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Involvement of dopamine in feeding behaviours Blackburn, James Robert 1985

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INVOLVEMENT OF DOPAMINE IN FEEDING BEHAVIOURS by JAMES ROBERT BLACKBURN B.Sc, McGill Universtity, 1983  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF ARTS  in THE FACULTY OF GRADUATE STUDIES Department of Psychology  We accept this thesis as conforming to the required standard  THE UNIVERSITY OF BRITISH COLUMBIA October, 1985 • James Robert Blackburn, 1985  In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, 1 agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives.  It is understood that copying or  publication of this thesis for financial gain shall not be allowed without my written permission.  J . R. Blackburn  Department of  Psychology  The University of British Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 D a t e  DE-6(3/81)  October 11, 1985  ABSTRACT  This study investigated feeding behaviours. responses.  A conditioned  dopamine in  feeding paradigm was used to study incentive  After conditioning rats responded to a conditional stimulus (CS+) by  approaching a feeding 0.6mg/kg  the involvement of the neurotransmitter  site.  of the dopamine  Approach responses were attenuated antagonist  pimozide.  revealed that exposure to the CS+ increased  Neurochemical  by 0.4 or investigation  dopamine turnover in the forebrain.  Thus, dopamine appears to be actively involved in the initiation of appetitive responses.  In contrast, another experiment indicated that consumption of a liquid  diet was not altered by up to 0.6mg/kg pimozide. These data were interpreted as supporting an "incentive-response hypothesis" of dopamine function, which states that "When an animal observes an incentive stimulus, the release of dopamine in the forebrain is increased, resulting in approach to the stimulus by the animal. Once the animal is in contact with a goal object, consummatory reactions occur which are not mediated by dopamine systems".  A final experiment investigated  the activity of dopamine systems following ingestion. After one hour during which food  pellets or liquid  diet were  available  to rats, dopamine turnover  increased in the n. accumbens and the striatum, relative to non-fed animals. increase quantities  was  observed  of saccharin  in the brains solution.  of rats  Thus,  which  had consumed  the increase  observed  was No  similar  following  consumption of pellets or liquid diet could not be attributed to motor or "reward" effects.  It was concluded that in addition to their involvement in incentive-  responding, dopamine systems are also affected by the ingestion of nutrients.  Dr. A.G. Phillips ' ii  T A B L E OF CONTENTS  Abstract  ii  List of Tables  v  List of Figures  vi  Acknowledgement  viii  Introduction  1  Reduction of feeding by dopamine lesions  5  Pharmacological blockade of dopamine receptors  8  Feeding induced by dopaminergic stimulation  10  Correlatons between feeding and dopamine release  15  Motivational interpretations of dopamine's role in feeding  28  Experiment 1  41  Methods  42  Results  45  Discussion  63  Experiment 2  65  Methods  66  Results  67  Discussion  73  Experiment 3  76  Methods  76  Results  77  Discussion  77  Experiment 4  81  Methods  82 iii  Results Discussion General Discussion, Conclusions References  LIST OF T A B L E S  Table I.  Concentrations of dopamine, DOPAC and HVA in various brain regions  of rats sacrificed before or after exposure to the CS+  Table II.  72  Concentrations of dopamine, DOPAC and HVA in various brain regions  of rats exposed to various feeding conditions  v  89  LIST OF FIGURES  Figure  1:  Cumulative  time  spent  in niche during CS+  period  by animals  receiving 0.6% tartaric acid vehicle on test day  Figure 2:  Cumulative  time spent  47  in niche during CS+  period  by animals  receiving 0.2mg/kg pimozide on test day  Figure  3:  Cumulative  time  49  spent in niche during CS+  period  by animals  receiving 0.4mg/kg pimozide on test day  Figure 4:  Cumulative  time spent  51  in niche during CS+  period  by animals  receiving 0.6mg/kg pimozide on test day  53  Figure 5: Mean latency to enter niche following CS+ onset  55  Figure 6: Mean number of nosepokes during CS+ period prior to onset of food delivery  57  Figure 7: Mean area under the cumulative response curve during CS+ prior to onset of food delivery  Figure 8:  59  Mean number of entries i n to feeding niche during CS+  following first entry but prior to onset of food  vi  delivery  period, 61  Figure 9:  D O P A C / D A ratios, in each of the three brain regions analyzed, after  the rats had been exposed to the CS+ for four minutes  Figure 10:  H V A / D A ratios, in each of the three brain regions analyzed, after  the rats had been exposed to the CS+ for four minutes  Figure 11:  79  DOPAC/DA ratios, in each of the three brain regions analyzed, one  hour after the onset of various feeding treatments  Figure 13:  71  Consumption of liquid diet in a twenty minute session four hours  after the injection of pimozide or vehicle  Figure 12:  69  86  H V A / D A ratios, in each of the three brain regions analyzed, one  hour after the onset of various feeding treatments  vii  88  ACKNOWLEDGEMENTS  Many people have given their kind assistance to me in preparing this work. Fritz  Le Paine  devoted  much  effort to setting  up the conditioned feeding  apparatus and in writing the software for it's control. dissections for the neurochemistry analyses.  He also performed the  Lisa Wong was most helpful in her  work on the feeding experiments. Neurochemical analyses were performed by Alex Jakubovic and Davina Lin. My advisor, Tony Phillips, has been very supportive throughout the entire study.  I would like to extend special thanks to Jake and  Linda for their inspiration and encouragement.  viii  INTRODUCTION  An adequate neurological analysis of behaviour must begin with an adequate description of theory,  in  principle.  behaviour  practice  experimental psychology  the  it  is  expediency. of  It  feeding  to  be  often Thus,  suffers  analyzed.  forgotten much  from  or  of  a  Although this  the  laid  aside  literature  failure  to  is simply not possible to determine  is recognized in for  on the  recognize  the  this  the  sake  of  physiological fundamental  neurological substrate  of  "feeding" if "feeding" is variously defined as operating the mouth and tongue in certain  ways,  ingesting  a  quantity  of  food,  gaining  weight,  contacting  food-related cue or performing an operant response for food reward.  a  Clearly such  events are distinguishable at a behavioural level, and will often refer to different underlying neurological events.  In order to relate these neurobiological events to  behaviour it is neccessary to be sure which behaviours they are being related to. One  strategy  available  in  describing feeding  behaviour into a series of separate stages.  is  to  fractionate  feeding  Although some stages may eventually  collapse or meld into each other, their tentative identification  at least provides  more managable units to which neurological enquiry can be directed. A  first  recognize  two  consummatory  step  in  broad  establishing categories:  behaviours  a  taxonomy  Preparatory  (Sherrington,  1906;  of  (or Craig,  "feeding  behaviours"  "appetitive") 1918).  behaviours,  Woodworth  these in his book Dynamic Psychology. A consummatory reaction is one of direct value to the animal - one directly bringing satisfaction - such as eating or escaping from danger. The objective mark of a consummatory reaction is that it terminates a series of acts, and is followed by rest or perhaps a shift to some new series... The preparatory reactions are only mediately of benefit to the organism, and their value lies in the fact that they  -1 -  is  to and  defined  lead to, and make possible, a consummatory reaction. Objectively, the mark of a preparatory reaction is that i t occurs as a preliminary stage in a series of acts leading up to a consummatory reaction. (Woodworth, 1918, p. 40) In addition to these two categories, which result in the ingestion of food, it is also necessary to recognize an additional two types of "feeding behaviour". The first of these is the cessation of feeding, or the commencement of satiety. The  second is the post-prandial period or intermeal interval, during which the  animal  is not feeding,  behaviours.  and is not engaging  in appetitive, feeding-related  These four catagories will now be examined in more detail.  Appetitive reactions are performed in the absence of food.  These can be  divided into three classes: general activity, approach, and procurement.  These  distinctions serve a heuristic function, and are logically distinct even i f they are not ethologically or neurologically valid.  The first of these, general activity, is  characterized by increased levels of locomotion and exploration. Because activity levels are higher with increasing time since the animal last fed, some relationship beween feeding and activity may be inferred, even i f not a l l activity is actually involved in feeding.  Approach behaviour  can be defined either as taxis towards  food or food related cues (Schneirla, 1959) or as increased time spent in their vicinity.  For the rat, examples of approach reactions include directed sniffing of  food odours, orienting to a light that signals imminent food reward (Holland 1977) or running down an alley toward food.  The third class of appetitive behaviour,  procurement, is defined as the performance of responses which result in the availability of food.  An operant response, such as a lever press, which  occurs  more often when i t is reliably followed by the presentation of a food pellet, will serve as an example of a procurement reaction. Obviously, running down an alley for  food may fall into this category as well as into "approach".  -2 -  Rather than  discarding the distinction between these classes, it should simply be accepted that some responses may  be considered as belonging to one, the other, or both  classes, depending on the context in which they occur. Consummatory feeding reactions are defined as those that occur after the animal has made contact with the food and that result in it's ingestion. Because is does not immediately  lead to ingestion, hoarding behaviour  is tentatively  identified as a naturally-occuring procurement response, even though the animal comes into direct contact with the food.  Biting, lapping, chewing and swallowing  are clear examples of consummatory responses.  The  handling of food as the  animal eats it shall also be considered to be a member of this class.  Typically,  consummatory behaviours occur in "bouts": Brief bursts of constant contact with the food (handling or eating) punctuated by other behaviours not directly tied to feeding, such as grooming. This  classification  of feeding behaviours  is still  incomplete.  As  the  consummatory reaction advances, the animal has consumed more and more food. At some point, the consumption must cease.  Often neglected, the problem of  satiety is as central to an analysis of feeding as are the problems of appetite and consumption (Smith and Gibbs, 1979). In addition to technical issues, such as the question of what physiological or psychological events bring feeding to a halt, satiety raises conceptual issues.  For example, should satiety be considered  simply as the end of feeding, or as the beginning of the post-prandial period? Both perspectives have some merit: At some point the food is no longer a sufficent stimulus to maintain feeding, while other stimuli beckon the animal to move on. Finally, the classification of feeding behaviour should include a description of the inter-meal period. After an animal has moved away from it's food, it is - 3 -  generally unresponsive to food and food-related stimuli.  This unresponsiveness is  not complete: if the animal is presented with fresh food, particularly a different food, the animal may begin eating again. Still, the animal is not as responsive to food in the inter-meal period as after a day of food deprivation. Historically, such unresponsiveness  was interpreted as reflecting an absence of hunger, but  logically it may equally well reflect  the presence  of active inhibition.  For  example, the terminal sensillae of blowflies are inhibited by a diuretic hormone, released by the osmotic actions of food, for an hour or more following the ingestion  of  a large meal.  Reducing sensory  input appears  to  reduce  the  probability of further feeding during this period (Bernays and Simpson, 1982). This analysis  provides only a crude outline  behavioural regulation of feeding.  of  the  intricacies  of  the  It does, however, provide a somewhat more  detailed account than is commonly employed as a basis for investigations of the neurobiological substrates of feeding.  As such it may provide a framework for a  modest advance in our understanding of these substrates. This thesis will begin by examining the experimental evidence accumulated to date concerning the involvement of the  neurotransmitter dopamine in the  various stages of feeding behaviour outlined above.  Dopamine is believed to play  a central role in feeding, yet at present there are few clearly articulated views regarding the nature of this role, and little consensus between these views. Consequentally, several theories of dopamine function shall then be critically examined in the light of the evidence reviewed.  As well, additional experimental  evidence relevant to the evaluation of these theories shall be presented and suggestions offered for their further development.  -4 -  REDUCTION OF FEEDING BY DOPAMINE LESIONS Lesions of the lateral hypothalamus (LH) result in severely reduced food intake (Anand and Brobeck, 1951). Complete aphagia is often observed after such lesions: Animals may  refuse food even when i t is placed in their mouths.  The  animals are also completely adipsic, refusing to drink water. If left on their  own,  such animals usually die.  However, i f kept alive through gastric intubation of  food they often gradually recover much of their normal behaviour (Teitlebaum and Stellar, 1954).  However, even after "recovery", the animal does not display fully  normal feeding. For example, i t will only drink water at meal times. "Recovered" animals are exceptionally "finicky" in their food selection: Highly palatable foods are  consumed  in considerably greater quantities  than  standard  chow, while  quinine-adulterated food is strongly avoided (Teitlebaum and Epstein 1962). Stellar  (1954),  in  his  classic  dual-hypothalamic  model  of  motivated  behaviours, attributed these deficits to damage of the brain's "feeding centre", said to be located in the LH. damage observed  could be  However, later work indicated that much of the  attributed  to the  through the LH (eg., Morgane, 1961a,b).  destruction  of fibres coursing  Among the fibre tracts damaged by  lesions are several ascending catecholamine (CA) systems.  LH  These include the  dorsal and ventral noradrenaline (NA) bundles, plus the so-called "mesolimbic" and nigrostriatal dopamine (DA) bundles.  The  "mesolimbic" dopamine system has its  cell bodies in the ventral tegmental area (VTA), and projects to many di- and telencephalic sites.  The heaviest innervation is of the n. accumbens, while other  projection sites include amygdala, olfactory tubercle, prefrontal cortex, septum and  globus  pallidus.  The  nigrostriatal  bundle  (NSB)  originates  in the  compacta of the substantia nigra (SN) and projects to the neostriatum. systems have been extensively described by Fallon and Moore (1978). - 5 -  pars Both  A link between the L H syndrome and destruction of ascending catecholamine systems was first indicated by Heller and Harvey (1963) and Moore and Heller (1967), who noted that lesions of the L H resulting in aphagia reduce brain levels of noradrenaline.  Oltmans and Harvey (1972) found that the extent of behavioual  disruption produced  by lesions of the NSB at the level of the L H was highly  correlated with the extent of the striatal catecholamine depletion. Ungerstedt  (1971b)  employed  the  catecholamine-selective neurotoxin  6-hydroxydopamine (6-OHDA) to investigate the possibility that aspects of the syndrome associated with catecholamine produced Such  L H lesions could be attributed to loss of forebrain  innervation.  Injections  of 6-OHDA  into  the substantia  aphagia similar to that seen following electrolytic lesions of the LH.  deficits  were  noradrenaline fibres.  not observed  following  6-OHDA  lesions  of ascending  The case for attributing L H lesion-induced deficits was  strengthened by Zigmond and Strieker (1972; Strieker and Zigmond, 1974). found  nigra  that  pretreatment  of animals  with  the monoamine  oxidase  They  inhibitor  pargyline, or pretreatment with both pargyline and desmethylimipramine  (DMI),  which resulted in 95-99% dopamine depletions while lowering noradrenaline levels by less than 5%, were highly effective in producing prolonged aphagia.  Recovery  of function, i n parallel with that seen following L H lesions, was observed by Fibiger, Zis and McGeer (1973), and was attributed to compensatory  increases in  the nigrostriatal system, such as post-synaptic receptor supersensitivity (Strieker and Zigmond, 1974).  Similar lesions have been observed to attenuate not only  consummatory, but also approach responding, which may be viewed as a form of appetitive feeding behaviour.  Fibiger, Phillips and Zis (1974) found that injection  of 6-OHDA into the substantia nigra completely prevented acquisition of a goal box approach response, even though the animals were no longer aphagic.  - 6 -  Lesions of the nigrostriatal dopamine projection consistently produce aphagia (eg., Oltmans  and Harvey,  1972; Fibiger,  Zis and McGeer,  1973; Marshall,  Richardson and Teitlebaum, 1974; see Strieker and Zigmond, 1976 for review). On the other hand, lesions of the mesolimbic dopamine system severe  disruption  of food  intake.  Although  Ungerstedt  do not result in  (1971b) found  that  injections of 6-OHDA into the VTA, the origin of this projection, did result in aphagia, the deficits  induced  by this treatment may have  been  caused by  incidental NSB damage, as almost no dopamine terminals could later be observed in the neostriatum. Ungerstedt only observed transient deficits when he lesioned the  pathway  dopamine from  more anteriorly, despite the almost  complete  the n. accumbens and olfactory tubercle.  disappearance of 6-OHDA lesions of  mesolimbic terminal sites, specifically the n. accumbens and olfactory tubercle, have actually been reported to increase feeding i n 30 minute sessions (Koob, Riley, Smith and Robbins, 1978). feeding have been found  In general, no significant decreases i n ad lib  following comparable  lesions (eg., Le Moal, Stinus,  Simon, Tassin, Thierry, Blanc, Glowinski and Cardo, Kelley and Stinus, 1985).  1977; Koob et a l ,  1978;  Curiously, such lesions appear to result i n sloppier  feeding: The animals spill more food through the floors of their cages (Le Moal et al, 1977) and leave more partially eaten pellets (Kelley and Stinus, 1985). In contrast to the lack of effect 6-OHDA injections into the V T A or n. accumbens have on free feeding, they dramatically reduce the hoarding of food by hungry rats (Le Moal et a l , 1977; Kelley and Stinus, 1985).  Thus although  nigrostriatal lesions disrupt both appetitive and consummatory feeding behaviours mesolimbic lesions appear to preferentially disrupt food procurement.  -7 -  PHARMACOLOGICAL  BLOCKADE OF DOPAMINE  RECEPTORS  If the nigrostriatal dopamine pathway is a necessary substrate of normal feeding behaviour, pharmacological blockade of dopamine transmission would also be expected to disrupt feeding. Compared to the consistent and profound effects of 6-OHDA lesions on feeding, the evidence on this point is suprisingly weak and inconsistent.  However, some reports have noted attenuated feeding following  administration of these drugs.  For example, Heffner, Zigmond and Strieker (1977)  found decreased food intake over l h when rats which had been deprived of food overnight were treated with the dopamine antagonist spiroperidol. Blundell and Latham (1978) provide interesting perspectives on the nature of the  feeding  deficit  produced  by  pimozide,  a  relatively  specific  dopamine  antagonist (Jansenn, Niemegeers, Schellekens, Breese, Lenaerts, Pinchard, Schgre, van Neuten and Verbrugger, 1968).  Rats deprived of food for 16h were allowed  access to food pellets 2h after the injection of 0.45mg/kg pimozide.  Over the  course of the next l h period food intake by these animals was 3 5 % less than that of controls.  Mean latency to begin feeding was not significantly reduced: I t  remained less than one minute. Feeding rate, while the animals were feeding, was reduced by half, although the number of feeding bouts remained constant.  The  duration of bouts was actually increased. Thus, the animals took longer to eat less. Tombaugh,  Tombaugh  and  Anisman  following injection of l.Omg/kg pimozide. Noyes pellets in their home cages.  (1979)  observed  different  effects  Animals were presented with five 45mg  Latency to begin feeding was increased  seven-fold by pimozide treatment, but the time required to consume the pellets, once feeding began, was not increased. Tombaugh et a l also found that the time required  to finish  consuming  a l l the pellets - 8-  after  feeding had begun  was  unaffected by pimozide.  Again, the primary deficit in feeding was  food procurement, rather than one of food consumption.  one involving  Note, however, that the  consumption time referred to here applies to a restricted meal of five 45mg pellets.  In contrast, Blundell and  Latham (1978) observed slower feeding over  several bouts in a one hour test.  More recently, Wise and Colle (1984) offered  rats five Noyes pellets every 36  seconds and  recorded both latency to begin  feeding and the total time to consume a l l pellets. were increased rapidly was  by  l.Omg/kg pimozide.  A  Mean latencies and  durations  general deficit in ability to respond  not observed: More pimozide treated rats exhibited short latencies to  begin feeding than did controls. It  is  methodological  difficult  to  integrate  these  studies  due  to  their  pronounced  differences. Their only point of agreement is the net disruption of  feeding by dopamine blockade, through increased latency to begin feeding or a decreased feeding rate.  However, other studies have failed to confirm even this.  Indeed, Lawson, Byrd and Reed (1984) found that intermediate doses of pimozide, as well as two other neuroleptics (chlorpromazine  and trifluperazine) a l l increased  the intake of milk, although high doses of each decreased intake. K.B.J. Franklin (personal communication) has similarly found that 0.5 mg/kg pimozide can increase the intake of mash or pellets in animals which are 6 or 24 hours food  deprived.  In summary, i t appears that profound destruction of dopaminergic systems, as produced by appropriate administration of 6-OHDA, results in severe disruption of feeding.  However, milder  interference with  dopaminergic transmission,  as  produced by dopamine receptor blockade, has at most a mild suppresant effect on food intake. Although the effects of neuroleptics on food intake may their effects on other feeding-related activities is clearer. - 9 -  be inconsistent,  Wise, Spindler, deWit  and Gerber (1978), Tombaugh et al (1979) and Tombaugh, Anisman and Tombaugh (1980) all observed marked reductions in lever pressing for food reward following injection of 0.5 or l.Omg/kg pimozide. by injection  of  as little  Acquisition of lever pressing was slowed  as 0.25mg/kg (Wise  and Schwartz,  1981).  Hoarding  behaviour, known to be disrupted by lesions of the mesolimbic dopamine system, was greatly suppressed by 0.45mg/kg pimozide, although latency to begin was not affected (Blundell, Strupp and Latham, 1977).  Again, food procuring behaviours  appear especially sensitive to disruption of dopamine systems.  This point shall be  addressed at more length in a later section.  FEEDING INDUCED BY DOPAMINERGIC STIMULATION If  reduced dopaminergic activity  and feeding related activity  behaviours, it  might  be  produces decreases in  expected that  produces increases in these behaviours.  but only in some situations. indirect  generally  stimulation  feeding  enhanced dopamine  Increases have been reported,  This section shall examine the effects of direct and  of dopaminergic systems by pharmacological, electrical  and  other means. Pharmacological  Stimulation:  Dopamine  release  is  enhanced  by  systemic  injection of d-amphetamine (Fuxe and Ugerstedt, 1970; McMillen, 1983), as is the release of noradrenaline receptors  are  amphetamine  directly and  these  agents  stimulated  apomorphine  dopamine receptors. of  (Glowinski and Axelrod, 1965). by  apomorphine  result  in  Post-synaptic dopamine  (Ernst,  increased  1967).  activity  at  Thus,  both  post-synaptic  However, instead of resulting in increased food intake, both  produce marked  anorexia  (Cole,  1978;  Heffner  et  al,  1977).  Amphetamine induced anorexia is partially attenuated by LH lesions, and Ahlskog and Hoebel (1973) have  shown that at  this  - 10 -  site  the  the  anorectic  effect  of  amphetamine is largely mediated by  noradrenaline.  Still, noradrenaline  is not  responsible for a l l of the anorectic effect: Fibiger et al (1973) reported  that  animals, largely recovered from the aphagia produced by 6-OHDA lesions of the NSB,  showed relatively little amphetamine-induced anorexia.  dopaminergic  involvement  in  amphetamine  includes reports that such anorexias  and  Further evidence for  apomorphine-induced  are attenuated  anorexia  by neuroleptics (Heffner et  al, 1977; Burridge and Blundell, 1979). Although amphetamine and apomorphine are usually considered  as effective  anorectic agents, low doses of each have sometimes been reported to increase food intake.  Holtzman (1977) found that 0.3mg/kg amphetamine increased  intake over 2h, while Winn, Williams and increased intake over 3h.  food  Herberg (1982) found that 0.25mg/kg  Blundell and Latham (1978) found that a single dose of  0.125mg/kg increased intake over the next 24h period.  Interestingly, Eichler and  Antelman (1977) found that some of the same doses which decreased food intake in hungry rats (from over 5.0 to less than l.Og) could increase food intake (up to 1.2 from 0.25g) in rats "pre-sated" by exposure to wet mash. Note that the intake reported by Eichler and Antelman after low doses of apomorphine was  nearly equal to the intake observed after high doses, and  apparantly "opposed" effects are attributable to different baselines. making the animal eat, apomorphine may  the  Rather than  make the animal less concerned with his  internal state, as opposed to external cues.  We  shall return to this possibility  later. It also seems reasonable to suggest that amphetamine and apomorphine have opposed anorectic and food-intake promoting effect by acting at multiple sites in the brain.  This hypothesis has been supported by studies in which dopaminergic  drugs have been micro-injected into specific dopamine terminal sites. - 11 -  Winn et al  (1982) observed increased  food  intake  amphetamine into the striatum, and when  amphetamine  amygdala.  was  following unilateral  injection of 2.0ug  Carr (1984) observed decreased food intake  injected bilaterally  into  the  n.  accumbens  or  the  Decreased feeding following injection into the n. accumbens may  attributable to the  general  increases  in activity  produced by  amphetamine at this site (Kelly, 1977; Makanjuola, Dow  the  action of  and Ashcroft, 1980;  1984): As with low doses of apomorphine, the animal may  be  Carr,  be relatively indifferent  in what i t responds to. Another treatment that induces feeding deserves mention here. injection of cholinergic substances into the substantia nigra. (1979) found  that  injection  of  acetylcholine into  the  This is the  Winn and Redgrave substantia  nigra  of  non-deprived rats increased food intake to more than four times that of control levels.  Winn, Farrell, Maconick and Robbins (1983) repeated the experiment using  the cholinergic agonist carbachol and enhancement appears to be  found similar increases in feeding.  specific to feeding: Even in the absence of food,  comparable injections did not increase gnawing, drinking, locomotion, sniffing or rearing.  tempting to suppose that these behaviours are mediated by nigrostriatal bundle, there Taha and  grooming,  This provides strong evidence for a cholinergic mechanism in  the substantia nigra that is selectively related to food intake.  present.  This  is little  Although i t is  the  dopaminergic  direct evidence to support this claim  Redgrave (1980) administered  at  0.5mg/kg haloperidol to rats  prior to injecting carbachol into the substantia nigra and found that food intake was  reduced to zero - well below the baseline observed with no injection of  either drug.  Haloperidol was  Thus, although  not injected in the absence of carbachol injections.  haloperidol did abolish the  12 -  increase  in feeding  produced  by  carbachol, this may  have been due  to general debilitation rather than selective  interference with carbachol-stimulated  mechanisms.  Electrical Stimulation: Lateral hypothalamic stimulation in the presence of food often results in feeding (Delgado and Anand, 1953; Coons, Levak and 1965).  This  effect was  originally attributed to activation of a  "feeding centre" in parallel to the analysis of LH  lesion-induced  recently, several investigators have indicated that much of feeding  may  pathways. the VTA  be  attributable  Feeding may  to  the  activation  of  Miller,  hypothalamic  aphagia.  More  stimulation-induced  ascending  dopaminergic  be elicited by stimulating the origins of these systems in  (Wyrwick and Doty, 1966) and the substantia nigra (Phillips and Fibiger,  1973b). Further, feeding elicted by LH stimulation is attenuated by intraventicular administration of 6-OHDA (Phillips and  Fibiger, 1973a) and  systemic injection of  haloperidol (Philllips and Nikaido, 1975). Feeding elicited by several respects.  The  specific to feeding "hunger drive". including  in  behaviour elicited by electrical stimulation is not at a l l  and  cannot be  Stimulation  hoarding,  behaviour. The  electrical stimulation differs from natural feeding  drinking,  of  the  attributed, for example, to an elevation of LH  grawing,  can  evoke a  attacking,  tail  plethora preening  of  activities,  and  sexual  different behaviours elicited in different rats cannot be attributed  to minor differences in anatomical localization within the LH,  rather they  are  related to subject and environmental variables (see review by Valenstein, Cox  and  Kakolewski, 1970). The  behaviour elicited by stimulation at any one site does not  appear to be related to any single motivational state.  For example, i f rats that  preferentially eat a particular food in response to LH  stimulation are  in  the  absence  of  that  food, another  "stimulus  bound" behaviour  stimulated gradually  emerges, and is as likely to be drinking as eating of a different food, however - 13 -  familiar and palatable that other food may new  be, and will generally maintain that  response even i f the initially-consumed food is returned (Valenstein, Cox  and  Kakolewski, 1968a, b; Valenstein and Phillips, 1970). Clearly, stimulation-induced feeding is different from that evoked by deprivation: A  hungry  rat does not  drink water in preference  to  food  eating  a  palatable food simply because the particular food he is eating is removed from the chamber.  The  true nature of stimulation-induced behaviours remains unclear.  They have been described (Valenstein, 1975) well-established  and  as  products  response  coping  responses to  a  state of high  arousal  of the excitation of neural systems underlying  patterns  (Valenstein et  al, 1970).  possibilities are of considerable interest in their own  Although  these  right, their relationship to  natural feeding is neither clear nor established. Tail pinch-induced  feeding: Feeding can be induced  of dopaminergic systems as well as direct stimulation. One  by indirect stimulation curious finding is that  moderately intense tail pinch provokes feeding, and such feeding is blocked neuroleptics or 6-OHDA lesions of the Antelman  Szechtman, Chin  and  MFB  (Antelman and  Fisher, 1975).  However, as  Szechtman, with  by  1975;  electrical  stimulation, tail pinch can also induce aggression, copulation, drinking, maternal behaviour,  licking and  gnawing, depending on  the stimuli in the  environment.  Again, there is no reason to believe that these are "normal" manifestations of motivated  behaviours.  In summary, stimulation of dopaminergic systems through administration of amphetamine or apomorphine, electrical stimulation, or tail pinch elicits a variety of behaviours.  These include locomotion,  behaviour and copulation.  drinking, licking, gnawing,  maternal  In the presence of food, the animals will often eat at  least small quantitites of food. Although these elicited behaviours may - 14 -  reflect the  activation of neurological substrates related to normal feeding, they may equally well reflect the non-specfic unrelated to normal behaviour.  activation of aberrant  patterns  of neural  firing  For example, the animals appear to be influenced  by environmental stimuli to an exceptional extent. The evoked behaviours may be related to those seen when an animal is highly stressed, and may have little to do with feeding in day-to-day life. few  On the other hand, i t is worth observing that  stimulation studies have addressed the question  involved in non-consummatory aspects of feeding  of whether dopamine is  behaviour.  CORRELATIONS B E T W E E N FEEDING AND DOPAMINE R E L E A S E The play  previous  some  role  sections have indicated that central dopamine systems may in feeding  dopaminergic transmission procurement, although  behaviour,  generally leads  that  to decreased food  disruption of  intake and food  enhancemant of dopamine activity will lead to enhanced  food intake in only some circumstances. thus f a r have  to the extent  addressed  the issue  However, few of the studies described of ethological validity:  Is the normal,  day-to-day feeding of animals or humans correlated with alterations in central dopamine activity?  Although i t appears that a minimal level of dopamine function  is required for feeding to occur, this may only indicate that dopamine plays a permissive role in feeding.  Furthur, although elevation of dopamine activity may  increase feeding, this usually appears to reflect a general increase in behavioural activity rather than a selective enhancement of feeding. Thus, lesion, neuroleptic and  stimulation studies may not be adequate to elucidate the neurobiological  substrates of natural feeding.  More direct evidence linking dopamine and feeding  behaviour is required.  - 15 -  In recent years evidence has accumulated that dopamine activity does in fact change i n relation to some aspect or aspects of feeding or nutrient balance. Dopaminergic activity has been studied following food or glucoprivation, during or subsequent to feeding, and following the administration of nutrients and putative satiety agents.  Each of these situations will be considered in turn.  Dopaminergic activity and lowered nutrient status:  Several authors have  reported that dopamine activity is increased by food deprivation. and  Gershon (1973) reported  that  dopamine  hypothalamus of rats which had been deprived rest of their brains.  the other hand, these tissues contained of  dopamine  alpha-methyl-para-tyrosine,  synthesis suggesting  increased  in the  of food for 22h, but not in the  Fuenmayor (1979) found that food  striatal levels of the dopamine metabolite  inhibition  levels were  Freidman, Starr  deprivation  increased  homovanillic acid (HVA) in mice.  On  high levels of dopamine following the  by  the  tyrosine  hydoxylase  a decrease in striatal dopamine  inhibitor turnover.  Fuenmayor suggested that there may be dual, antagonistic, actions of fasting on various dopamine  subpopulations.  Enhanced levels of amphetamine-induced activity were observed following food  deprivation (Campbell and Fibiger, 1971).  The  quantity  of stabilimeter  activity induced by l.Omg/kg d-amphetamine became progressively more intense over days, and was more than four times greater after four days of deprivation than after one.  This appears to indicate increased  availabilty of dopamine at  synapses.  Similarly, Glick, Waters and Milloy (1973) observed that amphetamine-  stimulated  dopamine release  in the striatum was  increased  by depriving the  animals of food for 24h. In contrast to these reports, other increased  investigators have failed to observe  dopamine activity with fasting. - 16 -  Heffner, Hartman and Seiden (1980)  measured levels of DOPAC and dopamine in rats which had continuous access to food  and  between  in rats which had groups  differences  been deprived were  found  of food in  the  for 20h.  No  striatum,  significant  n.accumbens,  hypothalamus, olfactory tubercle, or amygdala. An  electrophysiological study  also failed to indicate any  change in the  activity of single dopamine neurons in the substantia nigra of unrestrained cats as a result of food deprivation (Trulson, Crisp and Trulson, 1983). period of food deprivation plasma glucose cats maintained  levels dropped 21.4%  Over a  48h  in a group of  on a high carbohydrate diet, and increased slightly in cats fed a  high protein, low  carbohydrate diet.  baseline levels in either group. several reasons why  Nigral unit activity was  Although of considerable  the generality of this and  unchanged from  interest, there  similar studies may  are  be limited.  First, i t exclusively involved neurons in the substantia nigra, pars comapacta. It is possible that mesolimbic dopamine neurons, originating in the change their rates of firing while their nigral cousins do  not.  VTA,  could  Second, i t is  possible that only a small proportion of dopamine neurons change their rate of firing, but do  so in such a pronounced manner that net  sufficiently altered to affect behaviour. Trulson et al study may rodents.  dopamine release is  Third, the subjects employed in the  not provide an adequate model for feeding in humans or  Cats are carnivorous and  have somewhat unusual feeding habits (eg.,  they are among the only adult mammals that do not show a preference for sweet solutions, and dopamine  as carnivores they are typicallly binge-feeders).  systems  have  a  somewhat  different  anatomical  As  well, their  structure  dopaminergic neurons throughout the feline pars compacta contain the cholecystokinin: see below).  peptide  For these reasons at least, these results may  readily generalize to onmivorous humans or rats.  - 17 -  (eg.,  not  Increased has  been  dopamine turnover  consistently reported  as a result of insulin-induced hypoglycemia in studies  with  rats.  When  insulin  was  administered to anesthetized rats levels of dopamine decreased in limbic, striatal and  cortical regions increased as blood glucose  levels fell (Agardh, Carlsson,  Lindqvist and Siejso, 1979). A similar treatment increased dopamine release in the hypothalamus (Sauter, Ueta, Engel and Goldstein, 1981).  Lower doses of insulin  (5U/kg) which reduced blood gucose levels to 3 0 % of control levels increased levels of dopamine metabolites in the striatum and hypothalamus of freely moving rats, but not i n the n. accumbens (Cottett-Emard  and Peyrin, 1982).  Urinary  levels of the metabolites were also increased, and this could not be attributed to increased release of dopamine from the adrenals.  (Urinary levels of dopamine  were also elevated in humans following insulin injection: Woolf, Akowuah, Lee, Kelly and Feibel, 1983).  Similarly, Rowland, Bellush and Carlton (1985) recently  reported that 5U/kg insulin increased dopamine turnover in the striatum but not the n. accumbens. Finally, McCaleb and Myers (1979) used a push-pull cannulation technique to investigate the release of dopamine in the striatum of freely moving rats.  If insulin was added to the perfusate, recovery of ^H-DA was increased. Levels of the dopamine metabolites 3,4-dihydoxyphenylacetic  acid (DOPAC)  and homovanillic acid (HVA) were elevated in the cerebrospinal fluid of freely moving rats following injection of 6U/kg insulin (Danguir, 1984). turnover  Elghozi and Laude,  However, i f food was available glucose levels did not fall and dopamine did not increase.  Glucose prevented  similar increases when i t was  injected before blood glucose levels f e l l , and reversed increases i f injected after they had occurred. induced  by insulin  Similarly, increased telencephalic dopamine turnover levels, injection, were returned  to baseline following feeding or  spontaneous glucorecovery (Beliin and Ritter, 1981). - 18 -  Taken together, these studies suggest that dopamine activity will be reliably increased during pronounced hypoglycemia or severe food deprivation. However, in cases of less severe deprivation (eg., 24h without food for rats), increases are less consistently reported and are generally of lower magnitude.  This weakens  the case for the existence of a role for increased dopamine activity due  to  privation as a trigger for normal feeding, although increased dopamine activity may  accompany near-starvation when nutrient reserves reach a critical point.  On  the other hand, blood glucose levels fall in the few minutes prior to meal onset in rats with continuous access to food (Louis-Sylvestre and Campfiled, Brandon and  Smith, 1985).  Le Magnen, 1980;  This fall could produce an increase in  dopaminergic activity related to meal onset. Dopaminergic activity and feeding: Relatively few studies have examined the effect of feeding pjer se on dopamine activity.  Technically, i t is difficult to  separate the effects of having engaged in feeding behaviours from those induced by the physiological consequences of ingestion. One approach to this problem  has  been to monitor the activity of single dopamine neurons electrophysiologically while the animal feeds.  However, i t is necessary to reiterate that there are  possible limitations to the generality of these electrophysiological studies, both with  respect to the cell  employ.  populations they investigate and  Nonetheless, Trulson et al (1983) and  the  species they  Strecker, Steinfels and  Jacobs  (1983) both found no change in nigral unit discharge rate, discharge pattern or waveform when food deprived cats were allowed to eat.  Few  neurons in the  Strecker et al study changed firing rate by more than + 10%. Martin  and  Myers (1976) examined  the release of  feeding and lever pressing for food on an FR6 repeated push-pull perfusion.  ^C-dopamine during  schedule using the technique of  During free feeding, dopamine activity - 19 -  did not  increase at any site in the anterior hypothalamus, increased at one of five sites adjacent  to the third  ventrical  (in the vicinity  of the n. oriens and the  paraventricular n.) and at the most medial of five sites in the substantia nigra. There were also increases at two other  sites in the vicinity of the third  ventrical and at one site in the substantia nigra during lever pressing for food. These results are not conclusive because of limitations inherent in the technique, the  limited  number of sites  investigated, and the fact  that no sites were  examined for both free-feeding and lever pressing at the same site.  Still, the  study suggests that dopaminergic activity increases at some limited sites in the brain as a result of certain aspects of feeding behaviours. Other  studies that  have  examined  the effect  of feeding  on dopamine  activity have assayed chemically the levels of dopamine and its metabolites after sacrificing animals at some time following consumption of a meal.  For example,  Biggio, Porceddu, Fratta and Gessa (1977) reported that brain levels of HVA and DOPAC  levels were increased  by feeding in rats which had previously been  deprived of food for 21h. The increase was significant l h after food presentation and  reached a peak after 3h. In animals  that received food f o r 3h, levels  remained elevated for at least 4h after food was removed. The  most thorough study of the impact of feeding on dopamine turnover to  date was conducted by Heffner, Hartman and Seiden (1980).  They allowed rats  that had been deprived of food for 20h to eat for l h . A t the end of the hour the animals were decapitated and their brains immediately dissected. Amounts of dopamine and DOPAC in several brain regions were determined by radioenzymatic assay.  DOPAC/DA ratios were increased by 2 5 % i n n. accumbens, by 9 9 % in  amygdala, and by 2 2 % in hypothalamus, compared to non-fed controls. Ratios were unchanged in striatum, olfactory tubercle, septum or frontal cortex. - 20 -  Further experiments showed that tube feeding produced increases in the amygdala that were similar to those seen following feeding, but similar increases were not observed in other regions. that  increases  post-ingestive  observed effects  On this basis, Heffner et al (1980) argued  in n. accumbens  but rather  an  and hypothalamus do not reflect  effect  behaviours.  This interpretation was challanged  laboratory.  Heffner,  Vosmer  and Seiden  of having  performed  feeding  by later data from the same  (1984) reported  that  i f rats were  sacrificed l h after feeding had begun, when they had consumed an average of 10.3g of food, hypothalamic DOPAC levels were not significantly elevated. On the other hand, i f the rats were sacrificed two hours after feeding began, when mean consumption was 11.3g (a mere l.Og more than the l h group) hypothalamic DOPAC levels were nearly twice that of controls. Apparantly a large increase in dopamine metabolism occurred  in the second hour, when almost no food was  consumed. It seems probable that some post-ingestional factor must be responsible for this increase. Heffner  Although data were only reported for the hypothalamus in the  et a l (1984) report, one might speculate that such an increase also  occured in the n. accumbens and other structures. Although  Heffner  et a l (1980) only  found  increases  in mesolimbic,  opposed to nigrostriatal, dopamine turnover, Chance, Foley-Nelson,  as  Nelson, Kim  and Fischer (1985) have reported recently that elevated DOPAC and HVA levels were found in both n. accumbens and striatum following one hour of free access to food.  This is consistent with the long-hypothesized  dopamine system in feeding.  role for the nigrostriatal  On the other hand, both studies have reported  increases in the n. accumbens, a structure typically not implicated in feeding by lesion studies.  Apparantly, a full analysis of feeding and dopaminergic systems  - 21 -  will  require  consideration  of  both  mesolimbic  and  nigrostriatal  dopamine  projections. It is important to note an apparantly paradoxical aspect of the results of the Martin and Myers (1976), Heffner et al (1980, 1984) and Chance et at (1985) studies: Each report indicated that there are increases in dopamine turnover as a result of feeding, while previously severe  noted  feed.  have been no  that increases  deprivation, and  animals  there  reports of decreases.  in dopamine turnover  are  observed  It  was  folowing  that increases in dopaminergic system activity makes  Taken together, i t would seem that the effect of feeding  on  dopamine systems is to put them into a state of elevated activity, where feeding is more likely to occur. Suppression  of  dopaminergic  activity  by  satiety  factors:  disruption of dopamine systems results in attenuated feeding. be suspected satiated  Inhibition  or  Conversely, i t may  that decreased dopaminergic activity characterizes the brain of a  animal,  when  i t is phasically unresponsive  to  food.  In  order  to  investigate this hypothesis investigators have studied dopamine activity following administration of putative satiety factors. No  consensus has ever been reached on the question of what cues lead to  meal termination. cholecystokinin  Still, considerable evidence exists that both blood glucose play  some  role  in  satiety.  The  post-prandial  period  characterized by relatively elevated levels of both glucose (Steffans, 1969) CGK  (Walsh, Lamers and  Liddle and Williams, 1985). (Gibbs, Young and  Valenzuela,  1982;  Smith, Greenberg, Falasco,  Adminstration of both glucose (Mayer, 1953) and  Smith, 1973;  Antin, Gibbs,  Holt, Young and  and  Smith,  is and  Gibbs, CCK 1975;  Mueller and Hsiao, 1978; Smith and Gibbs, 1981; Collins, Forsyth and Weingarten,  - 22 -  1983) suppress food intake.  Finally, as the following paragraphs document, both  substances appear capable of suppressing central dopamine activity. Dopamine and glucose: In the push-pull cannualation experiment described above, McCaleb and Myers (1979) also found that, when glucose was the perfusate, release of study  of  striatal  H-dopamine was  slices,  amphetamine-stimulated  release  Dorris of  decreased.  (1978) a  false  found  added to  Similarly, in an in vitro that  dopaminergic  potassium-  or  neurotransmitter  q  ( H-alpha-methyl-m-tyramine) was inhibited by glucose infusion. Sailer and  Chiodo  (1980) injected glucose intravenously into anesthetized  rats while measuring the activity of dopaminergic neurons in the substantia nigra. Injection of 250mg/kg of glucose completely inhibited these neurons for at least 30 minutes, and a small injection of 15mg/kg decreased firing rate for 10 - 12 minutes. To round out their litany of negative findings, Strecker et al (1983) and Trulson et al (1983) found no such effect when glucose was injected into freely moving cats.  Further, Westerink and Spaan (1981) found that levels of dopamine  and its metabolites in rat striatum were unaffected by injection of 500mg/kg glucose. Several reports indicate that the behavioural effects of dopaminergic drugs are modulated  by blood glucose levels.  White and Blackburn (submitted) found  that i.p. injection of l.Og/kg d-glucose shifted the dose response curve for the stereotypy-inducing effect of amphetamine to the right, indicating suppression of dopaminergic release. amphetamine-induced  However, they found that similar injections did not affect motor activity (as measured by photocell interruptions) or  circling induced by amphetamine in rats with unilateral 6-OHDA lesions of the substantia nigra.  Amphetamine induced stereotypy, locomotion and circling are  mediated in part by dopamine systems  (Kelly, 1977; Ungerstedt, 1971a).  - 23 -  The  preferential attenuation of stereotypy may subpopulations  reflect differential effects on  of dopamine neurons (Kelly, 1977)  separate  or receptors (for review  see  Joyce, 1983). The  previous studies examined the effects of exogenously applied glucose  on dopamine activity.  Other work has examined dopamine activity in animals with  altered glucometabolism. activity  and  anorexia, are  Heffner, 1976, injections.  Amphetamine-induced stereotypy, as well as locomotor  1978;  The  reduced in diabetic rats (Marshall, Friedman  Marshall, 1978).  These effects are restored by  and  insulin  data support the suggestion that the decrease in sensitivity to  amphetamine observed in these animals is due to elevated blood glucose levels, rather  than  to  general  ill  health.  The  chronically depressed dopamine systems due furthur supported is  increased  increased  possibility  that  diabetic rats have  to elevated blood glucose levels is  by the finding that the number of striatal dopamine receptors  in rats with  experimentally  induced  diabetes, as  indicated  by  H-spiperone binding (Lozovsky, Sailer and Kopin, 1981). Such increased  binding was  not found in other diabetic rats that received insulin therapy for 12  days prior to sacrifice. Although the effects of amphetamine, which enhance dopamine transmission, are attenuated in rats with elevated blood glucose, those of haloperidol, which blocks dopamine effects post-synaptically, are enhanced. found that haloperidol-induced catalepsy was  Sailer and Kopin (1981)  enhanced by injection of 1.25g/kg  d-glucose. In summary, i t appears that many of the behavioural effects of amphetamine and  haloperidol are altered in a manner which is consistent with Sailer  Chiodo's  suggestion  that  elevated  blood  glucose  levels  inhibit  and  dopaminergic  acitivity. However, several reports indicate that this effect is not universal: It is - 24 -  quite  possible that  only  selected  subpopulations of dopaminergic  neurons or  receptors are affected. Dopamine and cholecystokinin: Several lines of evidence have indicated that the putative satiety hormone cholecystokinin (CCK) also affects the activity of dopamine systems.  Interestingly, this peptide  co-exists with dopamine in many  neurons in the V T A and some, mostly medial, neurons of the substantia nigra (Hokfelt, Skirboll, Rehfeld, Goldstein, Markey and Dann, 1980). appear to belong to the mesolimbic system, with  the heaviest  These neurons  projection, rather than the nigrostriatal  projection  to the posterior-medial  n. accumbens  (Williams, Gayton, Zhu and Dockray, 1981, Studler, Simon, Casselin, Legrand, Glowinski and Tassin, 1981; Marley, Emson and Rehfeld, 1982; Gilles, Lostra and Vanderhaegen, 1983).  Although these is a large C C K presence in the striatum, i t  does not appear to be of nigral origin (Meyer, Beinfeld, Oertel and Brownstein, 1982). Electrophysiological dopamine activity.  studies  have provided  evidence  Skirboll, Grace, Hommer, Rehfeld,  Bunney (1981) examined the effects of intravenously  of C C K  effects on  Goldstein, Hokfelt and (i.v.) or iontophoretically  applied C C K on cells of the substantia nigra and the ventral tegemental area (VTA).  Units in areas of the substantia nigra in which dopamine co-existed with  C C K showed transient increases in firing rate following i.v. application of CCK, but units in areas without CCK/DA cells were unresponsive.  In the VTA, of 31  cells examined, 7 were unaffected by i.v. CCK, 15 were fleetingly suppressed and 9 exhibited increases like those seen in the substantia nigra. increases  were  apparently  of sufficient  magnitude  In three cases the  to send  the cell  into  depolarization inactivation. Iontophoretically applied C C K increased firing rates i n VTA  and those areas of substantia nigra with CCK/DA co-existence. - 25 -  Hommer, Paklovitis,  Crawley, Paul and Skirboll  (1985) again showed that  nigral activity was increased some 50-80% in the 30 second period beginning 20 seconds after i.v. injection of CCK.  Chiodo and Bunney (1983) blocked a similar  increase i n activity i n cells of the V T A with the C C K antagonist proglumide. White and Wang (1984) determined that C C K could also increase activity in cells of the n. accumbens in the regions where the axons of many CCK/DA neurons appear to terminate.  Although C C K by itself produces transient increases in  dopamine unit activity, i t potentiated the inhibition apomorphine (Hommer and Skirboll, 1983). inhibitory  of dopamine activity by  This sugests that C C K also plays an  role on dopamine systems, possibly potentiating dopamine autoreceptor  sensitivity. Inhibitory, rather than excitatory effects of C C K on dopaminergic  systems  have also been indicated by several studies of dopamine turnover. Intraventricular injection  of C C K has been reported to decrease dopamine turnover in several  regions including the n. accumbens, striatum, hypothalamus, mesencephalon and septum (Fuxe, Andersson, Locatelli, Agnati, Hokfelt, Skirboll Fekete, Kadar  and Telegdy, 1981; Mashal, Owen, Deakin  and Mutt, 1980;  and Poulter, 1983).  Release of dopamine in the n. accumbens, as determined by push-pull canulation, was reduced when C C K was added to the buffer (Voigt and Wang, 1984).  In a  recent study employing i n vivo voltametry, Lane, Blaha and Phillips (personal communication) ten  have found that dopamine release was decreased beginning about  minutes after C C K injection,  reaching a minimum half an hour later, and  remaining greatly suppressed for over an hour. Similar suppressant effects are observed in vitro: Low concentrations of CCK  inhibited  release  of both  basal  and electrically  3  evoked  H-dopamine from slices of cat striatum (Markstein and Hokfelt, 1984). - 26 -  outflow of  Several reports have indicated suppression of dopaminergic behaviours and neuroendocrine effects methamphetamine-induced rearing  but  not  by  CCK.  Central  injection  of CCK  in rats  reduced  activity (Katsuura and Itoh, 1982), reduced spontaneous  locomotion (Schneider, Alpert  and  Iversen,  1983; Widerlov,  Kalivas, Lewis, Prange and Breese, 1983) and interfered with both acquisition and maintainance of active avoidance behaviour (Fekete, Szabo, Balasz, Penke and Telegdy, 1981).  In humans, i.v. injection  of CCK  suppressed the dopamine  mediated growth hormone-release response to apomorphine  (Lai, Nair, Eugenio,  Thavundayil, Lizondo, Wood, Etienne and Guyda, 1983). Two  other behavioural effects of CCK  are worth mentioning, although their  reationship to dopamine is less well established. in experiments with mice  First, Crawley has demonstrated  (Crawley, Hays, Paul and  Goodwin, 1981) and  rats  (Crawley, Hays and Paul, 1981) that exploration of an open field which contains several objects of interest to rodents is reduced by CCK. doses of CCK  Second, even modest  can lead to sedation or behavioural quiesence (Itho and Katsuura,  1981; Katsuura and  Itoh, 1981; Crawely, Rojas-Ramirez and  Mendelson,  1982;  Rojas-Ramirez, Crawley and Mendelson, 1982). In conclusion, i t is clear that CCK but  the  precise  nature  and  extent  and dopamine interact physiologically, of  this  interaction  is  uncertain.  Electrophysiological work suggests that only those neurons in which CCK dopamine co-exist are excited by CCK  (Skirboll et a l , 1981).  These  and  neurons  appear to project primarily to the medial posterior n. accumbens (Williams et al, 1981, Studler et a l , 1981; Marley et al, 1982). CCK  On the other hand, injection of  seems to decrease dopamine turnover in other brain regions as  well,  including the striatum (Fuxe et a l , 1980; Mashal et a l , 1983; Markstein and Hokfelt, 1984; Lane, Blaha and Phillips, personal communication). - 27 -  Possibly the  short term excitatory effect of CCK administration procedure CCK).  on CCK/DA cells is an artifact of the  (rapid bolus injections of moderately large amounts of  The longer term inhibitory effect on a larger population of dopamine cells  is likely more representative of what occurs following a meal, which would result in the slow release of a modest quantity of CCK  resulting in plasma levels  approximately equal to that seen after an injection of 2ug/kg (Smith et al, 1985). The  plausiblity of multiple CCK/DA interaction is increased by the recent  report of Hommer et al (1985) who found that excitatory effect of CCK cells was  attenuated, but not abolished, by lesions of afferents to or efferents  from the nucleus of the solitary tract (NTS).  The NTS  is a brainstem nucleus  responsible for integrating many sensory and gustatory inputs. vagal  on nigral  afferents,  it  has  been  implicated  as  playing  Along with its  a  role  in  the  exploration-inhibiting (Crawley, Hays and Paul, 1981, Crawley and Schwaber, 1984) and  satiety-promoting effects  Simansky, 1981;  Lorenz and  of  CCK  (Smith, Jerome,  Cushin,  Eterno  Goldman, 1982; Morley, Levine, Kreip and  and  Grace,  1982).  MOTIVATIONAL INTERPRETATIONS OF DOPAMINE'S ROLE IN FEEDING The  previous sections have reviewed  relationships between dopamine and feeding. theoretical interpretations how they may  of dopaminergic  the  experimental data  concerning  This section shall examine several contributions to behaviour and  see  be applied to an analysis of feeding. Of course, many studies have  examined the role of dopamine in other behaviours, and although no attempt will be  made here  to review  these  studies comprehensively,  those  that aid in  understanding the possible role or roles played by dopamine in feeding will be described.  - 28 -  The  Sensorimotor Hypothesis:  Following Ungerstedt's (1971a,b) reports that  6-OHDA lesions of the nigrostriatal bundle produced deficits, the first  general theoretical interpretation  receive serious consideration was based  deficits  (Marshall,  Turner  of dopamine function to  on the suggestion that the syndrome  observed following NSB or lateral hypothalamic sensorimotor  severe aphagia and motor  lesions could be attributed to  and  Teitlebaum,  Richardson and Teitlebaum, 1974; Ungerstedt, 1974).  1972; Marshall,  Following unilateral 6-OHDA  lesion of the NSB rats show a chronic tendency to turn towards the lesioned side (Ungerstedt, 1971a) and display difficulty in using the limbs contralateral to the lesion for righting, climbing and resisting gravitational pull (Marshall et al, 1974). This postural asymmetry does not merely reflect a motor deficit, i t appears to  be related  to a state of "sensory neglect": Stimuli do not evoke  normal  orienting responses when presented on the side of the body contralateral to the lesion.  Such deficits are not complete, rather, the orienting response  variable and quickly disappears. touched i t may turn toward afterward  appears  For example, i f the whiskers of a rat are  the stimulus, but i f they are brushed again soon  the rat does not orient.  Thus, i t appears  that deficits  observed  following NSB damage are neither wholly sensory nor wholly motoric, but rather they appear to reflect disruption of a higher level of sensorimotor integration: Apparently the animal perceives, but does not respond. Bilateral lesions have a much more severe  effect on the animal.  animals are initially akinetic, but do not seem somnolent.  The  When presented with a  novel stimuls, such as fresh food, they may orient to i t , and may even approach it. However, because all responses rapidly wane following the presentation of any stimulus, the animal does not sustain or even commence feeding. - 29 -  Although  Marshall et a l (1974) felt that sensorimotor deficits could not account for all of the observed feeding and drinking deficits observed (eg., the active rejection of food in the initial period after lesioning) such deficits may contribute strongly to the NSB and L H syndromes The  sensorimotor  experimental obsevations. increases  in dopamine  hypothesis  accounts  satisfactorily  f o r several  other  If dopamine is involved in responding to stimuli, then activity  would  be  expected  to  make  an  animal  hyper-responsive to environmental stimuli (as is observed), and suppression of dopaminergic  activity by neuroleptics would be expected to make animals less  responsive to the environment. preparatory  The preferential disruption of consummatory vs  aspects of feeding can be attributed  within the theory to the  relative lack of salience of food related cues compared to the salience of food itself. The  anhedonia  hypothesis: As described in the section  concerning the  effects of neuroleptics on feeding behaviours, pimozide treated animals decrease the rate of operant responding through the course of a test session. On the next test these animals begin at a lower rate of responding and rapidly fall to still lower rates of responding.  Similar response  decrements are observed  when  responding is reinforced by brain stimulation (Fouriezos and Wise, 1976; Fouriezos, Hannson and Wise, 1978; Franklin, 1978), water (Gerber, Sing and Wise, 1981), thermal stimulation (Ettenberg and Carlisle, 1985) and intravenous administration of amphetamine (Yokel and Wise, 1975) or cocaine (deWit and Wise, 1977). The  "anhedonia  hypothesis" attributes this  continuing decline in operant  rates to the proposition that "neuroleptics attenuate the hedonic impact of a variety of positive reinforcers" (Wise, 1985, p. 184).  - 30 -  Thus, once the reinforcer is  no longer rewarding, the response extinguishes. This analysis seems to apply to all rewards, not just feeding. Immediately after the anhedonia  hypothesis was proposed  by Wise et a l  (1978) several studies were conducted demonstrating that operant responding in animals, trained on intermittent schedules of reinforcement, are more seriously disrupted by neuroleptics than by nonreinforcement. For example, although animals trained  on intermittent  extinction  (the so-called  schedules partial  typically  show  considerable resistence to  reinforcement extinction  effect,  or PREE),  Phillips and Fibiger (1979) and Tombaugh et a l (1980) observed rapid deterioration in performance following administration of neuroleptics. responding was observed  Further, a decrease in  before the presentation of the first reinforcer on a  partial reinforcement schedule, that is before the first experience the animal had with the reinforcer while i n it's "anhedonic" state (Mason, Beninger, Fibiger and Phillips, 1980; Gray and Wise, 1980).  In addition, the effects of neuroleptics sum  with those of extinction (Ettenberg, Cinsavich and White, 1979; Gray and Wise, 1980; Mason et al, 1980; Tombaugh et al, 1980). That is, animals respond at still lower rates during extinction i f they are treated with neuroleptics. animals  are transferred  completely.  from  pimozide  to  extinction  Finally, when  responding  recovers  These effects should not be observed i f the effects of pimozide and  extinction are functionally equivalent. To explain the partial reinforcement and summation effects Gray and Wise (1980) proposed  that neuroleptics not only attenuate the hedonic  impact of  posiitve reinforcers, but also blunt the secondary reinforcing effects of stimuli associated with reward.  That is, during operant conditioning the animal comes to  associate various cues (such as the lever or the response itself) with reward. Normally, these "secondary reinforcers" act to elicit approach and manipualtion of  - 31 -  the bar for some time, even in the absence of reward (see Franklin and McCoy, 1979,  f o r a demonstration of how these effects apply  deficits).  to neuroleptic-induced  Other data is consistent with the idea that neuroleptics attenuate the  conditioned  reinforcing properties  of environmental  (Spyraki, Fibiger and Phillips, 1982).  cues  paired  In fact, it is tempting to speculate  neuroleptics only disrupt the salience of food-related cues without the  reward value  of food  with  itself: Animals often  food that  attenuating  eat as much as usual  when  drugged with moderate doses of pimozide; the same doses produce clear deficits in both operant responding for food and hoarding. The  anhedonia  hypothesis  of  neuroleptic  action  is similar  to the  sensorimotor deficit hypothesis of NSB lesion-induced deficits in that both predict deficits in responding to environmental stimuli. However, they differ in the nature of the stimuli to which they refer, and they differ in the severity of the deficits to  which they  are addressed.  This  may  reflect  differences i n the precise  substrate to which they refer. The sensorimotor deficits, observed by Marshall et al i n response to a l l environmental stimuli are typically seen only after nearly total  destruction  of the NSB.  In contrast, while  Wise reports  deficits in  responses for hedonically-positive rewards, or signals of these rewards, after relatively  mild  pharmacological  disruption  of  dopamine  transmission.  One  possibility is that NSB lesions disrupt a non-dopaminergic system. Another is that NSB lesions  destroy part of a dopaminergic system that is relatively insensitive  to the effects of neuroleptics.  On the other hand, the mesolimbic dopamine may  be an especially sensitive substrate, given the similarities between the deficits seen in hoarding following neuroleptics and V T A lesions. Although  i t is possible  that  NSB  lesions  and  neuroleptics  produce  qualitatively different deficits i t is also possible that the difference between the - 32 -  effects of the two  manipulations is purely quantitative.  anhedonia hypothesis, sensorimotor deficits may  By  extension of the  represent a loss of attractiveness  of all stimuli, including reinforcers. On the other hand, apparent "reward" deficits could reflect a general decrement in the salience of stimuli, most obvious in situations with clearly defined stimulus-response contingencies (such as in operant conditioning).  Yet  again  the  greater sensitivity  of  operant  and  appetitive  responses to the disruptive effects of neuroleptics could reflect the fact that these are typically learned responses, while consummatory and orienting responses are more reflexive and species-typical (see Beninger, 1983). The sensorimotor hypothesis and the anhedonia hypothesis differ in another way.  According to the sensorimotor hypothesis dopamine is actively involved in  responding.  Although Wise (eg., 1985) takes an explicitly agnostic position on the  issue of whether dopamine is involved in response production, i t is clear that the most straightforward form of the anhedonia passive, evaluative role.  hypothesis has dopamine playing a  That is, dopamine release is proportional to  "rewarding" a reward is; i f i t was will respond again in the future.  how  sufficiently rewarding in the past the animal Thus, the sensorimotor hypothesis advocates an  active role for dopamine, while the anhedonia hypothesis views dopamine's role as passive. The  response-initiation  deficit  hypothesis:  Another  model  of  dopamine  function requires the dopamine system to play an active role in responding. is the response Phillips, 1975). a  initiation deficit hypothesis (Posluns, 1962;  to  initiate  a  motor  reaction  environmental cue, even though the animal knows - and The  Fibiger, Zis and  This hypothesis suggests that an organism under the influence of  neuroleptic is unable  signals.  This  idea was  in response  to  an  cares - what the cue  originally advanced to explain deficits seen following - 33 -  neuroleptic  administration  responding paradigm.  or 6-OHDA lesions  of the NSB  in the avoidance  During avoidance learning a stimulus is presented for some  standard period of time (typically 10 seconds to a minute), while an animal is confined in a compartment equipped with a grid floor. the grid is electrified.  A t the end of this period  Shock is terminated by the performance of an arbitrarily  chosen response. By performing the response, the animal has "escaped" the shock. If the animal responds prior to shock onset, no shock is administered, the animal has successfully "avoided" the shock.  In cases where the response required is  movement out of the shock compartment into a "safe" place, most normal animals are  reliably avoiding shock within a few trials. In this paradigm, neuroleptic-treated animals do not avoid, but will  with a short latency once shock begins (Hunt, 1956).  escape  The quick escape response  indicates that the animal is physically capable of responding. What is more, prior to shock onset the animals squeal and defaecate.  In addition, their  subsequent  response to the cue i n a test for classically-conditioned fear elicitation indicates that they have learned the significance of the signal (Beninger, Mason, Phillips and Fibiger, 1980).  The response deficit is strongest during acquisition of the  response, and is not seen when well-trained animals are tested under the effects of neuroleptics (Fibiger et al, 1975; Beninger, Phillips and Fibiger, 1983). In order to interpret this deficit i t is interesting to note that well-trained animals will often perform an avoidance response without showing  any sign of  fear (Solomon and Wynne, 1953; Mineka, 1979; Mineka and Gino, 1980) and with too  short a latency  (Champion, 1964).  f o r autonomic  signs of fear  to have  been  generated  Rather than acting out of fear, these animals have been  described as acting "cognitively" (Solomon and Wynne, 1953, p. 17). Although no study has ever simultaneously examined the decline of fear during avoidance - 34 -  training  and the development  to immunity  from  the disruptive  effects of  neuroleptic, i t is possible to view this coincidence as indicating that dopamine release is required to make a response motivated by emotion (fear), but not for a response under "cognitive" control, or, alternatively, when the avoidance response habit is well established. The  anhedonia  hypothesis cannot readily explain the avoidance  deficits seen following neuroleptic administration.  response  Avoidance can be interpreted  as having a rewarding component (eg. Mowrer, 1947; Masterson and Crawford, 1982). If one assumes that termination of escape is also rewarding, then a simple reward deficit has trouble specifying why the escape from shock is sufficiently rewarding to produce reliable, low latency escape, i f the avoidance of shock is not rewarding enough to reinforce responding prior to shock onset. An alternative way to interpret the avoidance deficit data is to consider that aviodance and escape are the result of two different processes (Ehrman and Overmier, 1976; Jacobs and Harris, in press). can be seen  as an appetitive response, while escape  consummatory reaction. receptor  By this interpretation, avoidance  blockade  can be viewed  as a  Thus in avoidance, as in feeding behaviour, dopamine  appears  to produce  particularly  severe  deficits  in the  appetitive responding. The  Incentive-Response Hypothesis: I t is possible that neuroleptics  may  interfere with operant responding for positive reinforcement and with avoidance responding through separate neural mechanisms. devise a theory which  However, i t is preferable to  can account for both simultaneously. Accordingly, an  alternative hypothesis is provided here, one that combines elements of several other hypotheses. and  Phillips  It is an extension of ideas presented previously by Mogenson  (1976), Clody and Carlton  (1980), Phillips, McDonald  - 35 -  and Wilkie  (1981), Beninger (1983). Carr and White (1984) and Fibiger and Phillips (1985).  It  is also similar, in some respects, to a proposal made by Panksepp (1982). The  alternative hypothesis borrows the assertion that dopamine systems are  actively involved in reponse production from the response initiation hypothesis. In agreement with Wise, the current hypothesis dopamine systems and  recognizes  motivationally relevant stimuli.  a connection  However, the  between hypothesis  assigns dopamine an active role in responses to these stimuli, rather than merely in the post hoc evaluation of their consequences: It is concerned with incentive, not  reward.  Accordingly,  "incentive-response  the  hypothesis  shall  be  hypothesis" of dopaminergic function.  stated in the following way:  referred  to  as  the  It's core idea may  be  "When an animal observes an incentive stimulus, the  release of dopamine in the forebrain is increased, resulting in approach to the stimulus  by  the  animal.  Once the animal is in contact with a  goal object,  consummatory reactions occur which are not mediated by dopamine systems". Before elaborating the hypothesis and applying i t to data i t is necessary to indicate that i t is not tied to any specific theory of incentive motivation, such as  those  of  Spence  (1956),  Bolles  (1967,  1975)  or  Bindra  (1976,  1978).  Accordingly, i t is not based on any fully articulated statement concerning  the  relationship between stimuli, central representations, expectations and responses, or  concerning  the  associations  between  these  constructs.  Rather,  the  incentive-response hypothesis simply rests on the assumption that stimuli that are associated with primary rewards attain incentive value. No formal statement shall be presented  defining the incentive strength of a stimulus, but i t is assumed to  be determined by monotonically  increasing functions depending on the degree of  association between the stimulus and a biologically relevant stimulus, and on the magnitude of the biological significance of that relevant stimulus. - 36 -  Application of the incentive-response  hypothesis  to feeding:  The hypothesis  predicts that when the animal observes a food-related stimulus, the level of dopamine release in the forebrain is increased.  This increase in dopamine release  results i n approach to the incentive which may be a discrete cue or an element in a stimulus compound (see Schneirla, 1958 and White, Messier and Carr, 1984 for discussions of the complex nature of approach). the  animal would be expected to approach food  usually available.  Thus, the hypothesis  In the context of feeding,  or the place where food is  makes clear predictions with respect to  appetitive behaviours. Stimulation of dopamine activity should  be functionally equivalent  to an  increase in the incentive value of food and lead to approach of food related stimuli. that  This is observed with food itself and with conditioned-reinforcing signals  have previously  stimulation.  been paired  with  food,  I t may be suggested that higher  but only  with  some levels of  levels of dopamine stimulation  indiscriminantly enhance the incentive value of a l l stimuli, and beyond a certain level of stimulation the pre-potency of food-related stimuli is overwhelmed by any and a l l other objects in the environment. Alternatively, activation of dopaminergic mechanisms involved in appetitive behaviours may overwhelm other involved in consummatory behaviour.  mechanisms  The animal may repeatedly approach food  but immediately move on before feeding. The  status of dopamine systems during  consummatory behaviour is less  clear. On one hand, food is of biological significance and should have a naturally high incentive value.  On the other hand, there is some evidence that different  mechanisms  appetitive and consumatory  subserve  Jacobs and Harris, 1985). that  dopamine  neurons  behaviours  (Konorski, 1967;  It is possible that dopamine, and the forebrain regions project  to, are exclusively - 37 -  involved  in appetitive  behaviour.  Functional dopamine disruption does not disrupt escape, which may be  viewed as a consummatory response,  and even cecerebrate  animals will ingest  food i f i t is placed directly in contact with their mouths or on their (Woods, 1964). necessary  Although  bodies  high levels of dopamine activity are apparantly not  for the performance of a consummatory response,  normally accompany such behaviours.  high levels could  High dopamine release while feeding could  keep an animal i n contact with food, but i t could also result in the animal approaching extraneous environmental stimuli. Interpretation of the role of dopamine i n the onset of. satiety is again problematic.  Satiety is characterized by the cessation of contact with food that  should, according to the hypothesis, be associated with a decrease in dopamine activity. may  However, when an animal stops eating i t initiates other activities and  be quite active, a state which may well be associated with increases in  dopamine release. In the post-prandial period an animal incentives (eg., Cabanac, 1971).  is less attracted by food-related  The hypothesis predicts that during this period  incentives should evoke less response from dopaminergic systems, and dopamine neurons may even be actively suppressed.  This is consistent with the observed  suppression of dopamine activity by glucose and CCK.  However, this prediction is  incompatible with the elevation in dopamine turnover in the post-prandial period observed by Heffner et al (1980, 1984) and Chance et al (1985).  This point shall  be discussed more extensively below. In summary, the incentive-response hypothesis  handles  most of the data  available concerning dopamine and feeding quite well, with the exception of the observed increases in dopamine activity following ingestion of a meal.  However,  there is little evidence that is directly related to the fundamental assertion of - 38 -  the hypothesis, namely that incentive, food-related stimuli elicit an increase in dopamine activity, which in turn results in behavioural responses to these stimuli. One  way  of testing this is to observe respones to conditional stimuli that have  previously signalled the delivery of food, and to examine the role of dopamine in these  responses. Migler (1975) conducted such a study with results that are in accord with  the incentive-response hypothesis.  In his "conditioned approach" paradigm, four  monkeys were presented with a compound stimulus consisting of the illumination of a yellow panel for 15 sec, and the presentation of a tone in ther first second of panel illumination.  A food pellet was  the onset of the compound stimulus.  delivered behind a flap coincident with  Thus, the panel-tone combination  an excitatory conditional stimulus and acquired incentive value.  served as  Administration of  chlorpromazine increased the proportion of long-latency responses for each animal. Each  monkey  typically  took  the  pellet  in the  first  few  seconds of  panel  illumination while undrugged, but when drugged they often did not respond until the panel was no longer illuminated. Interestingly, responses were often initiated as soon as the panel light went off. Unfortunately, there are several problems with this study. monkeys were used, too chlorpromazine chlorpromazine It also has  as  the  few  for statistical  neuroleptic  in  this  analysis. study  was  First, only four  Second, the  use  of  unfortunate,  because  lacks the specifity to dopamine receptors that other drugs have. pronounced effects in other neurotransmitter  noradrenergic receptors. in responding was  systems, notably  on  Finally, no controls were run to ensure that the deficit  not due to some general performance deficit.  The incentive-  response hypothesis  requires a more definitive test, using a sufficiently large  number of animals  to provide  reasonable - 39 -  statistical  power, and  employing  a  specific dopamine receptor blocker. The present thesis presents the details of a related experiment incorporating these features and a second experiment directly investigating changes in dopamine turnover as a result of exposing animals to a food-related conditional stimulus. The results of both experiments confirm Migler's study and provide support for the incentive-response hypothesis. These  experiments  indicate  a  role  for dopamine systems in appetitive  feeding behaviours. However, a comprehensive feeding must extend Accordingly, two  to consummatory behaviour and  the post-prandial period.  other experiments investigated the role of dopamine in these  phases of feeding behaviour.  First, the effect of dopamine receptor blockade on  consummatory behaviour was investigated. same  analysis of the role of dopamine in  neuroleptic  used  in  the  Injections of equivalent doses of the  experiment  on  appetitive  behaviour  were  administered to rats prior to the onset of a free-feeding session. Finally,  a  fourth  experiment  was  conducted  to  clarify  the  nature  of  forebrain dopamine activity during the post-prandial period. To this end dopamine turnover following the consumption  of food was  analyzed using a more reliable  technique than the radioenzymatic assay employed by Heffner et al (1980), namely high pressure liquid chromatography coupled with electrochemical detection.  In  addition,  of  the  analysis  was  extended  to  the  ingestion  of  other  substances, to investigate whether different patterns of dopaminergic  types  activity  would be produced by feeding with different moter, incentive and post-ingestional consequences.  - 40 -  EXPERIMENT 1  Weingarten (1983, 1984) has developed an elegant technique to investigate responses to food-related stimuli.  Rats are housed in individual  chambers, with water available at a l l times. food  the animals  sound-attenuating  During a conditioning phase the only  receive is delivered as six discrete meals per day, each  consisting of an 8ml portion of liquid diet, delivered to a feeding niche at one end of the cage.  These meals provide the rats with as much food as they would  normally consume during free feeding. the  last minute of an extended  buzzer-light combination.  Presentation of the meal coincides with  conditional stimulus  (CS+) consisting of a  By the end of an 11 day training phase the animals  reliably enter the feeding niche with a short latency once meal begins. interestingly, the animals  More  spend much of the CS+ period in the niche, and as  soon as the meal is delivered they consume i t . After training, a test phase commences in which the animals have unlimited free access to food at a site distinct from the feeding niche. identical to that used in training.  The free food is  One CS+ trial is given per day. As i n the  training phase the animals approach the niche and consume the food when i t is delivered.  The presence of free food ensures that the animals are not eating i n  response to a nutritional deficit. Instead, the feeding appears to be a conditional response (CR) evoked by the CS+. In terms of the incentive-response  hypothesis  described  above the CS+  should, by acting as a food-related incentive stimulus, cause an increase in dopamine release, resulting in approach of the feeding niche. conditioned  feeding  paradigm  was  adopted  with  only  Weingarten's (1984)  minor modifications to  investigate this possibility . Animals received a l l their daily food rations as six - 41 -  discrete meals which were signalled, prior to delivery, by a conditional stimulus (CS+).  Once the animals were responding reliably to the CS+  by approaching the  food source they were given one of three doses of the dopaminergic antagonist, pimozide.  Attenuation  of  responding  was  attributed to  interference  with  dopaminergic transmission.  METHOD Subjects: A l l rats used in this study were hooded male rats obatained from Charles River Laboratories of Canada, and weighed 350-480g at the start of the experiment. Apparatus: Conditioning was  conducted in 8 individual sound attenuating  chambers (modified Coleman "Sno-Lite  Low  Boy"  coolers).  fitted with a dim houselight which was  illuminated from 6am  for air circulation and to provide background white noise. outer chamber was rat was  housed.  Below this compartment was Two  The  and  5 X  7cm  had  a 1cm  in which a  end wall of the  always available to  recessed into the opposite wall.  high lip. Entry into the niche  detected by the interruption of a photocell. generator  plus a fan  a bed of Sani-cel, seperated from  a Richter tube containing tap water was A feeding niche was  was  Contained within each  holes were drilled in one  the rat in one of these. niche was  to 6pm,  a smaller plexiglas compartment (29 x 23 x 18cm)  the rat by a wire grid floor. compartment and  Each chamber  was  For conditioning, a buzzer, a tone  and a bright cue light were mounted on the ceiling of the chamber,  outside the plexiglas compartment.  The  cue light and tone were located above  and to the left side of the feeding niche, while the buzzer and houselight were located at the opposite end. A peristaltic pump (Cole-Parmer) delivered liquid diet (Sustacal, Mead Johnson) into the rear of the feeding niche via silastic tubing. - 42 -  A l l cues, the pump and the photocells were connected to an interface under the control of a Nova 3 computer with Manx software. Procedure: Prior to conditioning a l l rats were pre-exposed to the liquid diet so that neophobia would not interfere with conditioning, and to ensure that each rat found overnight  the and  diet palatable. each rat was  consume the diet overnight water.  Any  Standard  lab chow and  given 40ml of liquid diet.  water were removed Any  rat which did not  received a similar 40ml portion the next day,  rat which did not consume the diet by the second day (about  of rats) was  discarded from the experiment.  plus 5-10%  Free food and water were returned  to the rats following pre-exposure, but food was  removed the day prior to the  onset of conditioning. During conditioning each rat was compartment.  The  housed continuously  in an individual test  chambers remained closed and undisturbed  daily mantainance period.  CS+  trials consisted of a 210sec buzzer-light compound.  An 8ml portion of liquid diet was the final 60sec of the CS+  except for a brief  delivered into the feeding niche coincident with  period. Thus, the CS+  alone period lasted 150sec. CS-  trials consisted of a 210sec tone which did not signal any other event. CS-  trails alternated, and  were presented on  mean inter-trial interval of 2h.  CS+  a quasi-random schedule with  Thus, each rat received apporoximately 6  trials per day, for a total volume of 48ml liquid diet.  This was  and a CS+  enough food for  some rats to maintain a constant body weight, though many lost up to 10%  of  their free feeding weight over the conditioning period. The occasional  conditioning phase lasted 9-15 equipment failures.  days.  Preliminary  would reliably eat in rsponse to the CS+  Some variability was  caused  by  experiments indicated that a l l rats after this period, even i f food  was  made freely available in a Richter tube. However, in order to study the effect of - 43 -  pimozide on conditioned appetitive responding, such responding was maximized by testing the rats in the absence  of free food.  Even so, some animals did not  reliably spend appreciable amounts of time i n the feeding niche, the operational definition of appetitive responding. Videotaped observation of some rats indicated that  they  would  spend  much of their  time in other, apparently appetitive  behaviours, such as orienting to the light, grooming, and running around the compartment.  As the only response which could be identified during drug tests  was time spent in the niche i t was necessary to exclude any animal not spending at least 5sec i n the niche during the CS+ period, prior to the delivery of food, on the final baseline day of testing.  This resulted in the exclusion of 10 of 28  animals subjected to conditioning. Most animals rarely entered the niche at a l l during CS- trials. some responding did occur, and was occasionally quite pronounced.  However, No attempt  was made to investigate the effect of pimozide on this behaviour. Drug testing was always conducted  during the first CS+ trial after the  onset of the dark phase of the cycle ie., between 1800 and 2200h.  (Some, but  not all, of the rats displayed diurnal variance in their responses, and this time appeared to be near the maximal peak for most of these.) Animals were randomly assigned to receive 0.2, 0.4 and 0.6mg/kg pimozide or it's vehicle (0.6% tartaric acid).  A l l injections were administered 4h prior to the test CS+, at least 40min  after the previous trial. No CS- occurred in the interim. Following pimozide tests rats  were  sacrificed  in a  carbon  dioxide  chamber.  Rats  receiving  vehicle  injections were given 1-2 days of additional baseline training and were then tested again at one of the doses of pimozide. each level of drug dose and vehicle.  - 44 -  A total of 6 rats were tested at  Statistical Analysis: Because of large differences in the quantity of baseline responding observed between different rats, the response  of each  rat while  drugged was compared to his response to the first CS+ of the previous evening. The latency of the response was determined as an index of response onset.  Rats  not entering the feeding niche prior to the onset of food delivery were assigned latency scores of 150sec.  Number of entries into the feeding niche and the total  area under the cumulative response curve were used response  intensity, while frequency  of entry  following  as global measures of the first  entry was  determined as an index of response intensity following response initiation. A l l measures were analyzed using two-way analysis of variance (ANOVA) with day (baseline day vs test day) and level of pimozide dose as the two factors.  When  significant effects were observed post-hoc analyses were conducted using the Newman-Kuel's test, with the alpha level arbitrarily set to 0.05.  RESULTS The  effect of different doses of pimozide and its vehicle on responding  during the CS+ period can is can be seen by examining the cumulative response diagrams of Figures 1 through 4.  In each figure, the response curve for the  animals during the drug test are shown in the lower diagram (B). The responses of the same rats on the control trial, that is the first of the previous evening, are shown in the upper half (A). It is evident from the figures that the animals receiving 0.4 or 0.6mg/kg pimozide were much less responsive to the CS+ in the period prior to food delivery. The  This was confirmed statistically.  latencies of the first entry into the feeding niche are presented in  Figure 5. The ANOVA indicated that there were significant effects of baseline vs  - 45 -  Figure  1:  Cumulative  time spent  in niche during CS+  receiving 0.6% tartaric acid vehicle on test day. prior to test trial.  period  by  A: Baseline trial of evening  B: Test trial, four hours after injection of vehicle.  - 46 -  animals  Figure  2:  Cumulative  time spent  in niche during CS+  receiving 0.2mg/kg pimozide on test day. test trial.  period  animals  A: Baseline trial of evening prior to  B: Test trial, four hours after injection of pimozide.  - 48 -  by  A.  TRIAL TIME / s e c . - 49 -  Figure 3:  Cumulative  time spent  in niche during CS+  receiving 0.4mg/kg pimozide on test day. test trial.  period  animals  A: Baseline trial of evening prior to  B: Test trial, four hours after injection of pimozide.  - 50 -  by  A 140 H  TRIAL TIME / s e c . - 51 -  Figure 4:  Cumulative  time spent  in niche during  receiving 0.6mg/kg pimozide on test day. test trial.  CS+  period  animals  A: Baseline trial of evening prior to  B: Test trial, four hours after injection of pimozide.  - 52 -  by  A. ONSET OF FOOD DELIVERY  TRIAL TIME / s e c . - 53 -  Figure  5:  Mean  latency to enter  niche  following  CS+  onset.  Dark  bars  represent baseline trial of evening prior to test trial. Light bars represent test trial, four hours after injection of pimozide or vehicle. standard error of the mean f o r six rats. pimozide doses in mg/kg.  - 54 -  Vertical lines represent  Figures along lower axis represent  Latency / sec cn _l  CM  o  l  >  Cn l  0>  o  I  cn I  CD  O  I  O  cn I  Figure 6:  Mean number of nosepokes during CS+ period prior to onset of food  delivery.  Dark bars represent baseline trial of evening prior to test trial.  Cross-hatched bars represent test trial, four hours after injection of pimozide or vehicle.  Vertical lines represent standard error of the mean f o r six rats.  Figures along lower axis represent pimozide doses in mg/kg.  - 56 -  40  35-  30-  - 57 -  Figure 7:  Mean area under the cumulative response curve during the CS+  period prior to onset of food delivery. Square root of area is shown. Dark bars represent baseline trial  of evening prior to test trial.  Cross-hatched  represent test trial, four hours after injection of pimozide or vehicle. lines represent standard error of the mean for six rats. axis represent pimozide doses in mg/kg.  - 58 -  bars  Vertical  Figures along lower  Square Root of Area Under Curve / sec cn _L_  ho o  cn  (j4  O  cn  _ l _  _ l _  o  [  Figure 8:  Mean frequency of niche entry during the CS+ period, after  first  entry, but prior to onset of food delivery. Dark bars represent baseline trial of evening prior to test trial.  Cross-hatched bars represent test trial, four hours  after injection of pimozide or vehicle. of the mean for six rats.  Vertical lines represent standard error  Figures along lower axis represent pimozide doses in  mg/kg.  - 60 -  0.32  -i  0.28-  - 61 -  test day (F(l,20)=8.94, £<.01) and level of drug  (F(3,20)=4.19,  significant drug x day interaction (F(3,20)=3.51, p_<.05).  E<05), plus a  Post-hoc tests revealed  that latencies were significantly longer following injection of 0.4mg/kg pimozide than in the vehicle and 0.2mg/kg conditions.  The 0.6mg/kg dose did not cause a  further increase in latency relative to baseline, over the effect observed with a dose of 0.4mg/kg. Rats  were  not only slower  to initiate  entery into  the feeding niche  following pimozide treatment, they also entered i t less frequently.  The number of  entries into the niche prior to onset of food delivery is shown in Figure 6. The ANOVA  again indicated a significant day effect (F(l,20)=19.46, E 0 1 ) and a < n  significant dose x day interaction (F(3,20)=5.79, p_<.01). that  0.4 and 0.6mg/kg significantly  decreased  Post-hoc tests revealed  the number of niche  entries,  curve  delivery  relative to baseline controls. The  area  under the cumulative  response  prior  to food  indicates the total amount of appetitive responding. The square rooot of the area was determined to restore linearity to the function, and is illustrated in Figure 7.  The A N O V A indicated a strong effect of day (F(l,20)=24.96, £<.0001) and a  significant day x dose interaction (F(3,20)=4.40,  p_<.05).  Post-hoc test revealed  that 0.4 and 0.6mg/kg pimozide decreased responding relative to baseline. Measures responding.  of total  responses  are influenced  by the latency  to begin  Thus, the decreased responding observed could simply reflect slower  response initiation, without any changes i n responding after initiation occured. However, Figure 8 reveals that the frequency of entries into the feeeding niche, in the period between the first entry and the onset of food delivery, was also decreased by the high doses of pimozide.  The A N O V A conducted on these data  excluded two rats from the 0.4mg/kg test and one from the 0.6mg/kg test, as - 62 -  these animals did not respond at all prior to food delivery.  A significant effect  effect of day was observed (F(l,17)=77.04, p_<.0001), as well as a significant dose x  day interaction  decreased  (F(3,17)=84.25, E<.0001).  response  frequency  by  rats  Both  0.4 and 0.6mg/kg  in this  period, relative  pimozide to their  performance on the baseline day.  DISCUSSION This experiment indicated that dopaminergic the production of appetitive responses.  transmission is necessary f o r  Entry into the feeding niche where a  signalled meal was about to be delivered was attenuatd by 0.4 and 0.6mg/kg pimozide.  Under these drug conditions rats took longer to initiate responding.  Once they began, the magnitude of these responses was diminished. Despite the clarity of these effects, some caution must be exercised in the interpretation of these data. validity  In particular, i t is necessary to question the  of niche-entering as a measure of appetitive responding.  Decreases  similar to those observed could occur i f , for example, the animals spent increased amounts of time grooming, orienting to the CS+ itself, or began drinking in response to the CS+.  Therefore, the effect of pimozide on conditioned appetitive  behaviour was directly examined by videotaping the responses  of three other  rats, not included i n the present study, both while they were undrugged and again after injections of pimozide. This analysis indicated that pimozide made the animals extremely unresponsive.  Their undrugged response to the CS+ was very  intense and had a very short latency. compartment and the cue light.  They would  explore the niche, the  They groomed and ran around. In contrast, under  the influence of pimozide they lay motionless for most of the CS+ period. slowly did they rouse themselves  Only  to stand, to groom, and to make their way 63 -  slowly across the chamber to the feeding niche.  Once there, they would remain  in the niche and eat the signalled meal in an apparently normal manner.  These  observations lend credibilty to the use of niche-entry as an index of appetitive responding.  Future  studies employing video analyses more extensively will be  conducted to examine the nature of the appetitive deficit more closely. The deficits observed in responses to the CS+ were greatly reduced by the onset of food delivery.  As may be seen clearly in Figure 3, following 0.4mg/kg  pimozide 4 of 6 rats spent virtually a l l (>58sec) of the 60sec food delivery (UCS) period i n the feeding niche, apparently consuming food.  These four rats include  one which had only entered the niche once in the previous 150sec.  Two rats  never entered the niche prior to food delivery, yet when they did enter i t (5.43 and 48.22sec later), they remained there for the remainder of the food delivery period without interuption. Figure 6 illustrates that even though all rats exhibited attenuated reactions to the CS+ when they were adminstered  0.6mg/kg pimozide,  three subjects spent >56sec of the food delivery period in the niche.  As with  0.4mg/kg, a l l rats remained in the niche almost constantly once they entered i t during  the food  delivery period.  Thus, although  appetitive reactions were  markedly reduced by 0.4 and 0.6mg/kg pimozide, consummatory reactions were apparently not disrupted. This suggests that dopamine systems may be exclusively involved in the appetitive aspects of feeding.  That is, dopamine may only be  involved in feeding behaviour when an animal is distant from the food, or must perform some response to get i t , and may not be required for the consumption of food once the animal is in direct contact with i t . This issue will be addressed further i n Experiment 3, but first a more direct examination  of dopaminergic  activity during conditioned appetitive responding will be presented.  - 64 -  EXPERIMENT 2  The  first  experiment  demonstrated  that  a  dopaminergic  substrate is  necessary  for the production of the appetitive reactions observed when a rat is  presented  with  a CS+  i n the conditioned  feeding  paradigm.  However, the  experiment did not directly address the question of whether the substrate was actively involved i n the production of the appetitive reactions. That is, although the results of the experiment indicated that dopamine was required for appetitive responses to occur, i t is not clear whether the response was actually a result of increased  dopaminergic  activity  or whether  i t was  simply  necessary  that  dopaminergic systems be functional f o r the animal to be capable of performing such responses.  Further, the use of a peripherally adminstrated  pharmacological  agent such as pimozide, which disrupts dopaminergic transmission at a l l dopamine receptor  sites  in the brain, did not permit  dopaminergic systems are involved in these The  second experiment was designed  the identification  responses. to shed light on these  through direct neurochemical investigation of dopaminergic activity. metabolites  of which  two issues The level of  of dopamine in brain tissue relative to the level of the parent  molecule' provides an index of the release of dopamine at the time of sacrifice. (La Vielle, Tassin, Thierry, Blanc, Hevre, Barthelemy and Glowinski, 1978). it is possible to test a major prediction of the incentive-response namely that presentation of an incentive stimulus should forebrain dopamine turnover.  Thus,  hypothesis,  result in increased  An increase in turnover would be consistent with  the incentive-response hypothesis, while a negative finding would be consistent with a suggestion that only basal levels of dopamine release are necessary f o r appetitive responding to occur.  - 65 -  Measurement of dopamine and its metabolites also provides an indication of which dopaminergic system or systems are involved in appetitive responding. Only those regions in which dopamine turnover is increased are implicated as playing an  active role in such responding.  Accordingly, tissue from  three different  dopamine projection sites was analyzed (refer to Fallon and Moore, 1978, for a detailed  description  forebrain).  of the anatomy of the dopaminergic innervation of the  The first of these was the striatum, the brain region with the  heaviest dopaminergic innervation. nigra.  This innervation originates in the substantia  Together, the nigra and the striatum  are major  components of the  extrapyramidal motor system. In addition, analyses were performed on tissue from two  limbic sites receiving dopaminergic projections from the ventral tegmental  area, namely the n. accumbens and the olfactory tubercle.  METHOD Materials and Apparatus: Conditioning chambers, diet and type of rats used in Experiment 2 were the same as those in Experiment 1. Procedure: The conditioning procedure was the same as i n Experiment 1 except that the CS+ duration was increased to 630sec, with liquid diet again being delivered in the final 60sec.  This longer CS+ period was used in an  attempt to maximize any induced neurochemical changes. days.  Conditioning lasted 8-9  16 rats were conditioned, and of these the 14 which spent the greatest  amount of time in the feeding niche during CS+ delivery were assigned to either the "CS+" group or the "control" group.  Each CS+ rat was exposed to the CS+  for 4min before being removed from the chamber and sacrificed by cervical fracture.  The brain was removed, mounted on a microtome and frozen. Slices  containing the neostriatum, n. accumbens and olfactory tubercle were placed on  - 66 -  ice. These structures were then bilaterally dissected from the slices and prepared for  analysis of dopamine  and i t s metabolites  (DOPAC) and homovanillic acid (HVA)  3,4dihydroxyphenylacetic  acid  by high pressure liquid chromatography with  electrochemical detection (HPLC-ED), as described by Jakubovic, Lin and Fibiger (in press).  Control rats were treated identically to those receiving exposure to  the CS+ except that they were removed from the chamber just prior to CS+ onset. Statistical  Analysis: Levels  of dopamine and the two metabolites  were  measured in terms of ug/g wet tissue, and the ratios of the levels of the metabolites  to dopamine  were  computed.  These  five  measures  were  each  subjected to a two way ANOVA. In addition to the group factor (CS+ ys control), hemisphere was treated as a factor, as both left and right samples were taken from each of the brain regions.  RESULTS The  ratio of DOPAC to dopamine in the three brain regions is shown in  Figure 9. The DOPAC/DA ratio was significantly increased in the n. accumbens, indicative of increased dopamine turnover (F(l,7)=6.678, increased from .325 to .389, a 2 0 % increase.  £<.05).  The ratio was  An apparantly similar 2 0 % increase  in the striatum was not statistically significant (F(l,7)=3.036, n.s.). No significant changes in DOPAC/DA  ratio  were observed  in the olfactory tubercle.  No  significant hemisphere effects were observed in any region. Ratios of HVA to dopamine are displayed in Figure 10. Comparison of this figure with Figure 9 suggests that increases HVA/DA ratio occurred which were  - 67 -  Figure 9: DOPAC/DA ratios in the three brain regions analyszed, after rats had been exposed to the CS+ for four minutes. hemisphere tissue.  Cross-hatched bars represent left  Dark bars represent right. Vertical lines represent standard  error of the mean for seven rats.  - 68 -  STRIATUM  ACCUMBENS  O. TUBERCLE  Figure 10:  HVA/DA ratios in the three brain regions analyszed, after rats had  been exposed to the CS+ for four minutes. hemisphere tissue.  Cross-hatched bars represent left  Dark bars represent right. Vertical lines represent standard  error of the mean for seven rats.  - 70 -  STRIATUM 0.12n  ACCUMBENS - i  O. TUBERCLE - i  Table I. Concentrations of dopamine, DOPAC and HVA in various brain regions of rats sacrificed before or after exposure to the CS+ DOPAMINE  DOPAC  Left  Right  Controls  11.343 0.412  11.671 * 0.356  CS+  10.643 t 10.971 *+ 0.249 0.302  Left  Right  HVA Left  Right  STRIATUM 2.839 .183  2.894 .156  0.837 .053  0.858 .073  3.077 .224  3.213 .204  0.963 .096  0.936 .090  ACCUMBENS Control  0.825 .022  0.814 .033  2.702 .094  2.602 .132  0.686 .032  0.652 .035  CS+  0.810 .012  0.708 * t .016  3.120 * .197  2.799t .170  0.798 t .077  0.677= .049  Controls  4.457 .330  4.567 .367  2.055 .241  2.124 .209  0.376 .033  0.356 0.026  CS+  4.256 .396  4.324 .393  1.842 .126  2.042 .183  0.352 .025  0.386 .031  OLF. T U B E R C L E  Values are expressed as mean ug/g wet tissue i n each hemisphere. Lower figure represents standard error of the mean of seven rats. * - differs from contralateral hemisphere, p < .05. t -- differs from ipsilateral control, p < .05.  - 72  similar to the significant increase observed i n the DOPAC/DA ratio i n the n. accumbens,  however  F(l,7)=2.331,  n.s.; n. accumbens:  the  olfactory  these  tubercle  were  not statistically  F(l,7)=3.732, £<.10).  significant  (striatum:  No increase is apparant in  Again, no significant hemisphere effects  (F<1.0).  were  observed. Absolute levels of dopamine, DOPAC and HVA are indicated in Table 1. No significant main effects brain region. the  E<-05)  As  There were, surprisingly, strong hemisphere effects, particularly in  n. accumbens.  hemisphere  of treatment were observed for any chemical i n any  There, higher levels of dopamine were found in the left  (F(l,12)=17.059,  and DOPAC  while higher levels of HVA  E< 005),  (F(l,12)=11.551,  £<.01)  were observed in the right hemisphere.  well, dopamine levels were elevated i n the right striatum  E<.005),  while  (F(l,12)=5.703,  DOPAC  levels  were  (F(l,12)=6.369,  higher  i n the right  (F(l,12)=17.058,  olfactory  E<-05).  Examination of Table 1 suggests that the hemisphere differences pronounced in the treated treatment  interaction  (F(l,12)=11.083,  tubercle  E^OD.  animals.  However, the only significant hemisphere x  was f o r dopamine which  are more  reflects  levels  a lower  i n the n.  accumbens  dopamine level i n the right  hemisphere of the CS+ animals.  DISCUSSION When rats were exposed to a CS+ which signalled the imminent onset of food delivery for four minutes there was a 20% increase in dopamine turnover in some forebrain prediction  regions.  This increase i n release is i n agreement with the  of the incentive-response  hypothesis thatexposure  to an incentive  stimulus should result in an increase in forebrain dopamine turnover. Such release  - 73 -  may occur to naturally attractive food related stimuli (eg., odours) and, as the current results show, are released as a conditional response (CR) to an arbitrary simulus, such as a buzzer or a light. that  indicated that  dopamine  Together with the results of Experiment 1,  receptor  blockade  interfered with  appetitive  responding, the result of this experiment is consistent with the suggestion that increased dopamine release in reponse to incentive stimuli dopamine release is a critical component of appetitive responding. Although  the effect was not statistically robust, in the case of the n.  accumbens i t is reasonably reliable, because there was a significant increase in DOPAC to dopamine ratio. An increase of apparently equal magnitude occurred in the striatum, certainly there is no evidence that the increase in release i n the n. acumbens was greater than that in the striatum. Thus, the results do not help in clarifying the relative roles of the mesolimbic and nigrostriatal dopamine systems in appetitive responding.  It appears that any increase in dopamine turnover in  the olfactory tubercle is not as large as that observed in the n. accumbens. An increase of twenty percent in dopamine turnover is quite remarkable, given the relatively brief period for which the CS+ was presented.  Other studies  examining changes in dopamine turnover as a result of behavioural activity often employ a much longer period. accompanying  For example, i n their studies of dopamine release  reinforced circling, Yamato  and  Freed  (1982, 1984) had  animals perform for twently minutes prior to sacrifice.  their  The increase after only  four minutes appears quite substantial in this context. The differences in absolute levels of dopamine and its metabolites in the two hemispheres was a complete surprise. Hemispheric differences in dopamine or metabolite  levels  are often  reported  in individual  rats,  but these  are not  consistent across individuals (jerussi and Glick, 1976; Jerussi and Taylor, 1982). - 74 -  That is, although some asymmetry is to be expected in a given rat, levels should not be consistently higher in right vs left accumbens across animals.  These  effects could be a spurious result of experimental procedure. Because hemispheric differences were not expected, no procedures were employed to control for them. Specifically,  the left  hemisphere tissues  were  always  dissected out and  homogenized before their right hemisphere counterparts, and were analyzed first in the HPLC columns. Thus, differing amounts of degredation could have occured in the samples prior to analysis.  This explanation is not very  satisfactory,  particularly in light of the finding that dopamine levels were higher in the right stiatum and the left accumbens, while DOPAC levels were higher i n the left accumbens and right olfactory tubercle. One possible interpretation of the data is that there is a bilateral increase n dopamine turnover but that in one hemisphere only (ie. the left n. accumbens) there is a compensatory increase in dopamine synthesis.  - 75 -  EXPERIMENT 3  The results of the first two experiments are consistent with the assertion of the incentive-response hypothesis that appetitive responding to an incentive stimulus is dependent on dopaminergic activity.  However, other intrepretations of  the results of these experiments are possible.  For example, in Experiment 1 the  decrease  following  in appetitive  responding  observed  dopaminergic receptor  blockade may not be specific to appetitive responding at all, but may merely reflect a general disruption in feeding behaviour, global motor deficits, or an attenuation of "hunger".  The apparent consumption of food in that experiment  argues against this interpretation, but in the absence of quantitative data it cannot  be ruled out.  Consequently, Experiment 3 examined the  effects of  pimozide, at the same doses used in Experiment 1, on the consumption of the same liquid diet which was used in the earlier experiment.  METHOD Subjects  and  apparatus:  18  male  rats  of  the  same  strain  used  Experiments 1 and 2, and of similar size, were used in this experiment.  in  Liquid  diet (Sustacal) was presented to the subjects in 50ml Nalgene tubes fitted with drinking spouts. Procedure: Rats were familiarized with a feeding regime consisting of a 20min period of access to liquid diet at about the same time each day, followed by a one hour break, and then a one hour period of ad lib. access to food pellets. After  Water was available at all times except during the liquid diet period. the  animals  were  reliably eating  - 76 -  a  constant  volume  of  liquid  diet  (17.6+0.6ml) in the 20min period, that is after nine days, they were assigned to three groups of six rats each, approximately equated for consumption. Drug testing was conducted on two days, separated by one baseline day. On the first day half of the rats in each group received pimozide, while the other half received  0.6% tartaric  acid vehicle.  On the second test day injection  conditions were reversed and the rats which had received pimozide were given vehicle, and vice versa. Rats from the three different groups received 0.2, 0.4 or 0.6mg/kg pimozide subcutaneously, 4h prior to liquid diet delivery, on their test day. Statisitical analysis: The results were analyzed using a two-way ANOVA. Drug vs vehicle administration constituted one factor, while dose of drug (0.2, 0.4 and 0.6mg/kg) constituted the second.  RESULTS Examination of Figure 11 indicates that no dose of pimozide had any noticable effect on home cage consumption of liquid diet.  This impression is confirmed by the  ANOVA, which showed no significant effect of drug or drug dose, and no significant interaction (F<1 in all cases).  DISCUSSION In this experiment no attenuation of feeding was seen even with 0.6mg/kg pimozide.  This  is in marked  contrast  to the strong  suppressant effects on  conditioned appetitive responding seen in Experiment 1, even with 0.4mg/kg. result is contrary to those of Heffner et al (1977), Blundell and Latham (1978),  - 77 -  This  Figure 11: Consumption of liquid diet in twenty minute session four hours after injection of pimozide or vehicle. following vehicle injection.  Light bars represent right consumption by the same  rats following pimozide injection. mean for six rats.  Cross-hatched bars represent consumption  Vertical lines represent standard error of the  Figures along lower axis represent dose of pimozide in  mg/kg.  - 78 -  28  Tombaugh  et a l (1979)  and Wise  and Colle  suppression of food intake by comparable  (1984), a l l of whom  doses of neuroleptics.  observed  Nor were the  results of this study similar to those of Lawson et a l (1984) or Franklin (personal communication), who observed increased food consumption following administration of pimozide.  These discrepancies may be due to differences in drugs, injection  procedures, food, deprivation factors.  levels, familiarity  of feeding regime  or other  For present purposes the critical fact is that doses of pimozide which  strongly suppressed conditioned appetitive responses in Experiment discernable effect on food consumption in the present experiment.  1 had no  This was true  even though the two experiments employed the same food, the same drug vehicle, the same injection procedure, and rats of the same stock. In each case the rats had been on restricted feeding regimes f o r about a week prior to the pimozide test. Clearly, conditioned appetitive responses are much more vulnerable than are consummatory responses to the disruptive effects of dopamine receptor blockade.  - 80 -  EXPERIMENT 4  The  previous experiment  demonstrated  that the doses of pimozide  that  seriously disrupt appetitive responding for cues related to food delivery do not diminish consummatory responding for the same food. Thus, dopamine release does not play an active role in the production of consummatory feeding behaviour as measured by amount of food consumed, allthough a certain minimal amount of dopamine activity (ie., levels above those seen following NSB neccessary to permit consumption  lesions) may  be  to occur, the quantity of dopamine release in  unlesioned animals is unlikely to ever fluctuate low  enough to interfere with  consummatory behaviour. In contrast to this analysis, Heffner et al (1980) interpreted the increased dopamine turnover they observed one hour after food delivery as evidence that dopamine  was  released  during  feeding.  The  lack  of  effect  of blocking  post-synaptic dopamine receptors during a feeding session suggests that such release has no immediate impact on consummatory behaviour.  Therefore, i t is  hard to understand why such release would occur. Heffner et al (1980) claim that the observed increase in dopamine turnover must have been due observed  following  to the act of feeding itself, because increases were not intubation  of food.  However, the  tube-fed  and  self-fed  treatments differ in several important ways. In addition to not going through the motor patterns of feeding, the tube-fed animals do not taste the food and not experience the post-ingestive effects of feeding in the same way animals.  Experiment  4 was  may  as self-fed  designed to extend the analysis of the impact of  feeding on dopamine turnover by examining the impact of manipulating motoric and nutritive aspects of this feeding.  Thus, while some animals ate solid food 81  pellets, similar to those used by Heffner et al, others consumed the liquid diet used in Experiments 1 through 3. chewing, but is dependent  Such consumption does not involve gnawing or  on a somewhat different set of tongue and mouth  movements. Another group of rats consumed comparable quantities of a saccharin solution. Rats in the saccharin group will have performed motor actions similar to those displayed by rats consuming liquid diet.  Those rats that consume saccharin  will also have experienced strong, i f different, taste sensations.  Consumption of  saccharin solution may also be confidently described as "rewarding", because rats avidly  consume  this  solution  in much  much  greater  quantities  than water.  However, although saccharin is sweet i t is a metabolically inert substance, so its' consumption  produces  consumption  of  no  saccharin  direct solution  post-ingestive a  useful  effects.  This  fact  makes  technique for separating  the  post-ingestive consequences of feeding from the motoric and reward properties of feeding itself.  METHOD Subjects and Apparatus: 30 male rats were used which were similar to those used in the other experiments. Liquid diet (Susatcal) and 0.4% saccharin (Fisher) solution were delivered in Nalgene tubes, as in Experiment 3. Standard Purina lab pellets were available to the rats in food hoppers mounted on the outside of the  cage. Procedure: The procedure employed was derived from that of Heffner et §1  (1980).  Rats were randomly assigned to five groups (n=6 for each group). Four  groups were adapted for a week to a feeding schedule in which they received food for only 4h/day in their home cages.  The feeding period occurred near the  middle of the 12h lights-on period in the colony. Times were slightly varied to  - 82 -  prevent the formation of strong associations between feeding and temporal cues. A fifth group of rats (CA) had continuous free access to food. available to all rats at a l l times.  Water was freely  Two groups, the food deprived group and the  pellet group (FD and Pe) received standard pellets in each 4h feeding period. One group (LD) received liquid diet during the 4h feeding period on the fourth day, and i n the first hour on the eighth and twelfth days, followed by 3h of pellets. On all other days they received 4h of pellets. Rats in the Sa group were treated exactly  like  substituted restricted  those  in group  f o r liquid feeding  diet.  groups  LD, except  that 0.4% saccharin solution  This procedure were  maintained  ensured  was  that rats i n the four  at nearly  equivalent  levls  of  deprivation, while i t allowed the rats in groups Sa and LD to become familiar with these other solutions. On the test day, the fifteenth overall, a l l the rats were sacrificed and their brains were removed. Rats in group FD were sacrificed when they had been deprived of food for about 20h, before food was delivered on the test day. was taken to avoid exposing these rats to odours delivery-  or sounds signalling food  Rats in groups Pe, LD and Sa were sacrificed l h after they had been  given pellets, liquid diet and saccharin solution, respectively.  Rats in group CA,  which had continuous access to food, were sacrificed at similar times. these  Care  rats were unlikely to have consumed much food  immediately  Note that prior to  sacrifice, because this occured in the first half of the lights on period. Once the the brain was removed, i t was dissected, homogenized and subsequently analyzed as described in Experiment 2. Data Analysis: Two-way ANOVAs (treatment by hemisphere) were conducted for dopamine, both metabolites and each ratio in each of the three brain regions.  - 83 -  As in Experiment 2 Newman-Keuls  post-hoc tests, with alpha arbitraily set to  0.05, were conducted when the ANOVA indicated a significant effect.  RESULTS In the hour i n which food was available  the LD rats consumed 24.25 +  0.75ml (mean + s.e.m.) of liquid diet, while the Sa rats consumed 27.60 + 1.86ml of saccharin solution.  Pellet intake was not measured for group Pe, but as with  Heffner et a l (1980) i t was apparant that most food intake by this group occurrred in the first hour food was available. The ratios of HVA to dopamine in the three brain Figure 12. ANOVA indicated treatment  (F(4,25)=3.538,  region are shown in  that i n the striatum there was a main effect of  £<.05)  but no  significant  effect  of  hemisphere  (F(l,25)=1.167, n.s.) and no significant hemisphere by treatment interaction (F<1). Post-hoc Newman-Kuels tests only indicated that the HVA/DA ratio was higher in the Pe group than in the FD group. In  treatment  effect  (F(4,25)=6.209, £<.005) on HVA/DA ratio, but no significant hemisphere  effect  (F<1).  the n. accumbens  There  was  also  (F(4,25)=2.715, £=.05).  a  there  was  significant  also  a  significant  treatment by hemisphere  Post-hoc tests indicate  that the Pe and LD groups had  significantly higher HVA/DA ratios than any other groups. indiated  interaction  As well, the tests  that the levels were higher in the right n. accumbens than in any  hemisphere  of any other  group, and were higher  than in the contralateral  hemisphere of the the same animals. No main effects on HVA/DA ratio were observed in the olfactory tubercle (Fs<l),  and there  was no  significant  treatment by hemisphere  (F(4,25)=2.623, n.s.).  - 84 -  interaction  Figure 12: HVA/DA ratios in the three brain regions analysed, one hour after various feeding treatments. (no food for 20h). sacrifice.  CA: Continuous access to food. FD: Food deprived  Pe: Had access to standard food pellets for l h prior to  LD: Had access to liquid diet for l h prior to sacrifice. Sa: Had  access to 0.4% saccharin solution for l h prior to sacrifice. represent left hemisphere tissue.  Cross-hatched bars  Dark bars represent right. Vertical lines  represent standard error of the mean for six rats.  - 85 -  STRIATUM  ACCUMBENS  0. TUBERCLE  0.18-1  0.160.14-  0  V  ^  #  0  v 45  §  0  v <P <c*  #  Figure 13: DOPAC/DA ratios in the three brain regions analysed, one hour after various feeding treatments. deprived (no food for 20h).  CA: Continuous  access to food. FD: Food  Pe: Had access to standard food pellets for l h  prior to sacrifice. LD: Had access to liquid diet for l h prior to sacrifice. Sa: Had access to 0.4% saccharin solution for l h prior to sacrifice. bars represent left hemisphere tissue.  Cross-hatched  Dark bars represent right. Vertical lines  represent standard error of the mean for six rats.  - 87 -  ACCUMBENS  0. TUBERCLE 0.8 n  cJf  <? $  #  cj  <? $  e?  Table II. Concentrations of dopamine, DOPAC and HVA in various brain regions of rats exposed to various feeding conditions. DOPAMINE HVA DOPAC Left Right Left Right Left Right STRIATUM Continuous Access 11.425 0.560  11.833 a 0.470  1.111 .072  1.197 a .068  2.281 .099  2.455 a .068  Food Deprived  11.408 0.651  12.750 0.530  1.081 .090  1.206 .061  2.194 .120  2.429 * .104  Pellets  11.383 0.370  11.550 0.370  1.393 .056  1.438 .096  2.164 .047  2.372 .064  Liquid Diet  10.958 0.449  10.539 0.436  1.263 .073  1.343 b .055  2.385 .115  2.714 *' .072  Saccharin  10.539 0.435  11.000 0.253  1.033 .038  1.100 .053  2.064 .094  2.274 .051  ACCUMBENS Continuous Access  9.174 .521  8.539 a .438  0.989 .068  0.898 .057  2.575 .225  2.507 .188  Food Deprived  9.113 .428  8.858 .267  1.026 .048  0.915 .060  2.513 .122  2.503 .114  Pellets  9.154 .304  8.677 .354  1.231 .074  1.159 b .074  2.704 .137  2.564 .102  Liquid Diet  9.248 .309  8.677 .314  1.218 .063  1.311 b .120  2.888 .163  3.100 b .071  Saccharin  8.634 .179  8.192 .315  0.895 .055  0.845 .062  2.475 .071  2.465 .051  Continuous Access  4.152 0.225  3.724 a 0.290  0.529 .069  0.538 .042  2.356 .326  2.230 a .294  Food Deprived  3.641 0.346  4.186 0.322  0.506 .053  .562 .047  1.853 .250  2.206 * .226  Pellets  3.515 0.310  4.058 0.436  0.496 .059  0.541 .054  1.663 .323  1.934 .297  Liquid Diet  4.570 + 0.448  4.927 + 0.475  0.570 .023  0.606 .033  2.201 + .276  2.454 .258  Saccharin  3.281 0.401  3.557 0.362  0.464 .050  0.450 .069  1.801 .314  1.974 .347  OLF. T U B E R C L E  Values are expressed as mean ug/g wet tissue in each hemisphere. Lower figure represents standard error of the mean of six rats. * - differs from contralateral hemisphere, p < .05. t -- differs from food deprived rats for ipsilateral hemisphere, p < .05. a - main effect of hemisphere in brain region, p < .05. b -- treatment differs bilaterally from food deprived rats, p < .05. - 89 -  DOPAC/DA ratios are shown in Figure 13. Treatment did not cause a significant change in DOPAC/DA ratios i n the striatum, although there was a trend in this direction <F(4,25)=2.185, levels in the LD group.  £<.l), apparantly due to slightly higher  There was a significant hemisphere effect (F(l,25)=17.52,  p_<.0005) with a higher DOPAC/DA ratio in the right striatum, but there was no significant hemisphere by treatment interaction (F<1). In the n. accumbens there was no significant main effect of treatment on DOPAC/DA ratios (F(4,25)=1.369, n.s.), however there was a significant effect of hemisphere interaction  (F(l,25)=15.597, £<.005) and a significant treatment by hemisphere (F(4,25)=4.113,  £<.05).  The  interaction  reflects  the elevated  DOPAC/DA ratio i n the right hemisphere of the LD animals which is higher than any observed in any hemisphere of any other group, and higher than i n the contralateral hemisphere of the animals in the same group.  The left hemisphere  of the LD animals had higher ratios than those observed in the same hemisphere of the FD animals.  Thus, liquid diet consumption increased DOPAC/DA ratios in  this brain region, but preferentially in the right hemisphere. In the olfactory tubercle there was no main effect of treatment (F<1) and no  treatment by hemisphere interaction  (F<1), but the DOPAC/DA  ratio was  higher in the right hemisphere (F(l,25)=4.605, £<.05). Examination of Table 2 indicates that observed increases in HVA/DA and DOPAC/DA ratios are primarily attributable to increases in metabolite levels, as opposed to decreases in dopamine levels.  In the n. accumbens and striatum  dopamine levels were not altered by feeding conditions (Fs<l), but treatment did alter HVA levels in the n. accumbens (F(4,25)=8.885, £<.0001) and in the striatum (F(4,25)=5.707, £<.005).  In the n. accumbens HVA levels were higher in the Pe  - 90 -  and LD groups than in rats of any other feeding treatment, while in the striatum HVA levels were higher in the Pe and LD groups than in the FD and Sa rats. There  were  also  significant  accumbens and the striatum. were  higher  in the LD  effects  on DOPAC  levels  in both the n.  In the n. accumbens (F(4,25)=3.050, p_<.05) levels  group  than in any other, while  i n the striatum  (F(4,25)=3.189, £<.05) DOPAC levels were higher in the LD group than in the Sa group. Although there were no significant treatment x hemisphere interactions in the n. accumbens or the striatum for dopamine, HVA or DOPAC levels, several main effects of hemisphere were observed.  Dopamine levels were higher in the  left n. accumbens (F(l,25)=8.986, £<.01) and in the right striatum (F(4,25)=13.531, £<.005). HVA levels not significantly different in the two hemispheres of the n. accumbens (F(l,25)=1.557, n.s.), but were higher in the left striatum (F(l,25)=6.932, £<.0001).  than the right  DOPAC levels did not differ between left and  right n. accumbens (F<1), but were 1 0 % higher in right than in left striatum (F(l,25)=51.319, £<.0001). One noteworthy effect was observed in the olfactory tubercle.  Although  there was no main effect of treatment on dopamine levels (F(4,25)=1.888, n.s.), there was a significant main effect of hemisphere (F(l,25)=7.603, £<.05) and a significant treatment by hemisphere interaction (F(4,25)=3.665, £<.05).  Post hoc  tests indicated that dopamine levels were elevated in the right hemisphere of LD animals relative to the same hemisphere of any other group.  With the exception  of group CA dopamine levels were higher i n the left hemisphere of rats of the LD group than in the sinister hemisphere of rats in any other group.  Thus,  dopamine levels were elevated in the olfactory tubercle by consumption of the liquid diet. - 91 -  Overall HVA  and DOPAC  olfactory tubercle (Fs<l). hemisphere  hemispheres,  but there  in the  However, DOPAC levels were higher in the right  (F(l,25)=14.230,  F(4,25)=*2.843, £<.05).  levels were not altered by treatment  p_<.001) except  HVA  levels  was  a  were  trend  in the CA  group  not significantly towards  higher  (interaction:  different  levels  between  in the right  (F(l,25)=3.287, < 1 ) . E  DISCUSSION In agreement with Heffner et a l (1980) the present study found increases in forebrain levels of dopamine metabolites relative to the level of dopamine one hour after rats were presented with food.  This increase does not appear to be  related specifically to the motor actions involved in the consumption of food pellets because such increases were even more pronounced i n the brains of animals which had consumed a liquid diet. The  changes observed in HVA/DA and DOPAC/DA ratios are even more  pronounced in light of the lack of decrease in dopamine levels. Possibly dopamine synthesis was increased suggestion  is supported  i n the hour during which food  was available.  This  by the observed increases in dopamine levels in the  olfactory tubercle of LD rats. Some differences with the results of the Heffner noted.  et a l study should be  In particular, in agreement with the results of Chance et a l (1985),  increases generally larger than those occurring i n the striatum were observed i n the  n. accumbens, whereas Heffner  turnover i n the accumbens.  et a l only observed  dopamine  These differences may have been due to the use of  somewhat different portions of these regions. tissue samples.  increased  Heffner et a l used much larger  For example, the striatal samples were dissected out of slices - 92 -  4.5mm thick, and weighed 68.0 +1.5mg (Heffner and Seiden, 1980).  The samples  used in the current experiment were taken out of thinner slices  approximately  1.2mm  thick, taken  midway through the rostral-caudal extent of the structure,  and weighed 12.2 +0.2 mg.  An increase in dopamine turnover in the mid portion  of the caudate i n the Heffner et a l (1980) study could have been obscured by the inclusion of other tissue. In marked contrast to the increases observed following consumption of liquid diet, dopamine turnover was not increased following consumption of similar volumes of saccharin solution. for  In the n. accumbens DOPAC/DA ratios were lower  Sa than i n LD and Pe rats.  higher in LD than i n Sa rats.  Absolute  DOPAC and HVA levels were also  In the striatum differences between LD and Sa  animals were less pronounced, but HVA and DOPAC levels were both higher in the L D rats, and there was a trend towards higher DOPAC/DA ratios in the LD rats. The consumed  pronounced difference between dopamine turnover in rats which had liquid  diet  and in those  that had consumed  saccharin  cannot be  attributed to differences in motor responding  because the Sa rats consumed at  least as much fluid from identical dispensers.  Nor can the differences be readily  accounted for by appealling to differences in the "reward value" between the two fluids.  Although no attempt was made to equate the attractiveness of the foods  through two bottle preference tests, other experiments conducted in this lab have demonstrated that 0.4% saccharin solution is consumed in considerably larger quantities than is water (Blackburn, Jacobs and Phillips, 1984). fact  that the rats consumed  similar quantities of liquid  diet  In addition, the and saccharin  solution i n the present experiment argues against the suggestion that the liquid diet is more attractive to the rats than is the saccharin solution. - 93 -  These considerations lead to the conclusion that the different effects of saccharin and  liquid diet on dopamine turnover  must be the result of differing  post-ingestive consequences of consuming these solutions. The data of Heffner et al (1984), which indicated that major increases in the level of dopamine turnover occurred  in the second hour in which food was  minimal amount of food was  indication  of  increased  due to post-ingestive factors. The  dopamine  turnover  non-nutritive substance firmly establishes the point.  following  absence of  ingestion  of  of  Experiment  3,  do  The not  a  It is still possible that some  dopamine release occurs during feeding, but i f i t is, levels have returned baseline within an hour.  a  ingested, is consistent with the assertion that the  increase in dopamine turnover was any  available, even though only  to  results of the current experiment, along with those support  the  hypothesis  that  dopamine release  is  necessary for the performance of consummatory feeding behaviours. The liquid  post-ingestive increase in dopamine turnover  diet must reflect  some post-ingestive  elicited by  pellets and  physiological event.  increase in dopamine activity seen following the i.v. injection of CCK  The  brief  may,  for  some reason, be more pronounced when CCK  is released from the gut following  food  Alternatively, i f CCK,  consumption by freely moving animals.  some other  post-ingestive factor decreases dopamine activity in the  glucose or immediate  post-prandial period, the increase observed one hour after food presentation could be a rebound effect, with dopamine activity increasing to above baseline levels following a period of inhibition.  A more precise analysis of the time course of  changes in dopamine turnover following feeding is necessary to settle this point. As in Experiment 2, the observed inter-hemispheric differences are difficult to interpret.  Again, no steps were taken to control for different sacrifice to  homogenization or homogenization to analysis intervals, but - 94 -  as  in the  earlier  experiment such explanations  are insufficient to explain why dopamine levels are  higher in the left striatum but are higher in the right n. accumbens and olfactory tubercle.  In some cases the hemisphere differencs are more pronounced in the  fed animals.  For example, the difference between HVA/DA and DOPAC/DA levels  which were observed  between right and left n. accumbens were particularly  pronounced in the LD animals.  Conceivably this difference could be attributed to  the fact that the Nalgene tubes which contained the liquid diet were mounted at the right side of the front of the cage (from the rat's perspective).  Possibly the  rats had a consistent postural asymmetry while feeding.  Postural asymmetry has  been related to asymmetrical dopamine release (Freed  and Yamato, 1985), but  posture would have to interact with nutrient content to explain why similar asymmetries are not observed in the DOPAC/DA and HVA/DA ratios of Sa rats.  - 95 -  GENERAL DISCUSSION  The  four  differentially feeding  experiments  described  involved in different  behaviour,  indexed  above  aspects  demonstrate  of feeding  that  dopamine is  behaviour.  Appetitive  as approach to a feeding site in response to an  incentive stimulus, appears to be dependent on the activation of a dopaminergic substrate.  Disruption of dopaminergic  blockade severly attenuated  transmission  by post-synaptic  receptor  these appetitive behaviours, while exposure to an  incentive stimulus f o r four minutes was sufficient to cause increased dopamine turnover in the forebrain. In contrast, consummatory behaviour does not appear to be dopaminergically mediated: Food intake was not altered by the same doses of  pimozide  that disrupted  appetitive behaviour.  examined during the consummatory phase itself.  Dopamine release was not  However, subsequent to feeding,  during the post-prandial period, increased dopamine turnover was observed in the n. accumbens and the striatum.  This increase does not appear to have been a  direct consequnce of having performed the consummatory behaviours, but rather appears to have been the result of some post-ingestive effect: Increased was only obvserved in groups of rats which had consumed nutritive  turnover  substances,  not in those which had consumed a non-nutritive saccharin solution. The used  results of these experiments provide additional evidence that can be  to evaluate  behaviour.  theoretical  interpretations of dopaminergic  invovement in  Experiments 1, 2 and 3 are particularly relevant to a comparison of  the anhedonia hypothesis (Wise, 1982; 1985) and the incentive-response  hypothesis  outlined in the introduction. First, the two hypotheses are in agreement that the deficits observed following dopamine receptor blockade are motivational i n nature, and are not purely motoric.  The unattenuated  - 96 -  feeding observed in Experiment 3,  plus the responding rule  that occurred in Experiment 1 following delivery of food,  out the possibility  that the animals  were  seriously  debilitated  by the  adminsitration of pimozide. The two hypotheses are at variance i n predicting deficits in various types of feeding behaviour.  For example, the anhedonia hypothesis predicts that the  animals of Experiment 3 would have found the taste of the food less emjoyable when they were drugged with the higher doses of pimozide, and so should have consumed less of the liquid diet. observed.  However, no decrease  in consumption was  Intake of the diet may have been attenuated i f the rats had repeated  experience with consummatory sessions while drugged (Wise and Colle, 1984), but this was not investigated in the current series of experiments. hypothesis blockade  offers no ready decreases  The anhedonia  explanation f o r the fact that dopamine receptor  the attractiveness of the food less severely on the first  occasion than on the second or third occasions on which the animal consumes food while drugged. In contrast to the anhedonia hypothesis, the incentive-response hypothesis does not predict any deficit at a l l in feeding behaviour once the animal is in close proximity to the food. all of the time.  In a home cage feeding experiment, this is virtually  Once the animal makes contact with the food, consummatory  behaviours are executed under the command of non-dopaminergic neural systems. The  anhedonia hypothesis is unable  appetitive  behaviour  produced  anhedonia  hypothesis, Mark  to explain the severe  by pimozide  II (Gray  in Experiment  and Wise,  1.  disruption of Although the  1980) predicts deficits in  responding to secondary reinforcing stimuli, i t unable to explain why responses to secondary  reinforcers are actually more vulnerable to the effects of pimozide  than are primary reinforcers, such as food. - 97 -  The anhedonia hypothesis could be  extended further to specifically incorporate properties  of seconndary  reinforcers are  a  statement that the  relatively  effects of neuroleptics than are primary reinforcers. are  semantically equivalent  resulting version of the  more susceptable  incentive- response hypothesis  than to the  to  the  However, secondary rewards  to incentives in most situations.  anhedonia hypothesis  rewarding  would  be  In effect,  the  more similar to  the  current version of the  anhedonia  hypothesis. The  incentive-response  hypothesis  predicts  the  deficit  in appetitive  responding seen after the administration of pimozide. By the hypothesis, when the animal is presented  with an incentive stimulus - the CS+  increased, but  to post-synaptic  transmitter production  due  has  no  effect.  of approach and  dopamine receptor  Because  - dopamine release is blockade the  dopamine systems are  other appetitive behaviours,  released  involved in  the animal  the  does not  advance toward the incentive stimulus or towards the feeding niche. This analysis is supported that presentation of the CS+  by the results of Experiment 2, which indicated for four minutes resulted in a twenty  percent  increase in forebrain dopamine turnover. Increased dopaminergic activity in the n. accumbens and striatum results in increased activity, locomotion and approach. It was  indicated in the introduction that elevated dopaminergic  activity  often results in feeding, but that this feeding does not appear to be normal in all respects.  For example, stimulation of the LH may  pellets, as long as pellets are present. animals  begin responding  induce consumption of food  However, i f the pellets are removed many  to the stimulation by  drinking water or engaging in  other behaviours, rather than by eating another palatable food which is available (Valenstein et al, 1970).  A similar situation may  occur in conditioned feeding:  After conditioning, even i f food is available ad lib an animal will not eat the - 98 -  free food during the CS+ period.  Rather i t will wait until the signalled meal is  delivered into the feeding niche, and then i t will consume that (Weingarten, 1984).  Although  apparantly maladaptive,  totally aberrant. activity  such specific responding  may not be  Unlike direct stimulation studies, where increased dopaminergic  is not related to any identifiable  environmental  stimulus, in the  conditioned feeding situation the eliciting stimulus has also been a good predictor of food availability i n the past.  Similarly, natural incentives may serve as both  eliciters of dopamine release and cues for goal availability.  A sufficiently salient  stimulus (which the CS+ has come to be through overtraining) may naturally, and usefully, evoke a "use-it-or-lose-it" reaction from the animal. The animals  data at hand do not settle the question of whether pimozide-treated perceive  the incentive as an attractive stimulus, to which they are  unable to respond, or whether they perceive the incentive as less attractive. In avoidance responding, neuroleptic-treated animals react to a warning signal as i f they were frightened by it, squealing and defaecating in advance of shock onset. The  same warning  signal  (Beninger et al, 1980).  can later  evoke  a conditional emotional  response  In the conditioned feeding paradigm, autonomic responses  to the CS+ could also indicate that the stimulus is perceived as attractive.  In  fact, the video analysis of one rat treated with 0.4mg/kg pimozide indicated that he salivated profusely following CS+ onset, even though he did not approach the feeding niche.  Further analysis of similarity treated rats will be necessary to  determine i f this is a typical response by a rat with an incentive-response deficit. The current experiments have also failed to shed any additional light on the relative Following  functions exposure  of the mesolimbic  and nigrostriatal  to the CS+, dopamine - 99 -  turnover  dopamine projections. was  only  significantly  increased in the n. accumbens, but an apparantly similar, though non-significant, twenty percent increase was observed in the striatum. Similarly, food consumption significantly increased DOPAC/DA ratios in the n. accumbens, while there was a trend  toward  significantly  significance in the striatum. elevated  However, HVA/DA  ratios  were  in both the striatum and the n. accumbens following  consumption of nutritive substances.  Thus, in each situation examined, the n.  accumbens and striatum appear to have acted in parallel. The  incentive-response hypothesis is a theoretical device that is useful for  interpreting the role of dopaminergic systems i n appetitive and consummatory aspects  of feeding.  However, as i t is currently formulated  i t provides  little  insight into the cause or the significance of the increased dopamine turnover observed  following the ingestion of nutrients.  In light  of the results of  Experiment 4 i t appears that no matter how important a role dopamine plays in appetitive responding, incentives are not the only causes of increased dopamine release. What could produce the increased ingestion of liquid diet or food pellets? factors discussed  hours  observed following  In addition to the purely physiological  earlier, the consumption of nutrients may have other, more  "psychological" effects as well. twenty  dopamine turnover  of food  Specifically, the consumption of a meal after  deprivation  may  provide  "satisfaction",  to borrow  Thorndike's (1899) term. This  "satisfaction"  However, i t is important  has an obvious  conceptual  relationship to "reward".  to note the limited sense of reward implied by the  release of dopamine following feeding, given that only the ingestion of nutrients is rewarding  by this criterion, while the ingestion of saccharin solution is not.  Both the saccharin and the liquid diet appear to taste good to the animals, given - 100 -  the avidity with which they are consumed.  As  well, i f the performance of a  consummatory response is in itself rewarding (Sheffield, Roby and Campbell,  1954)  then consumption of the two solutions should be equally rewarding, because equal volumes of each were consumed. However, the consumption of nutrients has other consquences which do not follow the ingestion of saccharin.  These consequences  include the elevation of blood levels of glucose, pyruvate and CCK, blood temperature and the relief of "hunger". to be  Any  sufficient or necessary factors for the  of these may increase  increases in  ultimately prove  in dopamine turnover  observed one hour after presentation of a nutritive food source to a rat. The  suggestion that central dopamine systems may  limited sense with "satisfaction" or "reward" may  be involved only in this  surprise some readers.  dopamine is actually involved in a more global set of rewards and events.  Ingestion of saccharin may  Perhaps  rewarding  in fact elevate dopamine turnover, but only  during the actual period of ingestion: If most consumption of saccharin solution occurred in the first few  minutes i t was  available then dopamine turnover could  return to baseline levels by the time the hour is over and More  detailed  analysis  of  the  time  courses  of  and  of  elevation of dopamine turnover following  the  dopamine release will be necessary to evaluate these No  matter what causes the  consumption of nutrients an additional question any functional consequences?  the brain extracted.  saccharin  ingestion  suggestions.  remains: Does this release have  It does not appear cause the animal to be more  responsive to food-related incentive stimuli.  Perhaps an hour after the beginning  of food availability the animal has recovered from the effects of twenty hour's food  deprivation  stimuli  and  (social, sexual,  is exceptionally cognitve  responsive to other sorts of  puzzles).  - 101 -  A  more thorough analysis  incentive of  the  behavioural responsiveness of similar animals would be necessary to evaluate this hypothsis. Can  the elevation of dopamine turnover following the ingestion of nutrients  have anything to do with feeding itself? suggested.  At least two potential functions can be  First, whatever the impact of elevated dopamine turnover during the  post-prandial  phase, the  elevated  release  may  function as  an  unconditional  response (UCR) to the ingestion of food. In this context, food is an unconditional stimulus (UCS)  and  incentive cues, such as the buzzer-light compound in the  conditioned feeding paradigm, function as conditional stimuli (CS+). repeated  conditioning trials the  CS+  may  dopamine release as a conditional reflex.  Thus, with  gradually come to evoke increased In this way  appetitive behaviour would  be conditioned through a conditioned dopamine release mechanism. A  second  possible  function  for  increased  dopamine  turnover  in  the  post-prandial period is to maintain the memory of the association between the cues which had White and release  signalled food delivery and the presentation of the food itself.  his colleagues have previously demonstrated that increased dopamine  in  the  striatum  (the  presumed  consequence  amphetamine into this site) is sufficient to enhance a  of  microinjection  classically  association between a tone and a shock (Carr and White, 1984).  of  conditioned  If consumption  of food increases dopamine turnover in a similar manner then association of a tone and shock should be stengthened by allowing animals to consume a nutritive solution  following  tone-shock  demonstrated just such an  pairings.  Messier  and  effect: Conditional suppression  White was  (1984)  have  enhanced when  rats were allowed to consume a glucose solution following contingent tone-shock pairings.  It is intriguing, in the context of the current experimental results, to  - 102 -  note that no such increase in suppression was observed when rats consumed a saccharin solution following tone-shock pairings. The  potential biological relevance  of such a mechanism is obvious: If an  animal investigates a place and finds food there, he will be more likely to retain the relationship between the food and the place i f consuming the food releases dopamine in the forebrain and consequently strengthens them. and  the association between  Further support for this hypothesis is found i n a recent report by White  Carr (1985) which indicated that consumption of a saccharin solution in a  chamber does not produce a conditioned although  consumption of an equally  preferred  chamber does produce a place preference. animal may consuming  associate both  sweet  the place  place  with  preference sucrose  f o r the chamber,  solution in the same  These authors agrue that although the a positive hedonic  solutions, the strength  state induced by  of the association  between  saccharin and the place is much weaker due to a minimal effect of saccharin on dopamine release during the post-prandial phase. This hypothesis was developed in the absence of solid neurobiological evidence of differing post-ingestive effects of consumption of sugar and saccharin solutions on dopamine release. The current study provides an independent validation of the hypothesis. CONCLUSIONS This thesis has developed a hypothesis appetitive and consummatory responding, The  describing the role of dopamine i n  with particular reference  formulation, referred to as the incentive-response  increased  forebrain release of dopamine is elicited  to feeding.  hypothesis, asserts that by food-related incentive  stimuli, and that this increase in release plays a crucial role in the production of approach and appetitive behaviours.  The hypothesis does not ascribe a role to  dopamine in consummatory responding. - 103 -  The  experimental  evidence  presented  here  provides  support  for the  incentive-response hypothesis. Presentation of an incentive stimulus was shown to increase dopamine turnover in the forebrain, and dopamine receptor blockade shown to seriously attenuate responses to an incentive stimulus.  was  On the other  hand, dopamine receptor blockade had no effect on consummatory behaviour.  A  further experiment indicated that dopamine is releasd in the post-prandial period, after an animal has consumed food pellets or a liquid diet, but not after the consumption of similar quantities of a saccharin solution.  The incentive-response  hypothesis, as currently formulated, cannot explain the relationship between this release and incentive-based behaviours. 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