.N. V e p r i n t s e u . S e r o t o n i n , dopamine and i n t r a c e l l u l a r c y c l i c AMP i n h i b i t the res p o n s e s of n i c o t i n i c c h o l i n e r g i c membrane i n s n a i l neurons. B r a i n Res. 201: 480-484, 1980. A l b e r t . D.J. and M.L. Walsh. The i n h i b i t o r y m o d u l a t i o n of a g o n i s t i c b e h a v i o r i n the' r a t b r a i n : A r e v i e w . N e u r o s c i .  Biobehav. Rev. 6: 125-143, 1982. Anden, N.-E., A. D a h l s t r o m , K. Fuxe, K. L a r s s o n , L. O l s o n , and U. U n g e r s t e d t . A s c e n d i n g monoamine neurons t o the t e l e n c e p h a l o n and d i e n c e p h a l o n . A c t a P h y s i o l . Scand. 67: 313-326, 1966. Anderson, E.G. B u l b o s p i n a l s e r o t o n i n - c o n t a i n i n g neurons and motor c o n t r o l . Fed". P r o c . 31: 107-112, 1972. Anderson, E.G. and L.O. H o l g e r s o n . The d i s t r i b u t i o n of 5-h y d r o x y t r y p t a m i n e and n o r e p i n e p h r i n e i n the c a t s p i n a l c o r d . J . Neurochem. 13: 479-485, 1966. Andrews, D.W., R.L. P a t r i c k , and J.D. V a r c h a s . The e f f e c t s of 5-h y d r o x y t r y p t a m i n e on dopamine s y n t h e s i s and r e l e a s e i n r a t b r a i n s t r i a t a l synaptosomes. J_;_ Neurochem. 30: 465-470, 1978. A s s a e l , M. , Y. P f e i f e r , and F.G. Sulman. I n f l u e n c e of a r t i f i c i a l a i r i o n i z a t i o n on the human e l e c t r o e n c e p h a l o g r a m . I n t . J . Biometeor. 18: 306-312, 1974. A z m i t i a . E.C. B i l a t e r a l s e r o t o n e r g i c p r o j e c t i o n s t o the d o r s a l hippocampus of the r a t : S i m u l t a n e o u s l o c a l i z a t i o n of 3H-5HT and HRP a f t e r r e t r o g r a d e t r a n s p o r t . J ^ Comp. N e u r o l . 203: 737-743, 1981. A z m i t i a , E.C. J r . , S. A l g e r i , and E. C o s t a . I n v i v o c o n v e r s i o n of 3 H - L - t r y p t o p h a n i n t o 3 H - s e r o t o n i n i n b r a i n a r e a s of a d r e n a l e c t o m i z e d r a t s . S c i e n c e 169: 201-203, 1970. A z m i t i a , E.C. and M. S e g a l . An a u t o r a d i o g r a p h i c a n a l y s i s of the d i f f e r e n t i a l a s c e n d i n g p r o j e c t i o n s of the d o r s a l and median raphe n u c l e i i n the r a t . J_;_ Comp. N e u r o l . 179: 641-668, 1978. B a l e s t r e r y , F.G. and Moberg, G.P. E f f e c t of m i d b r a i n raphe n u c l e i l e s i o n s on the c i r c a d i a n rhythm of plasma c o r t i c o s t e r o n e i n the r a t . B r a i n Res. 118/3: 503-508, 1976. Baraban, J.M. and G.K. A g h a j a n i a n . S u p p r e s s i o n of f i r i n g 52 a c t i v i t y of 5-HT neurons i n the d o r s a l raphe by a l p h a -a d r e n o c e p t e r a n t a g o n i s t s . Neuropharmacology 19: 355-363, 1980. Baraban, J.M., Wang, R.Y., and G.K. A g h a j a n i a n . R e s p e r i n e s u p p r e s s i o n of d o r s a l raphe n e u r o n a l f i r i n g : M e d i a t i o n by a d r e n e r g i c system. Eur. J . Pharmacol. 52: 27-36, 1978. B a r a s i , S. and M.H.T. R o b e r t s . The e f f e c t s of s t i m u l a t i o n of n u c l e u s raphe and i o n t o p h o r e t i c a l l y a p p l i e d 5 h y d r o x y t r y p t a m i n e on s p i n a l motorneurones. J_;_ P h y s i o l . (London) 236/1: 11P-12P, 1974. Barbeau, A. The p a t h o g e n e s i s of P a r k i n s o n ' s d i s e a s e : A new h y p o t h e s i s . Can. Med. A s s o c . J . 87: 802-807, 1962. B a r c h a s , J.D. and D.X. Freedman. B r a i n amines: Response t o p h y s i o l o g i c a l s t r e s s . B i o c h e m i c a l Pharmacol. 12: 1232-1235, 1963. Baumgarten, H.G., A. B j o r k l u n d , L. Lachenmayer, A. N o b i n , and U. S t e n e v i . Long l a s t i n g s e l e c t i v e d e p l e t i o n of b r a i n s e r o t o n i n by 5 , 6 - d i h y d r o x y t r y p t a m i n e . A c t a P h y s i o l . Scand. , S u p p l . 373: 1-15, 1971. Bhartendu and I.A. Menon. E f f e c t s of a t m o s p h e r i c s m a l l n e g a t i v e i o n s on the oxygen consumption of mouse l i v e r c e l l s . I n t . J . Biometeor. 22: 43-52, 1978. B l a c k b u r n , T.P., B. Cox, C G . Heapy, T.F. Lee, and D.N. M i d d l e m i s s . S u p e r s e n s i t i v i t y of n i g r a l s e r o t o n i n r e c e p t o r s and r a t r o t a t i o n a l b e h a v i o u r . Eur. J . Pharmacol. 71: 343-346, 1981. B l a n c h a r d , R.J., M.J. K e l l y , and D.C. B l a n c h a r d . Defense r e a c t i o n s and e x p l o r a t o r y b e h a v i o r i n r a t s . J_j_ Comp.  P h y s i o l . P s y c h o l . 87: 1129-1133, 1974. B l i g h , J . , W.H. C o t l e , and M. Maskrey. I n f l u e n c e of ambient te m p e r a t u r e on the t h e r m o r e g u l a t o r y responses t o 5-h y d r O x y t r y p t a m i n e , n o r a d r e n a l i n e and a c e t y l c h o l i n e i n j e c t e d i n t o the l a t e r a l c e r e b r a l v e n t r i c l e s of sheep, g o a t s and r a b b i t s . P h y s i o l . 212: 377-392, 1971. B l i s s , E.L. E f f e c t s of b e h a v i o u r a l m a n i p u l a t i o n s upon b r a i n s e r o t o n i n and dopamine. I n : S e r o t o n i n and B e h a v i o u r , e d i t e d by J . Barchas and E. U s d i n . New York: Academic P r e s s , 1973, 315-324. B l i s s , E.L., J . A i l i o n , and J . Zwanziger. M e t a b o l i s m of n o r e p i n e p h r i n e , s e r o t o n i n and dopamine i n r a t b r a i n w i t h s t r e s s . J^_ Pharmacol. Exp. Ther. 164: 122-134, 1968. Blondaux, C , A. Juge, F. S o r d e t , G. Chouvet, M. J o u v e t , and J.F. P u j o l . A l t e r a t i o n of s e r o t o n i n m e tabolism i n r a t b r a i n by 6-hydroxydopamine ( F r e n c h ) . B r a i n Res. 50: 101-53 114, 1973. B o b i l l i e r , P., S. S e g u i n , A. Degueurce, B.D. L e w i s , and J.F. P u j o l . The e f f e r e n t c o n n e c t i o n s of the n u c l e u s raphe c e n t r a l i s s u p e r i o r i n the r a t as r e v e a l e d by r a d i o a u t o g r a p h y . B r a i n Res. 166: 1-8, 1979. ' B o b i l l e r , P., S. S e g u i n , F. P e t i t j e a n , D. S a l v e r t , M. T o u r e t , and M J o u v e t . The raphe n u c l e i of the c a t b r a i n stem: a t o p o g r a p h i c a l a t l a s of t h e i r e f f e r e n t p r o j e c t i o n s as r e v e l a e d by a u t o r a d i o g r a p h y . B r a i n Res. 113: 449-486, 1976. B o l s t a d , G. and A. E r s l a n d . Energy m e t a b o l i s m i n d i f f e r e n t human s k e l e t a l muscles d u r i n g v o l u n t a r y i s o m e t r i c c o n t r a c t i o n s . Eur. J . A p p l . P h y s i o l . 38: 171-179, 1978. Bowker, R.M., K.N. Westlund, and J.D. C o u l t e r . S e r o t o n e r g i c p r o j e c t i o n s t o the s p i n a l c o r d from the m i d b r a i n i n the r a t : An immunocytochemical and r e t r o g r a d e t r a n s p o r t s t u d y . N e u r o s c i e n c e L e t t e r s 24: 221-226, 1981. B r a s e , D.A. and H.H. Loh. P o s s i b l e r o l e of 5-h y d r o x y t r y p t a m i n e i n m i m i n a l b r a i n d y s f u n c t i o n . L i f e S c i . 16: 1005-1016, 1975. B r e e s e , G.R., B.R. Cooper, and R.A. M u e l l e r . E v i d e n c e f o r i n v o l v e m e n t of 5 - h y d r o x y t r y p t a m i n e i n the a c t i o n s of amphetamine. Br i t . J . Pharmacol. 52: 301-314, 1 974. B r o d i e , B.B. and P.A. Shore. A concept f o r a r o l e of s e r o t o n i n and n o r e p i n e p h r i n e as c h e m i c a l m e d i a t o r s i n the b r a i n . A n n a l s N.Y. Acad. S c i . 66: 631-642, 1957. B r o w n s t e i n , M.J., M. P a l k o v i t s , J.M. Saavedra, and J.S. K i z e r . Trytophan h y d r o x y l a s e i n the r a t b r a i n . B r a i n Res. 97: 163-166, 1975. Carey, R.J. E f f e c t s of s e l e c t i v e f o r e b r a i n d e p l e t i o n s of n o r e p i n e p h r i n e and s e r o t o n i n on the a c t i v i t y and food i n t a k e e f f e c t s of amphetamine and f l e n f l u r a m i n e . Pharmacol.  Biochem. Behav. 5: 519-523, 1976. C a r l s o n , L.A. I n h i b i t i o n of m o b i l i z a t i o n of f r e e f a t t y a c i d s from a d i p o s e t i s s u e . Ann. N.Y. Acad. S c i . 131: 119-142, 1965. C a r l s s o n , A., B. F l a c k , K. Fuxe, and N.-A. H i l l a r p . C e l l u l a r l o c a l i z a t i o n of monoamines i n the s p i n a l c o r d . A c t a  p h y s i o l . Scand. 60: 112-119, 1964. C a r t e r , C.J. and C.J. Pycock. The e f f e c t s of 5,7-d i h y d r o x y t r y p t a m i n e l e s i o n s of e x t r a p y r a m i d a l and m e s o l i m b i c s i t e s on spontaneous motor b e h a v i o r , and amphetamine-induced s t e r e o t y p e . Naunyn-Schmied. A r c h . Pharmacol. 308/1: 51-54, 1979. 54 Cheng, L.C., E.M. Rogus, and K. Z i e r l e r . C a t e c h o l , a s t r u c t u r a l r e q u i r e m e n t f o r (Na* + K +)-ATPase s t i m u l a t i o n i n r a t s k e l e t a l muscle membrane. Biochem. B i o p h y s . A c t a 464: 338-346, 1977. C h r u s c i e l , T.L. and Z.S. Herman. E f f e c t of d o p a l a n i n e on b e h a v i o u r i n mice depeted of n o r e p i n e p h r i n e or s e r o t o n i n . P s y c h o p h a r m a c o l o q i a 14: 124-134, 1969. C l a r k , W.G. and Y.L. C l a r k . Changes i n body temperature a f t e r a d m i n i s t r a t i o n of a d r e n e r g i c and s e r o t o n e r g i c agents and r e l a t e d drugs i n c l u d i n g a n t i d e p r e s s a n t s . Neurosc i .  B i o behav. Rev. 4: 281-375, 1980. C o b b e t t , P. and G.A. C o t t r e l l . A c t i o n s of 5 - h y d r o x y t r y p t a m i n e on CA1 p y r a m i d a l neurones of r a t hippocampus i_n v i t r o . J .  P h y s i o l . 305: 101P-102P, 1980. C o l e , S. B r a i n mechanisms of amphtamine-induced a n o r e x i a , l o c o m o t i o n , and s t e r o t y p e : A r e v i e w . N e u r o s c i . Biobehav.  Rev. 2: 89-100, 1978. Coleman, M. S e r o t o n i n c o n c e n t r a t i o n s i n whole b l o o d of h y p e r a c t i v e c h i l d r e n . P e d i a t . 78: 985-990, 1971. Colomo, F., R. Rahaminoff, and E. S t e f a n i . An a c t i o n of 5-h y d r o x y t r y p t a m i n e on the f r o g motor e n d - p l a t e . E ur. J .  Pharmacol. 3: 272-274, 1968. Condrad, L.C.A., C M . Leonard, and D.W. P f a f f . C o n n e c t i o n s of the median and d o r s a l raphe n u c l e i i n the r a t : an a u t o r a d i o g r a p h i c and d e g e n e r a t i o n s t u d y . J_j_ Comp. N e u r o l . 156: 179-206, 1974. Coote, J.H. and V.H. Macleod. The i n f l u e n c e of b u l b o s p i n a l monoaminergic pathways on sy m p a t h e t i c nerve a c t i v i t y . J .  P h y s i o l . 241: 453-475, 1974. Cordeau, J.P., J . DeChamplain, and B. J a c k s . E x c i t a t i o n and p r o l o n g e d waking produced by c a t e c h o l a m i n e s i n j e c t e d i n t o the v e n t r i c u l a r system of c a t s . Canad. J . P h y s i o l . 49:627-631, 1971. C o s t a l l , B., S.-CG. H u i , and R.J. N a y l o r . D e n e r v a t i o n i n the dopa m i n e r g i c m e s o l i m b i c system: F u n c t i o n a l changes f o l l o w e d u s i n g (-)N-n-propylorapomorphine depend on the b a s a l a c t i v i t y l e v e l s of the r a t . Neuropharmacol. 19: 1039-1048, 1980. C o s t a l l , B., R.J. N a y l o r , C D . Marsden, and C.J. Pycock. S e r o t o n i n e r g i c m o d u l a t i o n of the dopamine response from the n u c l e u s accumbens. J_;_ Pharm. Pharmac. 28: 523-526, 1976. <. C r e s p i , F., M. Buda, A. McRae-Degueurce, and J.-F. P u j o l . A l t e r a t i o n of t y r o s i n e h y d r o x y l a s e a c t i v i i t y i n the l o c u s c o e r u l e u s a f t e r a d m i n i s t r a t i o n of p - c h l o r o p h e n y l a l a n i n e . 55 B r a i n Res. 191: 509, 1980. C r o n i n , M.J. and M.A. Baker. T h e r m o s e n s i t i v e m i d b r a i n neurons i n the c a t . B r a i n Res. 128: 461-472, 1977. Csaba, G. and F. Sudar. L o c a l i z a t i o n of r a d i o a c t i v e l y l a b e l l e d s e r o t o n i n i n the n u c l e u s of a d r e n a l m e d u l l a c e l l s . A c t a Anat. 100: 237-240, 1978. Curzon, G^ and A.R. Green. R a p i d method f o r the d e t e r m i n a t i o n of 5 - h y d r o x y t r y p t a m i n e and 5 - h y d r o x y i n d o l a c e t i c a c i d i n s m a l l r e g i o n s of r a t b r a i n . B r . J . Pharmacol. 39: 653-655, 1970. D a l h s t r o m , A. and K. Fuxe. E v i d e n c e f o r the e x i s t e n c e of monoamine-containg neurons i n the c e n t r a l nervous system. I . D e m o n s t r a t i o n of monoamines i n the c e l l b o d i e s of b r a i n stem neurons. A c t a p h y s i o l . Scand. 62 S u p p l . 232: 1-55, 1 964. D a h l s t r o m , A. and K. Fuxe. E v i d e n c e f o r the e x i s t e n c e of monoamine neurons i n the c e n t r a l nervous system. I I . E x p e r i m e n t a l l y induced changes i n the i n t r a n e u r o n a l amine l e v e l s of b u l b o s p i n a l neuron systems. A c t a p h y s i o l . Scand. 64, S u p p l . 247: 1-36, 1965. D a v i e s , J . and P. Tongroach. N e u r o p h a r m a c o l o g i c a l s t u d i e s on the n i g r o - s t r i a t a l and r a p h e - s t r i a t a l system i n the r a t . Eur. J . Pharmacol. 51: 91-100, 1978. D e a k i n , J.F.W., S.E. F i l e , J.R.G. Hyde, and N.K. MaCleod. A s c e n d i n g 5-HT pathways and b e h a v i o u r a l h a b i t u a t i o n . Pharmacol. Biochem. Behav. 10/5: 687-694, 1979. D e k l o e t , E.R., G.L. Kovacs, G. Szaba, G. T e l e g d y , B. Bohus, and D.H.G. V e r s t e e g . Decreased s e r o t o n i n t u r n o v e r i n the d o r s a l hippocampus of r a t b r a i n s h o r t l y a f t e r a d r e n a l e c t o m y : S e l e c t i v e n o r m a l i z a t i o n a f t e r c o r t i c o s t e r o n e s u b s t i t u t i o n . B r a i n Res. 239: 659-663, 1982. Diamond, M.C., J.R. Connor J r . , E.K. Orenberg, M. B i s s e l , M. Y o s t , and A. K r u e g e r . E n v i r o n m e n t a l i n f l u e n c e s on s e r o t o n i n and c y c l i c n u c l e o t i d e s i n r a t c e r e b r a l c o r t e x . S c i e n c e 210/4470: 652-654, 1980. Dray, A., T . J . Gonye, N.R. O a k l e y , and T. Tanner. E v i d e n c e f o r the e x i s t a n c e of a raphe p r o j e c t i o n t o the s u b s t a n t i a n i g r a i n the r a t . B r a i n Res. 113: 45-57, 1976. E l o , H., and R. T i r r i . E f f e c t of f o r c e d m o t i l i t y on the n o r a d r e n a l i n e and 5 - h y d r o x y t r y p t a m i n e m e t a b o l i s m i n d i f f e r e n t p a r t s of the r a t b r a i n . P s y c h o p h a r m a c o l o g i c a ( B e r l . ) 26/2: 195-200, 1972. Emerson J r . , T.E., P.D. M e i e r , and R.M. Daugherty J r . Dependence of s k e l e t a l muscle v a s c u l a r response t o s e r o t o n i n 56 upon the l e v e l of v a s c u l a r r e s i s t a n c e . P r o c . Soc. Exp  B i o l . Med. (N.Y.) 142/4: 1185-1188, 1973. Es s e n , B. and L. Ka y s e r . Glycogen u t i l i z a t i o n i n i n d i v i d u a l muscle f i b r e s d u r i n g i n t e r m i t t e n t and c o n t i n u o u s e x e r c i s e . A c t a P h y s i o l o g i c a S c a n d i n a v i c a : S u p p l . 440: 170, 1976. F e l d b e r g , W. and V . J . L o t t i . Temperature responses t o monoamines and an i n h i b i t o r of MAO i n j e c t e d i n t o the c e r e b r a l v e n t r i c l e s of r a t s . Br i t . J . Pharmacol. 31: 152-161, 1967. F e l d b e r g , W. and S.L. Sherwood. I n j e c t i o n s of drugs i n t o the l a t e r a l v e n t r i c l e of the c a t . P h y s i o l . 123: 148-167, 1954. • F e l t e n , D.L. and K.A. C r u t c h e r . N e u r o n a l - v a s c u l a r r e l a t i o n s h i p s i n the raphe n u c l e i , l o c u s c o e r u l e u s , and s u b s t a n t i a n i g r a i n p r i m a t e s . Am. J . Anat. 155: 467-482, 1979. F i b i g e r , H.C. and B.A. Campbell. The e f f e c t of p a r a -c h l o r o p h e n y l a l a n i n e on spontaneous locomotor a c t i v i t y i n the r a t . Neuropharmcol. 10: 25-32, 1971. F i b i g e r , H. and J . J . M i l l e r . An a n a t o m i c a l and e l e c t r o p h y s i o l o g i c a l i n v e s t i g a t i o n of the s e r o t o n e r g i c p r o j e c t i o n from the d o r s a l raphe n u c l e u s t o the s u b s t a n t i a n i g r a i n the r a t . N e u r o s c i . 2: 975-987, 1977. Fl a t m a n , J.A. and T. C l a u s e n . B 2 - a d r e n o c e p t o r s mediate the s t i m u l a t i n g e f f e c t of a d r e n a l i n e on a c t i v e e l e c t r o g e n i c N a + -K + - t r a n s p o r t i n r a t s o l e u s muscle. A c t a P h y s i o l . Scand. 102/1: 61A-62A, 1978. Frankhuyzen, A.L. and A.H. Mul d e r . N o r a d r e n a l i n e i n h i b i t s d e p o l a r i z a t i o n - i n d u c e d 3 H - s e r o t o n i n r e l e a s e from s l i c e s of r a t hippocampus. E ur. J . Pharmacol. 63: 179-182, 1980. F r e d e r i c k s o n , R.C.A., L.M. J o r d a n , and J.W. P h i l l i s . A r e a p p r a i s a l of the a c t i o n s of n o r a d r e n a l i n e and 5-h y d r o x y t r y p t a m i n e on c e r e b r a l c o r t i c a l neurons. Comp. Gen.  Pharmacol. 3: 443-456, 1972. F u j i w a r a , H., M. Uemoto, and C. Tanaka. S t i m u l a t i o n of the r a t d o r s a l raphe i_n v i v o r e l e a s e s l a b e l e d s e r o t o n i n from the p a r i e t a l c o r t e x . B r a i n Res. 216: 351-360, 1981. Fuxe, K. E v i d e n c e f o r the e x i s t e n c e of monoamine-containing neurones i n the c e n t r a l nervous system. IV. D i s t r i b u t i o n of monoamne nerve t e r m i n a l s i n the c e n t r a l nervous system. A c t a P h y s i o l . Scand. 64 S u p p l . 247: 37-85, 1965. G a l l a g e r , D.W. and G.K. Aghajanian-. E f f e c t of a n t i p s y c h o t i c drugs on the f i r i n g of d o r s a l raphe c e l l s . I . The r o l e of the a d r e n e r g i c system. E u r . J . Pharmacol. 39: 341-355, 57 1976. Geyer, M.A. Heterogenous f u n c t i o n s of d i s c r e t e s e r o t o n e r g i c pathways i n b r a i n . I n : B i o c h e m i s t r y of M e n t a l D i s o r d e r s Modern P h a r m a c o l o g y - T o x i c o l o g y . New York: M a r c e l Dekker, I n c . , 13: 233-260, i 978. Giambalvo, C.T. and S.R. Snodgrass. B i o c h e m i c a l and b e h a v i o r a l e f f e c t s of s e r o t o n i n n e u r o t o x i n s on the n i g r o s t r i a t a l dopamine system: comparison of i n j e c t i o n s i t e s . B r a i n Res. 152: 555-566, 1978. G i l b e y , M.P., J.H. Coote. V.H. Macleod, and D.F. P e t e r s o n . I n h i b i t i o n of s y m p a t h e t i c a c t i v i t y by s t i m u l a t i n g i n the raphe n u c l e i and the r o l e of 5 - h y d r o x y t r y p t a m i n e i n t h i s e f f e c t . B r a i n Res. 226: 131-142, 1981. G i l l e s p i e , C.A., D.R. Simpson, and V.R. E d g e r t o n . Motor u n i t r e c r u i t m e n t as r e f l e c t e d by muscle f i b r e g l y c o g e n l o s s i n a P r o s i m i a n (Bushbaby) a f t e r r u n n i n g and jumping. J_j_ N e u r o l .  N e u r o s u r g . P s y c h i a t . 37: 817-827, 1974. G l o w i n s k i , J . and L.L. I v e r s e n . R e g i o n a l s t u d i e s of c a t e c h o l a m i n e s i n the r a t b r a i n - - I . The d i s p o s i t i o n of [ 3 H ] n o r e p i n e p h r i n e , [ 3H]dopamine and [ 3H]dopa i n v a r i o u s r e g i o n s of the b r a i n . N e u r o c h e m i s t r y 13: 655-669, 1966. G o l d s t e i n M. , B. Anagnoste, E. Lauber, and M.R. McKereghan. I n h i b i t i o n of dopamine-b-hydroxyalse by d i s u l f i r a m . L i f e  S c i . 3: 763-767, 1964. G o l l n i c k , P.D., K. P i e h l , and B. S a l t i n . S e l e c t i v e g l y c o g e n d e p l e t i o n p a t t e r n i n human muscle f i b r e s a f t e r e x e r c i s e of v a r y i n g i n t e n s i t y a t v a r y i n g p e d a l r a t e s . J ^ P h y s i o l . 241: 45-57 1974. Grabowska, M. and J . M i c h a l u k . On the r o l e of s e r o t o n i n i n apomorphine-induced locomotor s t i m u l a t i o n i n r a t s . P harmacol. Biochem. Behav. 2: 263-266, 1974. Green, R.A., J.A. B a r c h a s , G.R. E l l i o t t , J.S. Carman, and R.J. Wyatt. The t r y p t o l i n e s : e f f e c t of i n t r a v e n t r i c u l a r a d m i n s t r a t i o n on spontaneous motor a c t i v i t y of r a t s . P harmocol. Biochem. Behav. 5: 383-385, 1976a. Green, R.A., J.C. G i l l i n , and R.J. Wyatt. The i n h i b i t o r y e f f e c t on i n t r a v e n t r i c u l a r a d m i n i s t r a t i o n of s e r o t o n i n on spontaneous motor a c t i v i t y of r a t s . Psychopharmacol. 51: 81-84, 1976b. Gromova, E.A., T.P. Semenova, and N.L. V e k s h i n a . F u n c t i o n a l i n t e r a c t i o n s of the s e r o t o n i n systems of the b r a i n d u r i n g the p r o c e s s of c o n d i t i o n i n g . Doklady B i o l o g i c a l S c i e n c e s 227: 149-151, 1976. G r o s s e r , B . I . , W. S t e v e n s , and D.J. Reed. P r o p e r t i e s of 58 c o r t i c o s t e r o n e - b i n d i n g macromolecules from r a t b r a i n c y t o s o l . B r a i n Res. 57: 387-395, 1973. Gumulka, W., A.R. D e l A n g e l , R. Samanin, and L. V a l z e l l i . L e s i o n s of s u b s t a n t i a n i g r a : b i o c h e m i c a l and b e h a v i o r a l e f f e c t s i n r a t s . Eur. Pharmacol. 10: 79-80, 1970. Harvey, J.A., A . J . S c h o l o s b e r g , and L.M. Yunger. B e h a v i o r a l c o r r e l a t e s of s e r o t o n i n d e p l e t i o n . Fed. P r o c . 34: 1796-1801, 1975. H e r r , B.E. and R.H. Roth. The e f f e c t of a c u t e raphe l e s i o n on the s e r o t o n i n s y n t h e s i s and met a b o l i s m i n the r a t f o r e b r a i n and hippocampus. B r a i n Res. 110/1: 189-193, 1976. Herve, D., H. Simon, G. B l a n c , A. L i s o p r a w d k i , M. Le Mo a l , J . G l o w i n s k i , and J.P. T a s s i n . I n c r e a s e d u t i l i z a t i o n of dopamine i n the n u c l e u s accumbens but not i n the c e r e b r a l c o r t e x a f t e r d o r s a l raphe l e s i o n i n the r a t . N e u r o s c i .  L e t t . 15/2-3: 127-133, 1979. Hery, F., P. S o u b r i e , S. B o u r g o i n , J.L M o t a s t r u c , F. A r t a u d , and J . G l o w i n s k i . Dopamine r e l e a s e d from d e n d r i t e s i n the s u b s t a n t i a n i g r a c o n t r o l s the n i g r a l and s t r i a t a l r e l e a s e of s e r o t o n i n . B r a i n Res. 193: 143-151, 1980. Heym, J . , M.E. T r u l s o n , and B.L. J a c o b s . Raphe u n i t a c i t i v i t y i n f r e e l y moving c a t s . I I . E f f e c t s of a d r e n e r g i c d r u g s . Soc. N e u r o s c i . A b s t . 6: 234, 1980. Heym, J . , M.E. T r u l s o n , and B.L. J a c o b s . Raphe u n i t a c t i v i t y i n f r e e l y moving c a t s : E f f e c t s of p h a s i c a u d i t o r y and v i s u a l s t i m u l i . B r a i n Res. 232: 29-39, 1982. H i r a i , K., T. Akasu, and K. K o k e t s u . E f f e c t of 5-h y d r o x y t r y p t a m i n e on the n i c o t i n i c a c e t y l c h o l i n e r e c e p t o r -c h a n n e l complex. N e u r o s c i e n c e L e t t e r s Supp. 6: S68, 1981. H o l e , K., K. Fuxe, and G. J o n s s o n . B e h a v i o r a l e f f e c t s of 5,7-d i h y d r o x y t r y p t a m i n e l e s i o n s of a s c e n d i n g 5 - h y d r o x t r y p t a m i n e pathways. B r a i n Res. 107: 385-399, 1976. H o l e , K., G.E. Jon s s o n , and O.-G. Berge. 5,7-d i h y d r o x y t r y p t a m i n e l e s i o n s of the a s c e n d i n g 5-h y d r o x y t r y p t a m i n e pathways: H a b i t u a t i o n , motor a c t i v i t y , and a g o n i s t i c b e h a v i o r . Pharmacol. Biochem. Behav. 7: 205-210, 1977. H o l l i s t e r , A.C., G.R. B r e e s e , and B.R. Cooper. E v i d e n c e f o r inv o l v e m e n t of b r a i n s e r o t o n i n i n the a c t i o n s of amphetamine and o t h e r p h e n y l e t h y l a m i n e d e r i v a t i v e s . Fed. P r o c . 33: 255, 1974. H o l l i s t e r , A.S., G.R. B r e e s e , C M . Kuhn, B.R. Cooper, and S.M. Schanberg. An i n h i b i t o r y r o l e f o r b r a i n s e r o t o n i n -c o n t a i n i n g systems i n the locomotor e f f e c t s of d-59 amphetamine. Pharmacol. 198: 12-22, 1976. Holmberg, E., I . S v e d i n g e r , and B. Waldeck. On the sympathometic induced e f f e c t s on s k e l e t a l muscle c o n t r a c t i o n s . I n : C a t e c h o l a m i n e s : B a s i c and C l i n i c a l F r o n t i e r s , e d i t e d by E. U s d i n , I . J . K o p i n , and J . Ba r c h a s . New York: Pergamon P r e s s , 1, 1979,p.986-988. Huang, C.C. and A.S. M a r r a z z i . A n a l y s i s of drug b l o c k of LSD/5HT/GABA by m o n i t o r i n g n e u r o n a l membrane changes. Fed.  P r o c . 32: 303, 1973. H u t c h i n s , D.A. and K.J. Rogers. Some o b s e r v a t i o n s on the c i r c a d i a n rhythm of locomotor a c t i v i t y of mice a f t e r d e p l e t i o n of c e r b r a l monoamines. P s y c h o p h a r m a c o l o g i c a V ( B e r l . ) 31/4:343-348, 1973. Ja c o b , J . J . and J.-A.T. G i r a u l t . 5 - Hydroxytryptamine. I n : Body Temperature, Modern Pharmacology and T o x i c o l o g y , e d i t e d by P. Lomax and E. Schonbaum. New York: M a r c e l Dekker I n c . 16: 183-230, 1979. J a c o b s , B.L. and A. Cohen. D i f f e r e n t i a l b e h a v i o r a l e f f e c t s of l e s i o n s of the median or d o r s a l raphe n u c l e i i n r a t s : Open f i e l d and p a i n - e l i c i t e d a g g r e s s i o n . J_^ Comp. P h y s i o l .  P s y c h o l . 90: 102-108, 1976. J a c o b s , B.L. and E.E. Eubanks. A comparison of the locomotor e f f e c t s of 5- h y d r o x y t r y p t o p h a n a d m i n i s t e r e d v i a two s y s t e m i c r o u t e s . Pharmacol. Biochem. Behav. 2/1: 137-139, 1974. J a c o b s , B.L., C. Trimbach, E.E. Eubanks, and M. T r u l s o n . Hippocampal m e d i a t i o n of raphe l e s i o n - and PCPA-induced h y p e r a c t i v i t y i n the r a t . B r a i n Research 94: 253-261, 1975. J a c o b s , B.L., W.D. Wise, and K.M. T a y l o r . D i f f e r e n t i a l b e h a v i o r and n e u r o c h e m i c a l e f f e c t s f o l l o w i n g l e s i o n s of the d o r s a l or median raphe n u c l e i i n r a t s . B r a i n R esearch 79: 352-361, 1974. Johnson, E.S., M.H.T. R o b e r t s , and D.W. Str a u g h a n . A m i n o - a c i d i n d u c e d d e p r e s s i o n of c o r t i c a l neurones. Br i t . J .  Pharmacol. 38: 659-666, 1970. Johnson, G.A., E.G. Kim, and S.J. Boukma. 5 - h y d r o x y i n d o l e l e v e l s i n r a t b r a i n a f t e r i n h i b i t i o n of dopamine b-h y d r o x y l a s e . J ^ Pharmacol. 180: 539-546, 1972. Jones D.L., G.J. Morgenson, and M. Wu. I n j e c t i o n s of d o p a m i n e r g i c , c h o l i n e r g i c , s e r o t o n i n e r g i c and g a b a e r g i c drugs i n t o t he n u c l e u s accumbens: e f f e c t on locomotor a c t i v i t y i n t h r r a t . Neuropharmacol. 20: 29-37, 1981. K a r l s s o n , J . and P.V. Komi. M o t i o n and i t s s i g n i f i c a n c e on i n n e r v a t i o n , f i b r e r e c r u i t m e n t and muscle metabolism. A c t a  P h y s i o l . Scand. S u p p l . 440: 12, 1976. 60 K a y s e r , Ch. and G. H i l d w e i n . Monoamines c e r e b r a l e s e t rythme c i r c a d i e n de l ' a c t i v i t e m o t r i c e spontanee du r a t . Soc.  B i o l . ( P a r i s ) 171: 450-455, 1977. K e l l e r , K . J . , P.A. Brown, J . M a r i d , M. B e r n s t e i n , J . V e r n i k o s - D a n e l l i s , and W.R. M e h l e r . O r i g i n s of s e r o t o n i n i n n e r v a t i o n of f o r e b r a i n s t r u c t u r e s . E x p e r i m e n t a l Neurology 56: 52-62, 1977. Key, B . J . and V.H. Mehta. Changes i n e l e t r o c o r t i c a l a c t i v i t y i n d u c e d by the p e r f u s i o n of 5 - h y d r o x y t r y p t a m i n e i n t o the n u c l e u s of the s o l i t a r y t r a c t . Neuropharmacol. 16: 99-106, 1977. Koe, K. and A. Weissman. p - C h l o r o p h e n y l a l a n i n e : a s p e c i f i c d e p l e t o r of b r a i n s e r o t o n i n . J_;_ Pharmacol. Exp. Therap. 154: 499-516, 1966. Komiskey, H.L. and T.A. Rudy. S e r o t o n e r g i c i n f l u e n c e s on b r a i n stem t h e r m o r e g u l a t o r y mechanisms i n the c a t . B r a i n  Res. 134: 297-315, 1977. Komissarov, I.V. and I . I . Abramets. E f f e c t of monoamines on motorneurons of the i s o l a t e d r a t s p i n a l c o r d . N e u r o p h y s i o l . 12: 391-396, 1980. Koob, G.F. and T.W. Robbins. The r o l e of the m e s o l i m b i c dopamine system i n locomotor a c t i v i t y , e a t i n g and d r i n k i n g i n the r a t . I n : C a t e c h o l a m i n e s : B a s i c and C l i n i c a l  F r o n t i e r s , e d i t e d by E. U s d i n , I . J . K o p i n , and J . B a r c h a s . New York: Pergamon P r e s s , 1753-1755, 1979. K o s t o w s k i , W. , E. G i a c a l o n e , S. G a r a t t i n n i , and L. V a l z e l l i . S t u d i e s on b e h a v i o r a l a r o u s a l and b i o c h e m i c a l changes i n r a t s a f t e r l e s i o n of m i d b r a i n raphe. E u r . J . Pharmacol. 4: 371-376, 1968. K o s t o w s k i , W., E. G i a c a l o n e , S. G a r a t t i n n i , and L. V a l z e l l i . E l e c t r i c a l s t i m u l a t i o n of m i d b r a i n raphe: B i o c h e m i c a l , b e h a v i o r a l and b i o e l e c t r i c a l e f f e c t s . E u r . J . Pharmacol. 7: 170-175, 1969. K o s t o w s k i , W., R. Samanin, S.R. Baregge, V. Marc, S. G a r a t t i n i , and L. V a l z e l l i . B i o c h e m i c a l a s p e c t s of the i n t e r a c t i o n between m i d b r a i n raphe and l o c u s c o e r u l e u s i n the r a t . B r a i n Res. 82: 178-182, 1974. Kovacs, G.L., J . K i s h o n t i , K. L i s s a k , and G. T e l e g d y . I n h i b i t o r y a c t i o n of m i d b r a i n raphe s t i m u l a t i o n on s t r e s s -i n d u c e d e l e v a t i o n of plasma c o r t i c o s t e r o n e l e v e l . N e u r o s c i .  L e t t . 3/5-6: 305-310, 1976a. Kr u e g e r . A.P., P.C. A n d r i e s e , and S. K o t a k a . The' e f f e c t s of i n h a l i n g n o n - i o n i z e d or p o s i t i v e l y i o n i z e d a i r c o n t a i n i n g 2-4% C02 on the b l o o d l e v e l s of 5 - h y d r o x y t r y p t a m i n e i n mice. I n t . J . B i o m e t e r o l . 10/1: 17-28, 1966. 61 K r u e g e r . A.P., and S. K o t a k a . The e f f e c t s of a i r i o n s on b r a i n l e v e l s of s e r o t o n i n i n mice. I n t . J . B i o m e t e r o l . 13: 25-38, 1969. K r u e g e r , A.P. and R.F. Smith. The b i o l o g i c a l mechanisms of a i r i o n a c t i o n . Gen. P h y s i o l . 44: 269-276, 1960. L a v e n t y , R. and K.M. T a y l o r . E f f e c t s of i n t r a v e n t r i c u l a r 2 , 4 , 5 - t r i h y d r o x p h e n y l e t h y l a m i n e (6-hydroxydopamine) on r a t b e h a v i o u r and b r a i n c a t e c h o l a m i n e metabolism. Br i t . J .  Pharmacol. 40: 839-846, 1970. L e g e r , L. and L. D e a c a r r i e s . S e r o t o n i n nerve t e r m i n a l s i n the l o c u s c o e r u l e u s of a d u l t r a t : a r a d i o a u t o g r a p h i c s t u d y . B r a i n Res. 145: 1-13, 1978. L e w i s , B.D., B. Renaud, M. Buda, and J.-F. P u j o l . Time-co u r s e v a r i a t i o n s i n t r y o s i n e h y d r o x y l a s e a c t i v i t y i n the r a t l o c u s c o e r u l e u s a f t e r e l e c t r o l y t i c d e s t r u c t i o n of the n u c l e i raphe d o r s a l i s or raphe c e n t r a l i s . B r a i n Res. 108: 339-349, 1976. L i d o v , H.G.W., R. Grzanna, and M.E. M o l l i v e r . The s e r o t o n i n i n n e r v a t i o n of the c e r e b r a l c o r t e x i n the r a t — An immunohistochemical a n a l y s i s . N e u r o s c i . 5/2: 207-227, 1 980. Loewy, A.D. and S. M c K e l l a r . S e r o t o n e r g i c p r o j e c t i o n s from the v e n t r a l m e d u l l a t o the i n t e r m e d i o l a t e r a l c e l l column i n the r a t . B r a i n Res. 211: 146-152, 1981. L o r e n s , S.A. Some b e h a v i o r a l e f f e c t s of s e r o t o n i n d e p l e t i o n depend on method: A comparison of 5 , 7 - d i h y d r o x y t r y p t a m i n e , p - c h l o r o p h e n y l a l a n i n e , p-chloroamphetamine, and e l e c t r o l y t i c raphe l e s i o n s . I n : S e r o t o n i n N e u r o t o x i n s , A n n a l s of the N.Y. Acad. S c i . 305: 532-555, 1978. L o r e n s , S.A. and H.C. G u l d b e r g . R e g i o n a l 5 - h y d r o x y t r y p t a m i n e f o l l o w i n g s e l e c t i v e m i d b r a i n raphe l e s i o n s on the c a t . B r a i n Res. 78: 45-56, 1974. L o r e n s , S.A., H.C. G u l d b e r g , K. H o l e , C. K o h l e r , and B. S r e b r o . A c t i v i t y , a v o i d a n c e l e a r n i n g and r e g i o n a l 5-h y d r o x y t r y p t a m i n e f o l l o w i n g i n t r a - b r a i n stem 5,7-d i h y d r o x y t r y p t a m i n e and e l e c t r o l y t i c m i d b r a i n raphe l e s i o n s i n the r a t . B r a i n Res. 108: 97-113, 1976. L y n e s s , W.H. and K.E. Moore. D e s t r u c t i o n of 5-h y d r o x y t r y p t a m i n e r g i c neurons and the dynamics of dopamine i n n u c l e u s accumbens s e p t i and o t h e r f o r e b r a i n r e g i o n s of the r a t . Neuropharmacology 20: 327-334, 1981. McEwen, B.S., J.M. Weiss, and L.S. Schwartz. Uptake of c o r t i c o s t e r o n e by r a t b r a i n and i t s c o n c e n t r a t i o n by c e r t i a n l i m b i c s t r u c t u r e s . B r a i n Res. 16: 227-241, 1969. 62 McRae-Degueurce, A., A. Berod, A. Mermet, A. K e l l e r , G. Chouvet, T.H. J o h , and J.F. P u j o l . A l t e r a t i o n s i n t y r o s i n e h y d r o x y l a s e a c t i v i t y e l i c i t e d by raphe n u c l e i l e s i o n s i n the r a t l o c u s c o e r u l e u s : e v i d e n c e f o r the i n v o l v e m e n t of s e r o t o n i n a f f e r e n t s . B r a i n Res. 235: 285-301, 1982. Mabry, P.D. and B.A. Campbell. S e r o t o n e r g i c i n h i b i t i o n of c a t e c h o l a m i n e induced b e h a v i o r a l a r o u s a l . B r a i n Res. 49/2: 381-391, 1973. M a c k e n z i e , R.G., B.G. H o e b e l , C. N o r e l l i , and M.E. T r u l s o n . I n c r e a s e d t i l t - c a g e a c t i v i t y a f t e r s e r o t o n i n d e p l e t i o n by 5 , 7 - d i h y d r o x y t r y p t a m i n e . Neuropharmacology 17: 957-963, 1 978. Magazanik, L.G., P. I l l s c h , and V.A. Snetkov. E f f e c t s of s e r o t o n i n upon the v o l t a g e dependence of the e n d - p l a t e c u r r e n t of muscle f i b e r s . Doklady B i o l o g i c a l S c i e n c e s 227: 163-166, 1976. M a t l i n a , E. Sh. Main phases of c a t e c h o l a m i n e m e t a b o l i s m under s t r e s s . I n : C a t e c h o l a m i n e s and S t r e s s , e d i t e d by E. U s d i n , R. Kvetnansky, and I . J . K o p i n . New York: Pergamon P r e s s , 1976,p.353-365. M a t t e , A.C. and H. Tornow. P a r a c h l o r o p h e n y l a l a n i n e produces d i s s o c i a t e d e f f e c t s on a g g r e s s i o n , " e m o t i o n a l i t y " and motor b e h a v i o u r . Neuropharmacology 17: 555-558, 1978. Mayer, S. R e g u l a t i o n of c a r d i a c and s k e l e t a l muscle g l y c o g e n m e t abolism by b i o g e n i c amines. I n : B i o g e n i c Amines as  P h y s i o l o g i c a l R e g u a l t o r s , e d i t e d by J . J . Blum. Englewood C l i f f s , New J e r s y : P r e n t i c e - H a l l , I n c . , 139-159, 1970. Mayer, S.E., D.H. Nammi, and J.P. Hickenbottom. R e g u l a t i o n of the p h o s p h o r y l a s e a c t i v a t i n g pathway i n i n t a c t c a r d i a c and s k e l e t a l muscle. I n : Advances i n Enzyme R e g u l a t i o n , e d i t e d by G. Weber. O x f o r d : Pergamon P r e s s , 8: 205-216, 1970. M i l l e r , F.P. and R.P. M a i c k e l . The r o l e of b r a i n amines i n the b e h a v i o u r a l d e p r e s s i o n produced by a b e n z o q u i n o l i z i n e . L i f e S c i . 8 P a r t 1: 487-491, 1969. M i l l e r , M., R. Hasson, P . J . Morgane, and 0. R e s n i c k . A d r e n a l e c t o m y : i t s e f f e c t s on s y s t e m i c t r y p t o p h a n metabolism i n normal and p r o t e i n m a l n o u r i s h e d r a t s . B r a i n Res. 5: 451-459, 1980. Moberg, G.P. and C R . C l a r k . E f f e c t of adrenalectomy and dexamethasone treatment on c i r c a d i a n r u n n i n g i n the r a t . Pharmacol. Biochem. Behav. 4: 617-619, 1976. M o n n i e r , M. and R. T i s s o t . A c t i o n de l a r e s e r p i n e e t de . ses m e d i a t e u r s ( 5 - h y d r o x y t r y p t o p h a n - s e r o t o n i n e e t dopa-n o r a d r e n a l i n e ) sur l e comportement e t l e c e r v e a u du l a p i n . 63 H e l v . P h y s i o l . Pharmacol. A c t a 16: 255-267, 1958. Moore, R.Y., A.E. H a r i s , and B.E. Jones. S e r o t o n i n neurons of the m i d b r a i n raphe: a s c e n d i n g p r o j e c t i o n s . Comp.  N e u r o l . 180: 417-438,1978. Morgane, P . J. and M.S. J a c o b s . Raphe p r o j e c t i o n s of the l o c u s c o e r u l e u s i n the r a t . B r a i n Res. B u l l . 4/4: 519-534, 1 979. M y s l i n s k i , N.R. and E.G. Anderson. The e f f e c t of s e r o t o n i n p r e c u r s o r s on «- and v-motorneuron a c t i v i t y . J_;_ Pharmacol. 204: 19-26, 1978. N a f t c h i , N.E., M. Demeny, A. K e t e s z , and E.W. Lowman. The CNS and a d r e n a l t y r o s i n e h y d r o x y l a s e a c t i v i t y and n o r e p i n e p h r i n e , s e r o t o n i n and h i s t a m i n e i n the s p i n a l c o r d a f t e r t r a n s e c t i o n . Fed. P r o c . 31: 832, 1972. Nagat s u , T., M. L e v i t t , and S. U d e n f r i e n d . T y r o s i n e h y d r o x y l a s e . J ^ B i o l . Chem. 239: 2910-2917, 1964. N e i l l , D.B., L.D. G r a n t , and S.P. Grossman. S e l e c t i v e p o t e n t i a t i o n of locomotor e f f e c t s of amphetamine by m i d b r a i n raphe l e s i o n s . P h y s i o l . Behav. 9: 655-657, 1972. Newsholme, E.A. The r o l e of the f r u c t o s e 6 - p h o s p h a t e / f r u c t o s e d i p h o s p h a t e c y c l e i n m e t a b o l i c r e g u l a t i o n and heat g e n e r a t i o n . Biochem. Soc. Tr a n s . 4/6: 978-984, 1976. Newsholme, E.A. and C. S t a r t . R e g u l a t i o n i n M e t a b o l i s m . London: John W i l e y and Sons, 1973. N i c o l a o u , N.M., M. Garcia-Munoz, G.W. A r b u t h n o t t , and D. E c c l e s t o n . I n t e r a c t i o n between s e r o t o n e r g i c and dopaminergic systems i n r a t b r a i n demonstrated by s m a l l u n i l a t e r a l l e s i o n s of the raphe n u c l e i . E u r . J .  Pharmacol. 57: 295-305, 1979. O l i v e r a s , J . L . , S. B o u r g o i n , F. Hery, J.M. Besson, and M. Hamon. The t o p o g r a p h i c a l d i s t r i b u t i o n of s e r o t o n e r g i c t e r m i n a l s i n the s p i n a l c o r d of the c a t : B i o c h e m i c a l mapping by the combined use of m i c r o d i s s e c t i o n and m i c r o a s s a y p r o c e d u r e s . B r a i n Res. 138: 393-406, 1977. O l i v e r e a u , J.-M. I n f l u e n c e of v a r i a t i o n s of b a r o m e t r i c p r e s s u r e on the spontaneous a c t i v i t y i n the r a t ( F r e n c h ) . V e r g l . P h y s i o l . 72/4: 435-441, 1971. O l i v e r e a u , J.-M. I n f l u e n c e des i o n s atmospheriques n e g a t i f s sur l ' a d a p t a t i o n a une s i t u a t i o n anxiogene chez l e r a t . I n t . J . B i o m e t e r . 17: 277-284, 1973. Ol p e , H.-R. The c o r t i c a l p r o j e c t i o n of the d o r s a l raphe n u c l e u s : Some e l e c t r o p h y s i o l o g i c a l and p h a r m a c o l o g i c a l p r o p e r t i e s . B r a i n Res. 216: 61-71, 1981. 64 Palkovits, M. , M. Brownstein, and J.M. Saavedra. Serotonin content of the brain stem nuclei in the rat. Brain Res. 80: 237-249, 1974. Palkovits, M., J.M. Saavedra, D.M. Jacobowitz, J.S. Koizer, L. Zaborszky, and M.J. Brownstein. Serotonergic innervation of the forebrain: effect of lesions on serotonin and tryptophan hydroxylase. Brain Res. 130/1: 121-134, 1977. Parizek, J ., R. Hassler, and I.J. Bak. Light and electron microscopic audioradiography of substantia nigra of rat after i n t r a v e n t r i c u l a r administration of t r i t i u m l a b e l l e d norepinephrine, dopamine, serotonin and precursors. Z.  Ze l l f o r s c h . 115: 137-148, 1971. Pasguier, D.A. and F. Reinoso-Suarez. D i f f e r e n t i a l efferent connections of the brain stem to the hippocampus in the cat. Brain Res. 120: 540-548, 1977. Pataky, I. and A.K. P f e i f e r . Physiological significance of the acetyocholine blocking agent in the central nervous system. Acta Physiol. Acad. S c i . Hung. 8: 221-229, 1 955. Patkina, N.A. and I.P. Lapin. Effect of serotoninergic drugs on positive and negative reinforcing systems in cats. Pharmacol. Biochem. Behav. 5: 241-245, 1976, Pedersen-Bjergaard, K. and M. Tonnesen. The ef f e c t s of steroid hormones on muscular a c t i v i t y in rats. Acta  Endocrinoloqica 17: 329-337, 1954. Pellegrino, L.J. and A.J. Cushman. A Stereotaxic Atlas of the  Rat Brain. New York: Appleton-Century- Crofts, 1967. P f e i f e r , A.K. and I. Pataky. Acetylcholine blocking agent in the central nervous system. Acta Physiol. Acad. S c i .  Hung. 8: 209-219, 1955. P h i l l i s , J.W., A.K. Tebecis, and D.H. York. Histamine and some other antihistamines: Their action on cerebral c o r t i c a l neurones. Br i t . J. Pharmacol. 33: 426-440, 1968a. P h i l l i s , J.W., A.K. Tebecis, and D.H. York. Depression of spinal motorneurones by noradrenaline, 5-hydroxytryptamine and histamine. Eur. J. Pharmacol. 4: 471-475, 1968b. Pi c k e l , V.M., T.H. Joh, and D.J. Reis. A serotonergic innervation of noradrenenergic neurones in the locus coeruleus: demonstration by immunocytochemical l o c a l i z a t i o n of the transmitter s p e c i f i c enzymes tyrosine and tryptophan hydroxylase. Brain Res. 131: 197-214, 1977. Pijnenburg, A.J.J., W.M.M. Honig, J.A.M. Van der Heyden, and J.M. Van Rossum. Ef f e c t s of chemical stimulation of the 65 mesolimbic dopamine system upon locomotor a c t i v i t y . Eur.  Pharmacol. 35: 45-58, 1976. Pope, S.G., P. Dean, and P. Redgrave. Dissociation of d-amphetamine-induced locomotor a c t i v i t y and stereotyped behaviour by lesions of the superior c o l l i c u l u s . Psychopharmacology 70: 297-302, 1980. Proudfit, H.K. and E.G. Anderson. Blockade by serotonin antagonists of brain stem-evoked potentials recorded from spinal dorsal and ventral roots. Fed. Proc. 32: 303, 1 973. Pujol, J.-F., A. Buguet, J.-L. Froment, B. Jones, and M. Jouvet. The central metabolism of serotonin in the cat during insomnia. A Neurophysiological and biochemical study after administration of p-chlorophenylalanine or destruction of the raphe system. Brain Res. 29: 195-212, 1971. Pujol, J.F., .A. McRae- Degueurce, F. Crespi, P. Keane, B. Renaud, L. Leger, and M. Buda. Serotoninergic control of tyrosine hydroxlase (TH) and dopamine-b-hydroxylase (DBH) in the rat locus coeruleus (LC). In: Catecholamines: Basic and  C l i n i c a l Frontiers, edited by E. Usdin, I.J. Kopin, and J. Barchas. New York: Pergamon Press, 1979, p.52-54. Quirk, M. and T.L. Sourkes. Central dopaminergic and serotonergic systems in the regulation of adrenal tyrosine hydroxylase. J ^ Neurochem. 28: 137-147, 1977. Raleigh, M.J., G.L. Brammer, A. Y u i v i l e r , J.W. Flannery, M.T. McGuire, and E. G e l l e r . Serotonergic influences on the s o c i a l behavior of vervet monkeys (Ceropithecus aethiops sabaeus). Experimental Neurol. 68: 322-334, 1980. Reader, T.A. Serotonin d i s t r i b u t i o n in rat cerebral cortex: radioenzymatic assays with thin-layer chromatography. Brain  Res. B u l l . 5: 609-613, 1980. Reader, T.A., A. Ferron, L. Descarries, and H.H. Jasper. Modulatory role for biogenic amines in the cerebral cortex. Microiontophoretic studies. Brain Res. 160: 217-229, 1979. Renaud. B., M. Buda, B.D. Lewis, and J.-F. Pujol. E f f e c t s of 5,6-dihydroxytryptamine on tyrosine hydroxylase a c t i v i t y in central catecholaminergic neurons of the rat. Biochem.  Pharmacol. 24: 1739-1742, 1975. Richards, J.G., H.P. Lorez, and J.P. Tranzer Indolealkylamine nerve terminals in cerebral v e n t r i c l e s : i d e n t i f i c a t i o n by electron microscopy and fluorescence histochemistry. Brain  Res. 57: 277-288, 1973. Richardson, J.S. N. Cowan, R. Hartman, and D.J. Jacobowitz. On the behavioral and neurochemical actions of 6-hydroxydopa and 5,6-hydroxytryptamine in rats. Res. Commun. Chem. 66 P a t h . P h a r m a c o l . 8: 29-44, 1974. R i c h t e r , E.A., H. G a l b o , a nd N . J . C h r i s t e n s e n . C o n t r o l o f e x e r c i s e - i n d u c e d m u s c u l a r g l y c o g e n o l y s i s by a d r e n a l m e d u l l a r y hormones i n r a t s . J_;_ A p p l . P h y s i o l • ; R e s p i r a t .  E n v i r o n . E x e r c i s e P h y s i o l . 50: 21-26, 1981. R i n a l d i , P., M. S u t k o , J.H. Mahnke, a n d M. V e r z e a n o . S e r o t o n i n i n t h e l a t e r a l g e n i c u l a t e . P h y s i o l . B e h a v . 14/1: 9 5 - 1 0 2 , 1975. R o b e r g e , A.G. A m o r p h o l o g i c a l a n d b i o c h e m i c a l d i s s o c i a t i o n b e t w e e n dopamine a n d s e r o t o n i n i n c a t b r a i n . I n : C a t e c h o l a m i n e s : B a s i c a n d C l i n c a l F r o n t i e r s , e d i t e d by E. U s d i n , I . J . K o p i n , J . B a r c h a s . New Y o r k : Pergamon P r e s s , 2: 1979, 1110-1112. Romanes, G . J . The m o t o r c e l l c o l u m n s o f t h e l u m b o - s a c r a l s p i n a l c o r d o f t h e c a t . J ^ Comp. N e u r o l . 94: 3 1 3 - 3 6 3 , 1951. Ro m a n o w s k i , W. I I . S t u d i e s on t h e i n h i b i t o r y s u b s t a n c e e x t r a c t e d f r o m t h e b r a i n s o f r a t s s u b m i t t e d t o a c u t e p h y s i c a l e f f o r t . A c t a P h y s i o l . P o l . 18/2: 2 2 5 - 2 3 2 , 1967. Ro m a n o w s k i , W. and S. G r a b i e c . The r o l e o f s e r o t o n i n i n t h e m e c h a n i s m o f c e n t r a l f a t i g u e . A c t a P h y s i o l . P o l . 25/2: 127-134, 1974. Rom a n o w s k i , W. and J . J a n o t a - L u k a s z e w k a . I . S t u d i e s o f t h e i n h i b i t o r y s u b s t a n c e e x t r a c t e d f r o m t h e b r a i n s o f r a t s s u b m i t t e d t o a c u t e p h y s i c a l e f f o r t . A c t a P h y s i o l • P o l . 18/2: 2 1 5 - 2 2 3 , 1967. R o m m e l s p a c h e r , H. and S. S t r a u s s . E f f e c t o f l e s i o n s o f r a p h e n u c l e i on t h e a c t i v i t y o f c a t e c h o l a m i n e r g i c a n d s e r o t o n e r g i c n e u r o n e s i n v a r i o u s b r a i n r e g i o n s o f t h e r a t in v i v o . J .  N e u r a l T r a n s m i s s i o n 49: 51 - 6 2 , 1980. S a a v e d r a , J.M., H. G r o b e c k e r , a n d J . Z i v i n . C a t e c h o l a m i n e s i n t h e r a p h e n u c l e i o f t h e r a t . B r a i n R e s . 114: 339 - 3 4 5 , 1976. S a k a i , K., M. T o u r e t , D . S a l v e r t , L. L e g e r , a n d M. J o u v e t . A f f e r e n t p r o j e c t i o n s o f t h e c a t l o c u s c o e r u l e u s a s v i s u a l i z e d by t h e h o r s e r a d i s h p e r o x i d a s e t e c h n i q u e . B r a i n R e s . 119: 2 1 - 4 1 , 1976. S a s t r y , B.S.R. and J.W. P h i l l i s . M e t e r g o l i n e a s a s e l e c t i v e 5 - h y d r o x y t r y p t a m i n e a n t a g o n i s t i n t h e c e r e b r a l c o r t e x . C an.  P h y s i o l . P h a r m a c o l . 55: 130-133, 1977a. S a s t r y , B.S.R. and J.W. P h i l l i s . I n h i b i t i o n o f c e r e b r a l c o r t i c a l n e u r o n e s by a 5 - h y d r o x y t r y p t a m i n e r g i c p a t h w a y f r o m m e d i a n r a p h e n u c l e u s . C an. J . P h y s i o l . P h a r m a c o l . 55: 7 3 7 - 7 4 3 , 1977b. 67 Satoh, K. The o r i g i n of r e t i c u l o s p i n a l f i b e r s i n the r a t : A HRP s t u d y . H i r n f o r s c h . 20: 31 3-332, 1979. S c h i l d k r a u t , J . J . and S.S. K e t y . B i o g e n i c amines and e m o t i o n . S c i e n c e 156: 21-30, 1967. Schimmel, R.J. The r o l e of c a l c i u m i o n i n e p i n e p h r i n e a c t i v a t i o n of l i p o l y s i s . Horm. Metab. Res. 8: 195-201, 1 976. S c h r e i b e r , G.O.S. Space charge and a t m o s p h e r i c p r e s s u r e . I n t .  J . B i o m e t e o r . 11 S u p p l . 3 : 323, 1967. Seeman, P., K. Westman, D. C a s c i n a , and J . J . Warsh. S e r o t o n i n r e c e p t o r s i n hippocampus and f r o n t a l c o r t e x . E u r . J . Pharmacol. 66: 179-191, 1980. S e g a l , M. P h y s i o l o g i c a l amd p h a r m a c o l o g i c a l e v i d e n c e f o r a s e r o t o n e r g i c p r o j e c t i o n t o the hippocampus. B r a i n Res. 94/1: 115-131, 1975. S e g a l , M. The a c t i o n of s e r o t o n i n i n the r a t hippocampal s l i c e p r e p a r a t i o n . J ^ P h y s i o l . (London). 303: 423-439, 1980. S e g a l , M. R e g i o n a l d i f f e r e n c e s i n n e u r o n a l r e s p o n s e s t o 5-HT: I n t r a c e l l u l a r s t u d i e s i n hippocampal s l i c e s . P h y s i o l . ( P a r i s ) 77: 373-375, 1981. Segu, L. and A. C a l a s . The t o p o g r a p h i c a l d i s t r i b u t i o n of s e r o t o n e r g i c t e r m i n a l s i n the s p i n a l c o r d of the c a t : q u a n t i t a t i v e r a d i o a u t o g r a p h i c s t u d i e s . B r a i n Res. 153: 449-464, 1978. Semenova, T.P., V.A. Ivanov, and T.M. T r e t ' y a k . B r a i n l e v e l s of n o r a d r e n a l i n , dopamine, and s e r o t o n i n i n r a t s w i t h d i f f e r e n t l e v e l s of motor a c t i v i t y . N e u r o s c i . Behav.  P h y s i o l . 11: 153-155, 1981. Sharma, J.N. M i c r o i o n t o p h o r e t i c a p p l i c a t i o n of some monoamines and t h e i r a n t a g o n i s t s t o c o r t i c a l neurones of the r a t . Neuropharmacol. 16/2: 83-88, 1977. Shimuzu, K., T. Yamamoto, and J . O c h i . P r o j e c t i o n p a t t e r n s of the b r a i n stem s e r o t o n e r g i c neurons i n the c e n t r a l nervous system of the r a t . N e u r o s c i e n c e L e t t e r s Supp. 6: S18, 1981. S r e b r o , B. and S.A. L o r e n s . B e h a v i o u r a l e f f e c t s of s e l e c t i v e m i d b r a i n raphe l e s i o n s i n the r a t . B r a i n Res. 89: 303-325, 1 975. S t e i n , L and C D . Wise. S e r o t o n i n and b e h a v i o u r a l i n h i b i t i o n . In:' S e r o t o n i n - New V i s t a s , Advances i n B i o c h e m i c a l Pharmacology, e d i t e d by E. C o s t a , G.L. Gessa, and M. S a n d l e r . 11: 281-291, 1974. 68 S t e w a r t , R.M., J.H. Growdon, D. C a n c i a n , and R.J. B a l d e s s a r i n i . 5- H y d r o x y t r y p t o p h a n - i n d u c e d myoclonus: i n c r e a s e d s e n s i t i v i t y t o s e r o t o n i n a f t e r i n t r a c r a n i a l 5,7-d i h y d r o x y t r y p t a m i n e i n the a d u l t r a t . Neuropharmacol. 15: 449-455, 1976. Svendgaard, N.A., A. B j o r k l u n d , and U. S t e n e v i . R e g e n e r a t i v e p r o p e r t i e s of c e n t r a l monoamine neurons. Advances i n  Anatomy, Embryology, and C e l l B i o l o g y 5 1 / ( 4 ) : 1-77, 1975. Svenson, T., B.S. Bunney, and G.R. A g h a j a n i a n . I n h i b i t i o n of both n o r a d r e n e r g i c and s e r o t o n e r g i c neurons i n b r a i n by the «c-agonist c l o n i d i n e . B r a i n Res. 92: 291-306, 1975. S z a b a d i , E., E.M. Bradshaw, and P. Bevan. E x c i t a t o r y and d e p r e s s a n t n e u r o n a l responses t o n o r a d r e n a l i n e and 5-h y d r o x y t r y p t a m i n e and m e s c a l i n e : the r o l e of the b a s e l i n e f i r i n g r a t e . B r a i n Res. 126: 580-583, 1977. • S z a f a r c z y k , A., G. A l o n s o , G. I x a r t , F. M a l a v a l , J . N o u g u i e r - S o u l e , and I . Assenmacher. S e r o t o n e r g i c system and c i r c a d i a n rhythms' of ACTH and c o r t c o s t e r o n e i n r a t s . Am. P h y s i o l . 239: E482-E487, 1980. Sze, P.Y. G l u c o c o r t i c o i d r e g u l a t i o n of the s e r o t o n e r g i c system of the b r a i n . I n : Advances i n B i o c h e m i c a l Psychopharmacology, e d i t e d by E. C o s t a , E. G i a c o b i n i , and R. P a o l e t t i . New York: Raven P r e s s , 15: 251-265, 1976. T a k a s h i , K. and T. Kuga. Role of b r a i n monamine systems i n the jumping b e h a v i o r i n d u c e d i n r a t s by the c o m b i n a t i o n of harmine and apomorphine. Japan. J . Pharmacol. 31: 677-688, 1981. T h i e r r y , A.-M., M. F e k e t e , and J . G l o w i n s k i . E f f e c t s of s t r e s s on the metabolism of n o r a d r e n a l i n e , dopamine and s e r o t o n i n (5HT) i n the c e n t r a l nervous system of the r a t . ( I I ) M o d i f i c a t i o n s of s e r o t o n i n m e tabolism. E u r . J .  Pharmacol. 4: 384-389, 1968. Tohyama, M., K. S a k a i , M. T o u r e t , D. S a l v e r t , and M. J o u v e t . S p i n a l p r o j e c t i o n s from the lower b r a i n stem i n the c a t as demonstrated by the h o r s e r a d i s h p e r o x i d a s e t e c h n i q u e . I I . P r o j e c t i o n s from the d o r s o l a t e r a l p o n t i n e tegmentum and raphe n u c l e i . B r a i n Res. 176: 215-231, 1979. T o r s k a y a , I.V. and V.N. Goloborod'ko. R e l a t i v e amount of neurons w i t h d i f f e r e n t t r a n s m i t t e r m e t a b o l i s m i n the motor n u c l e i of c a t c e r v i c a l s p i n a l c o r d ( R u s s . ) . N e i r o f i z i o l o g i y a 9/2: 191-197, 1977. T r u l s o n , M.E. and B.L. J a o c b s . B e h a v i o r a l e v i d e n c e f o r d e n e r v a t i o n s u p e r s e n s i t i v i t y a f t e r d e s t r u c t i o n of c e n t r a l s e r o t o n e r g i c nerve t e r m i n a l s . I n : S e r o t o n i n N e u r o t o x i n s N.Y. Acad. S c i . 305: 497-509, 1978. 69 T r u l s o n , M.E. and B.L. J a c o b s . E f f e c t s of 5-methoxy-N,N-d i m e t h y l t r y p t a m i n e on b e h a v i o r and raphe u n i t a c t i v i t y i n f r e e l y moving c a t s . Eur. J . Phamacol. 54: 43-50, 1979a. T r u l s o n , M.E. and B.L. J a o c b s . Raphe u n i t a c t i v i t y i n f r e e l y moving c a t s : c o r r e l a t i o n w i t h l e v e l of b e h a v i o r a l a r o u s a l . B r a i n Res. 163: 135-150, 1979b. T r u l s o n , M.E. and B.L. J a c o b s . A c t i v i t y of s e r o t o n i n -c o n t a i n i n g neurons i n f r e e l y moving c a t s . I n : S e r o t o n i n  N e u r o t r a n s m i s s i o n and B e h a v i o r , e d i t e d by B.L. Jacobs and A. G e l p e r i n . Cambridge, M a s s a c h u s e t t s : MIT P r e s s , 1981, 339-365. U n g e r s t e d t , U. S t e r e o t a x i c mapping of the monoamine pathways i n the r a t b r a i n . A c t a P h y s i o l . Scand. S u p p l . 367: 1-48, 1971. Unvas, B. 2. The mechanism of h i s t a m i n e r e l e a s e from mast c e l l s . I n : H i s t a m i n e 11 and A n t i - H i s f a m i n e s . Handbook of  E x p e r i m e n t a l Pharmacology, e d i t e d by M. Rocha e S i l v a . 18/2: 75-92, 1978. Uzbekov, M.G., S. Murphy, and S.P.R. Rose. O n t o g e n e s i s of s e r o t o n i n ' r e c e p t o r s ' i n d i f f e r e n t r e g i o n s of r a t b r a i n . B r a i n Res. 168/1: 195-199, 1979. Van de Kar, L.D. and S.A. L o r e n s . D i f f e r e n t i a l s e r o t o n e r g i c i n n e r v a t i o n of i n d i v i d u a l h y p o t h a l a m i c n u c l e i and o t h e r f o r e b r a i n r e g i o n s by the d o r s a l and median raphe n u c l e i . B r a i n Res. 162: 45-54, 1979. Van Woert, M.H. and V.H. Sethy. Therapy of i n t e n t i o n myoclonus w i t h L - 5 - h y d r o x y t r y p t o p h a n and a p e r i p h e r a l d e c a r b o x y l a s e i n h i b i t o r , MK 486. Neurology 25: 135-149, 1975. Vermes, I . , P.G. S m e l i k , and A.H. M u l d e r . E f f e c t s of hypophyectomy, adrenalectomy and c o r t i c o s t e r o n e t r e a t m e n t on uptake and r e l e a s e of p u t a t i v e c e n t r a l n e u r o t r a n s m i t t e r s by r a t h y p o t h a l a m i c t i s s u e i_n v i t r o . L i f e S c i . 19/11: 1719-1726, 1976. Waldmeier, P.C., R. Kam, and L. M a i t r e . Dopamine-serotonin i n t e r a c t i o n s i n the n i g r o - s t r i a t a l feedback l o o p . I n : C a t e c h o l a m i n e s : B a s i c and C l i n i c a l F r o n t i e r s , e d i t e d by E. U s d i n , I . J . K o p i n , and J . B a r c h a s . New York: Pergamon P r e s s , 2: 1979, p. 1104-1106. W a r b r i t t o n , J.D. I l l , R.M. S t e w a r t , and R.J. B a l d e s s a r i n i . Decreased locomotor a c t i v i t y and a t t e n u a t i o n of amphetamine h y p e r a c t i v i t y w i t h i n t r a v e n t r i c u l a r i n f u s i o n of s e r o t o n i n i n the r a t . B r a i n Res. " 143/2: 373-382, 1978. Weiss, B.L. and G.K. A g h a j a n i a n . A c t i v a t i o n of b r a i n s e r o t o n i n m e tabolism by h e a t : r o l e of m i d b r a i n raphe 70 neurons. B r a i n Res. 26: 37-48, 1971. Weiss, B. and V.G. L a t i e s . B e h a v i o u r a l pharmacology and t o x i c o l o g y . Ann. Rev. Pharmacol. 9: 297-326, 1969. Westermann, K.H., K. Funk, and L. P a w l o w s k i . E f f e c t s of harmine and b r a i n l e s i o n s on apomorphine induced motor a c t i v i t y . Pharmacol. Biochem. Behav. 4: 1-6, 1976. Whit e , S.R. and R.S. Neuman. F a c i l i t a t i o n of s p i n a l m o t o n e u r o n s e x c i t a b i l i t y by 5 - h y d r o x y t r y p t a m i n e and n o r a d r e n a l i n e . B r a i n Res. 188: 119-127, 1980. W i k l u n d , L., A. B j o r k l u n d , and A. Nobin. R e g e n e r a t i o n of s e r o t o n i n neurons i n the r a t b r a i n a f t e r 5,6-d i h y d r o x y t r y p t a m i n e - i n d u c e d axotomy. I n : S e r o t o n i n N e u r o t o x i n s , N.Y. Acad. S c i . , 305: p. 370-384, 1978. Winsor, T., and J.C. B e c k e t t . B i o l o g i c a l e f f e c t s of i o n i z e d a i r i n man. Am. J . P h y s i c a l Med. 37: 83-89, 1958. Wong, D.T., F.P. Bymaster, J.S. Horng, and B.B. M a l l o y . A new s e l e c t i v e i n h i b i t o r f o r uptake of s e r o t o n i n i n t o synaptosomes of r a t b r a i n : 3- ( p - t r i f l u o r o m e t h y l p h e n o x y ) - N -m e t h y l - 3 - p h e n y l p r o p y l a m i n e . Pharm. 193: 804-811, 1975. Woolf, C.J., H.P. La b u r n , G.H. W i l l i e s , and C. Rosendorf. Hypothalamic h e a t i n g and c o o l i n g i n monoamine d e p l e t e d r a t s . Amer. P h y s i o l . 228/2: 569-574, 1975. 

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