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An animal model of Huntington’s disease : behavioral, pharmacological and morphological changes following… Sanberg, Paul Ronald 1978

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AN ANIMAL MODEL OF HUNTINGTON'S DISEASE: BEHAVIORAL, PHARMACOLOGICAL AND MORPHOLOGICAL CHANGES FOLLOWING INTRASTRIATAL INJECTIONS OF KAINIC ACID' by PAUL RONALD SANBERG B.Sc.(Hons), York University, 1976 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE IN THE FACULTY OF GRADUATE STUDIES in THE FACULTY OF MEDICINE DEPARTMENT OF PSYCHIATRY DIVISION OF NEUROLOGICAL SCIENCES We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA November, 1978 © Paul Ronald Sanberg,1978 In presenting th i s thes is in pa r t i a l fu l f i lment of the requirements for an advanced degree at the Univers i ty of B r i t i s h Columbia, I agree that the L ibrary sha l l make it f ree ly ava i l ab le for reference and study. I further agree that permission for extensive copying of th is thesis for scho lar ly purposes may be granted by the Head of my Department or by his representat ives. It is understood that copying or pub l i ca t ion of th is thes is fo r f inanc ia l gain sha l l not be allowed without my written permission. Paul R..Sanberg Department of Psychiatry, Division of Neurological Sciences The Univers i ty of B r i t i s h Columbia 2075 Wesbrook Place Vancouver, Canada V6T 1W5 Date November 9, 1978 • i ABSTRACT Compared with saline injected controls, rats with b i la t era l injections of kainic acid (KA) in the dorsal striatum showed temporary aphagia and adipsia, long-lasting body weight decreases, increased locomotor response to d-amphetamine, increased spontaneous nocturnal locomotor act iv i ty , increased resistance to extinction, impaired acquisition and retention of avoidance behavior and increased latencies to leave start boxes in various mazes. The KA injections resulted in loss of loca l neurons in the dorsal striatum, with no appreciable damage either to dopaminergic terminals or to extr inis ic myelinated axons, thus supporting both the selective neurotoxic action of KA on neuronal perikarya and the proposed s imilari ty of KA-induced s t r i a t a l lesions with those found in the caudate-putamen of patients with Huntington's disease (HD). The present results demonstrate that KA s t r ia ta l lesioned rats also show behavioral and pharmacological s i m i l a r i -ties with HD patients. In addition, they support the view that HD is characterized by a "subcortical dementia syndrome". A review of HD is also presented. Dr. H. C. Fibiger Research Supervisor i i i TABLE OF CONTENTS Page ABSTRACT i i TABLE OF CONTENTS i i i LIST OF TABLES v LIST OF FIGURES v i ACKNOWLEDGEMENT v i i INTRODUCTION 1 Neuropathology 6 Neurochemical Pathology 11 Dopamine 13 Serotonin and norepinephrine 14 Acetylcholine 15 GABA 15 Angiotensin II 16 Substance P 17 Summary " 17 Therapeutic Rationale Based on Neurochemical Pathology 19 Dopamine Acetylcholine GABA Neurotransmitter receptors Psychopathology Animal Models Str ia ta l kainic acid model METHODS Subjects Apparatus Locomotor act iv i ty Appetitive bar pressing Step-down avoidance Spontaneous alternation Alleyway maze exploration Shuttle-box avoidance 21 22 22 23 26 31 33 37 37 37 37 37 38 38 38 39 i v Page Procedures 39 Body weight, water intake and food intake 39 Locomotor a c t i v i t y 40 A c q u i s i t i o n and e x t i n c t i o n of bar pressing 40 Step-down passive avoidance 41 Spontaneous a l t e r n a t i o n 42 Alleyway maze exploration 43 Shuttle-box avoidance 44 Histology 45 Biochemistry 46 RESULTS 47 Aphagia and Adipsia 47 Body Weight 47 Foot and Water Intake 49 Locomotor A c t i v i t y 49 Appetite Bar Pressing 49 Step-down Passive Avoidance 53 Spontaneous A l t e r n a t i o n 57 Alleyway Maze Exploration 57 Shuttle-box Avoidance 62 Histology 62 Biochemistry 68 DISCUSSION 72 Neuropathology 72 Body Weight and Regulatory Behaviors 74 Motor Behavior 78 Psychopathology 79 REFERENCES 87 APPENDIX I V LIST OF TABLES Page Table 1 Prevalence of Huntington's disease 4 Table 2 Pathological areas in Huntington's diseased brains 10 Table 3 Relative neurotransmitter levels in basal ganglia of HD 18 Table 4 Neurotransmitter receptors in basal ganglia of HD 24 Table 5 Psychopathology of Huntington's disease 28 Table 6 Results of neuropsychological test batteries in 29 Huntington's disease Table 7 Animal models for producing dyskinesias 32 Table 8 A comparison of biochemical and morphological changes in the striatum reported in rats given in tras tr ia ta l injections of kainic acid and Huntington's disease 35 Table 9 A comparison of motor response to various pharmacologi-cal agents in rats given in tras tr ia ta l injections of kainic acid (KA) and patients with Huntington's disease 36 Table 10 Food intake for 20 minutes following, and water intake during, 24 hours food deprivation in kainic acid s t r i a t a l lesioned rats 50 Table 11 Effect of b i la tera l kainic acid lesions of the striatum on acquisition and retention of step-down passive avoidance 56 Table 12 Effect of b i la tera l kainic acid lesions of the striatum on shock thresholds of f l inch , jump and vocalization 58 Table 13 Effect of b i la tera l kainic acid lesions of the striatum on spontaneous alternation 60 Table 14 Effect of b i la tera l kainic acid lesions of the striatum on shock thresholds of f l inch , jump and vocalization 66 Table 15 Choline acetyltransferase, glutamic acid decarboxylase and tyrosine hydroxylase act iv i t ies and noradrenaline levels in control and kainic acid lesioned rats 71 v i LIST OF FIGURES Page Figure 1 Genetics of Huntington's disease 2 Figure 2 Dopamine and acetylcholine balance theory for Huntington's disease and Parkinson's disease 20 Figure 3 Mean body weights and mean water intake for control and KA s t r i a t a l lesioned rats ^ Figure 4 Mean locomotor act iv i ty of rats in each group before and after administration of d-amphetamine 51 Figure 5 Mean nocturnal act iv i ty of the control and KA s t r i a t a l lesioned rats recorded every 30 minutes between 7 p.m. and 9 a.m. 52 Figure 6 Mean responses during acquisition of continuously reinforced bar pressing 54 Figure 7 Mean responses and mean latency to cr i ter ion during extinction of bar pressing 55 Figure 8 Freezing time and number of fecal bo l i after a 3 mA footshock in control and KA s t r i a t a l lesioned rats 59 Figure 9 Mean latencies to depart from alleyway maze start-box and to consume the f i r s t food pellet in goal box for control and KA s t r ia ta l lesioned rats 61 Figure 10 Mean exploratory act iv i ty of an alleyway maze in control and KA s t r i a t a l lesioned rats 63 Figure 11 Acquisit ion, retention, and extinction of a shuttlebox one-way avoidance task 64 Figure 12 Retaining of one-way active avoidance and subsequent acquisition of a passive avoidance response in a shuttle-box apparatus 65 Figure 13 Area of s t r i a t a l neuronal loss in a rat treated with in tras tr ia ta l injections of kainic ac id 69 Figure 14 Microphotographs and pictoral representation of control and kainic acid lesioned s tr iata 70 ACKN0WMX3MENT I wish to express my deepest appreciation to Drs. H. C. Fibiger, E. G. McGeer, P. L . McGeer and M. Pisa for their expertise and support during the course of the present studies. The assistance of S. Atmadja, B. Richter, K. Singh and E. Lyson is also greatly appreciated. F ina l ly , to my wife, Karen, who was the best reward possible after writing this thesis. 1 Humanity has long regarded a f f l e c t i o n s which r e s u l t i n gross changes of mood and movement w i t h an a i r of mystery. When the symptoms were as d e b i l i -t a t i n g as those seen i n grand-mal e p i l e p s y and many of the extrapyramidal movement d i s o r d e r s , i t was not uncommon f o r s o c i e t i e s to l a b e l such persons as "possessed". Paramount among the extrapyramidal movement d i s o r d e r s i s Huntington's disease (HD). Despite i t r e l a t i v e l y low prevalence i t seems to have a t t r a c t e d c onsiderable i n t e r e s t and a t t e n t i o n , probably because of i t s dramatic symptoms, r e l e n t l e s s course and h e r e d i t a r y c h a r a c t e r . Recently, i n t e r e s t i n the nature of HD has increased as a r e s u l t of the f r u i t f u l i n v e s t -i g a t i o n s i n t o the nature of Parkinson's disease and i t s subsequent treatment w i t h L-dopa. Unf o r t u n a t e l y , no one such s p e c i f i c abnormality has been found i n HD. This chapter w i l l attempt to review our present knowledge of HD, i n order to s t r e s s the need of an appropriate animal model upon which we may evaluate both the neurodegenerative phenomena which occur i n HD and p o s s i b l e therapeutic regimes. O r i g i n a l l y denoted as "chronic chorea", George Huntington (1872) demon-s t r a t e d i t s h e r e d i t a r y nature and renamed i t h e r e d i t a r y chorea. The subse-quent renaming to Huntington's chorea i s s e l f explanatory. Huntington's disease i s now p r e f e r r e d since i n some cases chorea i s not present. The genetic abnormality i s t r a n s m i t t e d by a s i n g l e autosomal dominant gene and so only one parent need be a f f e c t e d to transmit the disease. About f i f t y percent of the o f f s p r i n g of an a f f e c t e d person can be expected to develop the disease (see Figure 1). There appears to be no .sexual b i a s s i n c e , pre-sumably, autosomes are o r d i n a r i l y p a i r e d chromosomes and not sex chromosomes. But r e c e n t l y B i r d et a l (1974) have demonstrated a sex r e l a t e d f a c t o r i n the occurrence of HD when i t s onset begins i n childhood or adolescence. They found that approximately 75% of childhood HD i s i n h e r i t e d from G e n e t i c s of Hunt ing ton ' s D i s e a s e Figure 1. Genetics of Huntington's disease (HD). Arrows represent males and crosses, represent females. 3 the father and that of these childhood patients twice as many are females. Bird and his colleagues (1974) also reported data suggesting that affected offspring of males with HD die at a much earl ier age than their fathers, whereas offspring of females with the disorder die at an age not much below that of their mothers. However, Vergter-Van der Vl i s et a l (1976) more recently demonstrated that this "anticipation" phenomenon in HD, may be an art i fact due to sampling biases. The childhood or juvenile form of HD is commonly associated with r i g i d i t y and akinesia (Korenyi and Whittier, 1973), whereas the adult form is usually characterized by the choreic or jerky, twisting, uncontrollable, involuntary movements c lass ica l ly attributed to HD. Although HD is often regarded as a disease of adulthood, i t appears that there may be important po lya l l e l i c genetic modifiers, perhaps sex linked accounting for the childhood variant. This juvenile rigid-hypokinetic variant of HD accounts for approximately six to ten percent of a l l HD patients (Dewhurst and Oliver, 1970; Markham and Knox, 1965). HD can be found in v i r tua l ly a l l ethnic and rac ia l groups but prevalence rates may be different. Overall the prevalence rate in the United States is about 50 per 1,000,000 (Reed and Chandler, 1958). The prevalence rate of HD in other countries including Canada can be seen in Table 1. Reference to HD in the remainder of this chapter w i l l primarily be concerned with the adult form of the disease, unless otherwise specified. C l i n i c a l l y , the physical features of the disease consist of constant choreiform movements of the whole body, which are irregular and involuntary. These movements are often uni lateral for a time, later recruiting a l l the limbs (Pinel, 1976). The face may often look quite grotesque dut to constant writhing contortions of fac ia l muscles. Dysarthria, dysphagia and disturbances in ocular motil i ty may also i 4 TABLE 1 Prevalence of Huntington's Disease Place // of patients/10 Source Australia Queensland Tasmania Victoria Canada United States England Northamptonshire Cornwall Belgium i Germany Japan Switzerland 63 patients 174 patients 56 patients 84 patients 50 patients 65 patients 56 patients 94 patients 32 patients 4 patients 50 patients Wallace (1972) Brothers (1949) Teltsher and Davies (1972) Shokier (1975a) Reed and Chandler (1958) Oliver (1970) Bickford and El l i son (1953) Husquinet (1973) Panse (1942) Kishimoto et a l (1959) Zoll iker (1949) Note: It is interesting that the higher prevalence rates are related with countries associated with the Br i t i sh Empire,suggesting particular prevalence of the gene in the Anglo-Saxon race. 5 become quite evident (Dix, 1970; Starr, 1967), and the speech eventually becomes quite uninte l l ig ible (Davis, 1976). The primary mental features of HD are generally considered similar to those in dementia (Slaby and Wyatt, 1974)': The i n i t i a l signs may consist of lack of grooming (carelessness in hygiene and dress), eccentric tra i t s (hoarding of useless items), i r r i t a b i l i t y , carelessness in social behavior (such as spitt ing or obscene language), memory fa i lure , lack of judgement . and insight, emotional ins tabi l i ty and delusions of paranoid nature. Person-a l i t y disorders may become apparent, leading to outbursts of rage, callous behavior, sexual promiscuity, violent temper and a generally unstable personality. Conversely, some patients may be slow and apathetic. It has been suggested (Klawans et a l , 1972) that s imilarit ies in anatomical-biochemical abnormalities may exist between HD and schizophrenia. A review of the neuropsychology of HD w i l l be given . : separately. There seems to be a general consensus that the mental symptoms occur prior to the motor symptoms at the onset of the disease (Bruyn, 1968). HD symptoms generally appear at the age of about 40. But this may be misleading unless i t is understood that the standard deviation is approximately 12 years (Pinel, 1976). Cases have been documented in the f i r s t year of l i f e (Bird and Paulson, 1971) as well as in the eighth decade (Lyon, 1962). Brackenridge and Teltscher (1975) demonstrated that the age at onset of HD is possibly a function of the difference between the patients birth, and the age of onset of the affected parents symptoms. The larger the difference the later the onset age i n the child (patient). In another study Brackenridge (1974) also presents evidence showing that the environment (climatic temperature) can affect the time when symptoms ensue. The average person l iv ing in cold . regions develop signs of HD about a decade after those l iv ing in the tropics. f 6 It may be that correlational investigations such as these may prove beneficial in providing genetic counselling, since there is no early detection methodology for HD available (Shoulson and Chase, 1975). The lack of presymptomatic detection has contributed to the continued existence of the disease, since most patients have their families prior to the onset of symptoms. Shokeir (1975b) recently showed that HD patients have more offspring than unrelated normal controls and members of the general population of corresponding age. This in i t s e l f is damaging since the higher reproducibil ity fac i l i ta tes an exponential increase in the prevalence of the a l l e l e for HD and thus, the disease i t s e l f . Therefore, i t is evident that some method of early detection of HD needs to be found i f i t s prevalence is to be arrested or even attenuated. Neuropathology Gross observations of the brains of deceased HD patients reveal a marked reduction in size and weight. Dulap (1927) found that the brains of patients dying from HD weighed only 980 grams compared with 1,153 grams in normal subjects. Forno and Jose (1973) report weights of 900 grams in adult deceased patients. Class ica l ly , HD is associated with gross generalized cerebral atrophy involving the cortex and basal ganglia, both the white and grey matter. Most testbook references stress the loss of small neurons in the neostriatum and in the th ird , f i f t h , and sixth layers of the fronto-Rolandic cortex. The severe damage to the neostriatum results in a compensatory secondary hydrocephalus with gross d i la t ion of the ventricu-lar system. Some references (e.g. , Pinel , 1976) also point out that the neostria-tum is characterized by severe g l ios i s , and that the globus pal l idus, thalamus, 7 and brainstem "are not usually affected". The present section attempts to extend these conceptions by giving a comprehensive account of most of the areas which have been implicated in the neuropathology of HD. Many of the reported areas are based on only a few studies and further investigations are required before pathology in such areas is accepted as a general feature of HD. Marked pathology in the striatum is exhibited in a l l HD patients, but there is debate as to whether an increase in the absolute number of g l i a l ce l l s within this structure actually.occurs (Lange et al,1976). Instead, Lange et a l (1976) found that the increased numerical density of g l i a l ce l l s was caused by shrinkage of the caudate and putamen. Lange and his colleauges (1976) also showed that the globus pallidus is more severely affected than is commonly appreciated. The average volume reduction of the globus pallidus is similar to that of the striatum (approximately 50%), and the absolute number of nerve ce l l s of the globus pallidus is decreased by about 40%. The globus pallidus also shows a high degree of g l ios i s . Although damage to the claustrum is rarely mentioned, this area is as severely affected as the striatum and pallidum, and in some cases i ts width is reduced to a few cel ls (Bruyn, 1968) . Unlike previous conceptions, i t appears that the substantia nigra may be involved in the pathological process of HD. The major damage seems to occur in the pars reticulata with dentri t ic loss, neuronal degeneration, thinning of the s t r i a t a l bundles (Gebbink, 1967; 1968) and f i b r i l l a r y g l ios is (Forno and Jose, 1973). The zona compacta remains re lat ive ly normal except for "sl ightly more extraneuronal melanin pigment" than usual (Forno and Jose, 1973; Enna et a l , 1976b). 8 The subthalamic nucleus shows a loss of about 25% of nerve cel ls (Lange et a l , 1976) and apparent gl ios is (Forno and Jose, 1973). In the thalamus, the centromedian nucleus was found to have gl ios is and nerve c e l l loss (Forno and Jose, 1973) . The dorsomedial nucleus frequently showed "slight pallor and slight gliosis" (Forno and Jose, 1973); and .. recently the ventral anterior and ventral la tera l nuclei were shown to have approximately 50% atrophy of internuncial neurons (Dom et a l , 1976). Bruyn (1973) has demonstrated considerable neuronal depletion in the la tera l hypothalamic nucleus, and marked c e l l depletion, shrinkage, and disintegration in the ventromedial hypothalamic nucleus. Previously, he demonstrated neuronal loss in the paraventricular and supraoptic nuclei of the medial zone of the hypothalamus (Bruyn, 1968) . This is interesting since i t may help to explain cachexia and autonomic system disturbances associated with HD as discussed later . Lesions to the hypothalamus may also affect growth hormone secretion and gonadotropin releasing hormone secretion, changes in which have recently been reported in HD patients (Phillipson and Bird , 1976; Bird et a l , 1976, respectively). In the brainstem Forno and Jose (1973) found a marked loss of cel ls in the superior olive of some patients. This pathology, however, has been known for many years, as demonstrated by Weisschedel (1938) and Kooos (1938). Forno and Jose (1973) also demonstrated a marked f i b r i l l a r y g l ios is in the occulomotor nucleus and the tegmentum of the midbrain. The occulomotor def ic i t may underlie reported abnormal l ight reflexes (Esteban and Gimenez-Roldan, 1975) in HD patients. Much gl ios is and some neuronal degeneration has been found in many other brainstem areas (Facon et a l , 1957; Bruyn, 1968; Roizin et a l , 1976). As mentioned previously the frontal and precentral cort ica l atrophy is extensively documented, but recently Petro et a l (1976) revealed the poss ibi l i ty of selective disappearance of groups of neurons within the visual 9 association cortex. The temporal area was shown to have nerve c e l l shrinkage, vacuolation and gl iosis in the hippocampus (Mattsson et a l , 1974). "The cerebellum invaribaly shows pathological changes though to a varying degree and extent" (Bruyn, 1968; translated from Vogt and Vogt, 1920). Cerebellar pathology has been alluded to for many years and has recently been reviewed by Castaigne et a l (1976). The Purkinje layer of the cerebellum shows the most neuronal degeneration and g l ios i s . The dentate nucleus is quite commonly affected with gl ios is and neuronal depletion (Bruyn, 1968). In many reported HD brains the inferior olivary nucleus is atrophic, showing neuronal degeneration and gl ios is (Jervis, 1963; Bruyn, 1968). It is evident that in discussions of the .pathology of HD one must consider not only the cor t i ca l and s t r ia ta l atrophy but the poss ib i l i ty of some g l i a l prol i ferat ion and/or neuronal degeneration in a multitude of areas (see summary Table 2). Bruyn (1968) sums i t up as such: "Ubiquitous prol i ferat ion of astrocytes throughout the central nervous system appears to me the principal neuropathological feature of Huntington's chorea, reflecting the underlying metabolic derangement. Nerve c e l l depletion varying in intensity from one region to another is the second leading phenomenon. Both are closely related to one another." Alternatively, a few investigators believe that the principal neuro-pathological feature is vascular (Feremutch, 1954) and that the neural and g l i a l changes are a sequelae of blood vessel pathology (Bruyn, 1968). Even today a lack of definite and specific information on many important aspects of HD results in a diversity of opinion regarding the fundamental nature of the disease. However, one thing is clear: in.view of the diversity of lesions found in the brains of HD patients, we can not stay with Vogt and Vogt's (1920) or ig inal theory that HD represented a primary abiotrophic degeneration of the small nerve cel ls of the neostriatal system and t 10 TABLE 2 PATHOLOGICAL AREAS IN HUNTINGTON'S DISEASED BRAINS Area Gross brain Ventricular system Caudate & putamen Globus pallidus & Claustrom Thalamus nuclei centromedian dorsomedial ventral anterior ventral la tera l Hypothalamus nuclei la tera l ventromedial paraventricular supraoptic Cortex Hippocampus Cerebellum dentate nucleus Purkinje layer Inferior ol ive Subthalamic nucleus Substantia nigra Pars ret iculata Brainstem nuclei superior olive occulomotor midbrain tegmentum paramedian recticular -dorsal vagues aquaduct area red nucleus -Pathology weight & size reduced di lat ion volume reduced loss of neurons increase g l i a l density volume reduced loss of neurons gl iosis loss of neurons & gl ios is slight g l ios is loss of neurons loss of neurons loss of neurons shrinkage & loss of neurons loss of neurons loss of neurons loss of neurons neuronal atrophy gl iosis shrinkage g l ios is neurofibril lary tangles loss of neurons & gl ios is loss of neurons & gl ios is loss of neurons, atrophy & gl ios is loss of neurons & gl ios is loss of neurons, atrophy & gl ios is loss of neurons gl ios is g l ios is loss of neurons g l ios is g l ios is loss of neurons Source (Dulap,. 1927) (Dulap, : 1927) (Lange et a l . , 1976) (Lange et a l . , 1976) (Bruyn, 1968) (Forno & Jose, 1973) (Dom et a l , 1976) (Bruyn, 1968; 1973) (Roizin et a l . , 1976) (Mattsson et a l , 1974) (Mcintosh et a l , 1978; Forno & Jose, 1973) (Bruyn, 1968) (Castaigne et a l , 1976) (Jervis, 1963) (Lange et a l , 1976) (Gebbink, 1967, 1968) (Weisschedel, 1938) (Forno & Jose, 1973) (Facon et a l , 1957) (Bruyn, 1968) (Roizin et a l , 1976) 11 the t h i r d and f i f t h cerebral c o r t i c a l l a y e r s . Although, many believe that these c e l l s represent a " b i o l o g i c a l l y combined organ" (Wilson, 1941)• . • _ damage to only one "organ" i s not a feature of HD. One thing that i s c l e a r , though,' i s that i n the vast majority of cases there i s a g e n e t i c a l l y determined defect which i s manifested by degenerative changes i n d i f f e r e n t parts of the nervous system. In'.;this regard i t should be r e c a l l e d that the abnormalities associated with many genetic diseases are a r e s u l t of a deficiency of a s p e c i f i c enzyme (Garrod, 1923). I t may be reasonable to postulate that a s i m i l a r biochemical defect occurs i n HD. I do not attempt to review the vast number of biochemical studies which have been performed'in HD, but the following section b r i e f l y reviews: some of the current r e s u l t s on biochemical changes i n the CNS of HD patients. A basic understanding of the neurochemical changes associated with HD i s a p r e r e q u i s i t e for determining therapeutic approaches to the disease. Neurochemical Pathology The r o l e of catecholamines i n extrapyramidal function has been under extensive investigation,-'partly because of the well received a p p l i c a t i o n of L-dopa (dopamine precursor) i n ameliorating motor signs of Parkinson's disease (a disorder shown to have a dopamine de f e c t ) . In Huntington's disease p a t i e n t s , L-dopa tends to exacerbate the involuntary movements (Klawans and Weiner, 1976). In f a c t , i t seems that there i s a tendency for drugs that help Parkinsonian patients to worsen HD patients, and those that worsen Parkinson's disease to be somewhat b e n e f i c i a l to HD patients... Although a'*somewhat crude comparison, -HD has been considered a mirror image of Parkinson's disease (Shoulson and Chase, 1975). 12 Barbeau extensively reviewed the l i terature on the neurochemistry of HD in 1973. In this section an attempt w i l l be made to review the neuro-chemistry of HD, But with a primary emphasis on the research performed since 1973, which has concentrated almost entirely on neurotransmitter metabolism. The "pre-L-dopa era" was a time when investigators concentrated their research efforts on possible analogies with Wilson's disease, in which an abnormality of copper metabolism was found. This led f i r s t to reports which described disorders of trace metals in HD, and subsequent reports fa i l ing to confirm these. Some investigators described the beneficial effects of chelating agents, but subsequent workers, again, denied such beneficial effects. Copper, iron, magnesium, strontium and calcium have a l l been implicated at one time or another of this double process, but there is now no convincing evidence for abnormal metabolism of any of these substances in HD (Neilson and Butt, 1955; Kenyon and Hardy, 1963; Haslam, 1967; Fleming et a l , 1967; Bruyn et a l , 1965; Perry, 1961; Courville et a l , 1963). Amino acid metabolism was a more recent concern of HD investigators. I n i t i a l l y , Oliphant et a l (1960) found no abnormalities of amino acid excretion in the urine, and there were similar negative reports by other investigators (Bruyn, 1968; Oepen and Bickel , 1964). Then in 1968, using more sensitive techniques, Bruck and his colleagues found sl ight abnormalities of several amino acids in the CSF, and s l ight ly increased pyruvic acid in the serum. But the most convincing evidence was reported one year later when Perry et a l (1969) demonstrated abnormally small amounts of six essential amino acids in the serum of 19 patients with HD. It was suggested that these low levels of proline, alanine, tyrosine, and the three branched-chain amino acids -valine, leucine and isoleucine - might reflect the basic biochemical error underlying this disorder. 13 Dopamine The discoveries of the role of dopamine as a neurotransmitter in the nervous system, the demonstration of a dopamine def ic i t in the substantia nigra in Parkinson's disease (PD), the beneficial effect of i t s precursor L-dopa in treatment of PD and the fact that the symptoms of PD to some extent represent an opposite pole of HD, suggested to many workers that an opposite condition to PD might exist in HD, i . e . , abnormally high dopamine synthesis. However, brain dopamine has not been found to be elevated in HD (Bird and Iversen, 1974). Since the n igro-s tr ia ta l dopaminergic tract is essentially intact in HD, i t is not surprising that dopamine's synthesizing enzyme tyrosine hydroxylase (TOH) was found to show relat ively normal levels in the corpus striatum of HD (McGeer and McGeer, 1976a). Bernheimer et a l (1973) reported, however, a significant reduction in both dopamine and homo-v a n i l l i c acid concentrations in the caudate nucleus (with normal levels in the putamen). I t 1 i s possible though that this reduction in dopamine metabolism may reflect a compensatory, functional response to the s t r ia ta l c e l l degeneration (Shoulson and Chase, 1975). The pathology of HD is commonly associated with atrophy of the caudate nucleus and putamen with l i t t l e or no change in the substantia nigra (zona compacta); therefore, the normal or moderately low s t r i a t a l concentrations together with the low weights of s t r i a t a l regions would lead to low total contents of dopamine and homo-van i l l i c acid at autopsy (Curzon, 1976). Consistent with this is the report of an inverse correlation of lumbar CSF homovanillic acid with increasing severity of symptoms (Curzon et a l , 1972). Normal excretion of homovanillic acid was previously reported in the urine of patients with HD (Williams et a l , 1960). Aminoff et a l (1974) have described abnormally high dopamine and serotonin uptake by platelets from patients with HD. This increased uptake of dopamine 14 by the platelets has since been confirmed (Barbeau and Ando, 1975; McLean and Nihei, 1977), but normal platelet uptake of serotonin was reported by McLean and Nihei (1977). Although the importance of this finding in the pathogenesis of HD is not apparent at present, there may be potential value of this simple assay in the detection of prec l in ica l HD. In summary, dopamine metabolism in the basal ganglia of adult-form HD is re lat ively normal and this is consistent with morphological studies of dopaminergic tracts in diseased brains. Serotonin and Norepinephrine Bernheimer and Hornykiewicz (1973) reported no significant changes in the levels of serotonin and norepinephrine (NE) in eight different regions of HD brains. The role of serotonin in HD is not clear at present. Neither neurochemical nor neuropharmacological evidence appears to support a significant role in the pathogenesis of HD (Shoulson and Chase, 1975). A more recent search through the l i terature did not y ie ld any new evidence. As for NE, i t was shown recently that cerebrospinal f lu id (CSF) NE levels were signif icantly low in HD patients when compared to controls (Wood et a l , 1976; Ziegler et a l , 1976). However, Chase (1973) found no change in the levels of CSF 3-methoxy-4-hydroxyphenylethylene glycol (one product of NE metabolism), suggesting that the turnover of NE is unchanged in HD. It was also demonstrated that resting plasma NE concentration and dopamine-beta-hydroxylase are s ignif icantly lower in HD patients, yet during act iv i ty no deficits in neurochemical and vasomotor responses were found (Shoulson et a l , 1976). On the basis of these recent findings i t is apparent that a pathology, although perhaps not a primary one, in NE metabolism may exist in HD. 15 Acetylcholine There is a general consensus that the post-synaptic neurons of the nigro-s t r ia ta l dopaminergic tract are small interneurons (Golgi type II) in the corpus striatum. Many of these internuncial cel ls are cholinergic, that is they contain acetylcholine as their neurotransmitter. With the pathological loss of these interneurons in HD i t i s evident why a number of laboratories have reported a significant decrease (about 50%) in choline acetyltransferase (CAT-the acetylcholine synthesizing enzyme) act iv i ty in the neostriatum of HD brain (McGeer et a l , 1973; Bird and Iversen, 1974; Stahl and Swanson, 1974; Aquilonius et a l , 1975; McGeer and McGeer, 1976a). More spec i f ica l ly , Aquilonius et a l (1975) studied seven different regions of the neostriatum and showed that in HD, CAT act iv i ty is unevenly reduced throughout these areas, with highest depletion in the rostromedial part of the caudate nucleus (reduced 95%). It is interesting to note that localized injections of dopamine into the rostromedial part of the caudate induce choreiform hyperkinesia in cats (Cools, 1972). Aquilonius et a l (1975) also investigated CAT act iv i ty in many other areas of the brain and revealed normal or s l ight ly reduced act iv i ty in most other brain regions. CAT act iv i ty was increased in the gyrus c ingul i , thalamus, claustrum, and pallidum in their HD post-mortem brain tissue. GABA A recent finding by Perry et a l (1973) has revealed a deficiency of GABA in the substantia nigra, caudate, putamen, and globus pallidus in post-mortem HD brains. Although this has not been direct ly substantiated, studies of enzyme levels in brains of HD have indirect ly confirmed and expanded the orig inal finding of a GABA deficiency. 16 Glutamic acid, decarboxylase :-("GAD) , 'the enzyme.which converts, glutamic'acid to GABA and which is a stable and specific marker for GABA-containing neurons, was lower in the caudate, globus pal l idus, putamen (McGeer et a l , 1973; Bird and Iverson, 1974), substantia nigra (Bird, 1976) . .. dentate nucleus (Bird, 1976) and occ ip i ta l cortex (Urquhart et a l , 1975) of autopsied HD brains. , ' As is the case of CAT act iv i ty , GAD act iv i ty in the corpus striatum is primarily associated with small, local c i rcu i t neurons (Golgi type II) in this structure. Therefore, the decrease in GAD reflects the atrophic state of these ce l l s in the HD s tr ia ta . But, unlike CAT act iv i ty , the decrease in.GAD act iv i ty is more widespread throughout the basal ganglia. This is also the case for Parkinson's disease (McGeer and McGeer, 1976a). The decrease in GAD act iv i ty in the substantia nigra probably reflects atrophy of the s tr iato-nigral GABAergic tract (Kanazawa et a l , 1977). The CSF concentrations of GABA also appear to be decreased in HD ^ (Glaeser et a l , 1975; Achar et a l , 1976), although Perry and Hansen (1976) argue:-, that GABA is not detectable in the CSF with present techniques and what the other investigators are detecting is an ar t i fac t . GABA aminotransferase, the enzyme which degrades GABA, was found to be normal in HD (Urquhart et a l , 1975). On the other hand, the levels of homocarnosine (a dipetide derived from GABA) are reduced in the caudate nucleus, putamen, globus pallidus and cerebellar cortex of HD tissue (Urquhart et a l , 1975). These investigators suggest that this homocarnosine defect may reflect a prolonged def ic iency; of GABA. in HD. Angiotensin II Angiotensin II has been postulated to be a putative peptide neurotransmitter (Fitzsimons and Simons, 1969) in the CNS. The angiotensin II converting enzyme 17 which converts angiotensin I into angiotensin II was recently shown to be reduced by 83-92% in the globus pallidus and 62T-.69% in; the corpus striatum (Arregui et a l , 1977) . This implies a reduced angiotensin II synthesis in these areas, but what significance this has is yet unknown. Substance P Recent evidence suggests that substance P is the excitatory neurotransmitter of a s tr iato-nigral tract:.(Kanazawa et a l , 1977; Mroz et a l , 1977). This would compliment the known GABA inhibitory s tr iato-nigral tract;' (Barbeau, 1973). Like GAD act iv i ty , the level of substance P in the substantia nigra and globus pallidus was signif icantly reduced in HD post-mortem tissue (Kanazawa, 1977; Gale et a l , 1978). This probably reflects a loss of substance P-containing neurons in the diseased striatum. Again, the significance of this is yet unknown. Summary A summary of the various neurochemical findings in HD basal ganglia is given in Table 3. Apparently many changes occur in the neurochemical environment during the pathogenesis of HD, yet the question as to whether these changes are a primary or secondary result of the genetic mutation of HD can not be answered by measuring levels of various neurochemicals alone. Recently, T.D. Bird (1976) indirectly attempted to answer this question speci f ical ly with regard to GABA. She- hypo-thesized that "if the gene mutation of Huntington's disease has a primary action on the GAD/GABA system, i t is possible that i t s effects could be demonstrated in non-neural tissue." B i r d measured the act iv i ty of GAD in the kidney of deceased HD patients and found no differences between HD and control act iv i t ies of GAD in the kidney samples. On the basis of these results she conclude that a "deficiency in the GAD/GABA system is not the basic biochemical defect TABLE 3 RELATIVE NEUROTRANSMITTER LEVELS IN BASAL GANGLIA OF HD Transmitter* Caudate Dopamine s l ight ly low Noradrenaline s l ight ly low Acetylcholine low GABA Low Serotonin about normal Angiotensin II low Substance P normal Putamen s l ight ly high normal low low about normal low Globus Pallidus normal normal low low about normal low low Sub. Nigra normal low low s l ight ly low - Also low serotonin in hippocampus; low dopamine and NE in hypothalamus * Relatively same values for synthesizing enzymes, breakdown enzymes may d i f f somewhat. 19 produced by the Huntington's gene." However, i t should be noted that many people believe that there is either no GAD act iv i ty in the kidney or that i t is a different enzyme than in the brain (E. G. McGeer, personal communi-cation) . Although, this is the only study available which even remotely attempts to address this important question, at a recent workshop on HD at Tel Aviv (Wallace, 1977) the participants concluded that: "Interesting in their own right as these investigations of neurotransmission are, i t would appear that the well marked changes to be found in Huntington's chorea are almost certainly nothing more than secondary effects of a primary neuronal disturbance responsible for the condition." Therapeutic Rationale Based on Neurochemical Pathology The most basic therapeutic rationale of HD based on neurochemical and neuropharmacological evidence is that there appears to be a delicate balance between the state of functional act ivi ty of cholinergic and dopa-minergic systems, part icularly in the striatum (Aquilonius and Sjdstrom, 1971). A "balance system" has been proposed (see Barbeau, 1973) which is i l lustrated in Figure 2. Drugs which apparently normalize the balance tend to be moderately effective in suppressing the motor symptoms of the respective diseases. More recent findings on the pharmacology of HD have been reviewed by Klawans and Weiner ( 1976). Over the last 25 years the drugs of choice have been . reserpine and tetrabenazine, which deplete monoamine stores, and the phenothiazines and butyrophenones , which block monoamine receptors. To date, these have had very limited success in attenuating motor symptoms and limited usefulness in Huntington's dementia. The following sections deal with therapeutic t r i a l s over the past few years which have not been previously reviewed. B A L A N C E T H E O R Y DA ACh • Normal Huntington's D. Park inson 's D. Figure 2. Dopamine (DA) and acetylcholine (ACh) balance theory for Huntington's disease and Parkinson's disease. Therapeutic rationale is based on restoring the balance of the respective diseases to normal. 21 Dopamine To decrease the dopaminergic side of the balance or to block dopaminergic function, Leonard et a l (1975) attempted to use lithium chloride and haloperidol but had no success. Huang et a l (1976) tried a long term study with tetrabenazine, also without much success. Mesoridazine (a phenothiazine) was used in a recent study for thirty-four weeks with six HD patients (Drymiotis et a l , 1976). These investigators found very l i t t l e beneficial effect of mesoridazine in HD, although a sl ight decrease in depression was noted. The only recent study which used a phenothiazine and in which a positive effect was observed on the choreiform movements has been reported by Terrence (1976). Terrence used fluphenazine decanoate for four weeks and noted improvement. It should be noted, though, that complete amelioration of the movements was not attained, but only a subjective change was observed, i . e . , from "severe" to "moderate". Reference can be found to two recent studies in which dopamine agonists were employed. The long term use of L-dopa (Sishta and Templer, 1976) and bromocriptine (Kartzinel et a l , 1976a; 1976b) both fai led to be of benefit in HD patients. In fact as would be expected from the balance theory both studies resulted in worsening of symptoms. However, the use of drugs, such as apomorphine and bromocriptine, which would be expected to increase dopaminergic act iv i ty have been shown to produce beneficial effects in HD patients. The "paradoxical" effect of low doses of these drugs are presumably mediated through stimulation of pre-synaptic dopaminergic receptors, i . e . , autoreceptors (Corsini et a l , 1978; Frattola et a l , 1978). 22 Acetylcholine Recent studies which have attempted to restore the cholinergic side of the balance have also been performed. Physostigmine (a cholinesterase inhibitor) was used by Davis et a l (1976) and Welch et a l (1976) with only an "acute favorable" response. Choline chloride (an acetylcholine precursor) has been reported to increase acetylcholine levels in the brain (Cohen and Wurtman, 1976) and was used with reported moderate success in three recent t r i a l s (Cohen et a l , 1976; Growden et a l , 1977; Davis et a l , 1976). No present therapy which attempts to correct the dopamine-acetyl-choline balance, offers dramatic (or even s l ight ly dramatic) success for ameliorating abnormal movements, let alone the dementia, of Huntington's disease patients. Either our present pharmacology is desperately lacking or else the problem is much more complicated than the balance system leads us to believe. GABA The marked def ic i ts of GABA in HD has led many investigators to try to restore GABA levels in the brain as a therapeutic approach to HD. Barbeau (1975) has reviewed such c l i n i c a l t r i a l s . Essential ly, his review shows that many c l inic ians attempted to administer GABA with very confl ict ing results. Attempts were also made to use imidazole-4-acetic acid (a GABA receptor agonist) in order to activate the GABAergic system in HD, but again without much success. However, neither imidazole-4-acetic acid nor GABA penetrate the blood-brain barrier well , which may explain the negative results obtained. More recently, Paulson (1976a) attempted the use of Lioresal (a GABA cogener) without success, and Shoulson et a l (1976) employed dipropylacetic acid (an anticonvulsant which is thought to inhibit GABA transaminase, the enzyme which degrades GABA) alone and in combination 23 with GABA, again without success. Bachman et a l (1977) has also tried long term dipropylacetic acid in the Westphal variant (juvenile) form of HD, but l ike Shoulson without success. . A further four studies have been attempted using sodium valproate (sodium dipropylacetate). Although large doses were used no benefit was encountered in any study (Lenman et a l , 1976; Tan et a l , 1976; Pierce et a l , 1977; Symington et a l , 1978). McGeer et a l (1977) reported negative findings using gamma-hydroxybutyrate, a mild soporific, in HD. The only study reporting positive results was that of Perry et a l (1977) in which they used isoniazid, a GABA transaminase inhibi tor . However, a controlled study using this compound should be performed for confirmation. Neurotransmitter Receptors As previously discussed in this section, the attempts to overcome the GABA and acetylcholine deficiencies by administering GABA and acetyl-choline agonists, etc. have met with only very limited success. However, as indicated by Enna et a l (1976b), for such approaches to be successful re lat ively normal levels of GABA and acetylcholine synaptic receptors are required. Unt i l recently, the measurement of neurotransmitter receptors was technically impossible. But the advent of new radioactive binding techniques has allowed measurement of some neurotransmitter "receptors" (Snyder and Bennett, 1976). However, there is no guarantee that the binding sites measured by these methods are actually equivalent to physiological postsynaptic receptors. The results of recent studies on binding sites in HD are summarized in Table 4. The post-synaptic neurons to the dopaminergic n igrostr iata l bundle are greatly reduced in HD. It is no wonder then that the number of dopamine 24 TABLE 4 NEUROTRANSMITTER BINDING SITES', in BASAL GANGLIA OF HD DA GABA ACh NE 5-HT Area ( 3H--spiroperidol) (3H) ( 3H QNB) (3HDHA) (3H) Globus pallidus 50% 100%* 50% 100% 25% Caudate 50% 100%* 50% 100% 50% Putamen 50% 100%* 50% 100% 50% Substantia nigra 125% 200% - Values presented in percent of control values NE = norepinephrine; ACh = acetylcholine; 5-HT = serotonin;, DA - dopamine; GABA = Y-aminobirfcyric. acid *Controversy exists at present over actual values, Lloyd et a l (1976) reports 70-80% decrease. 25 receptors have been shown to be s ignif icantly decreased in the striatum as measured by the binding of ^ - sp iroper ido l (Reisine et a l , 1977). Early in 1974, Hiley and Bird f i r s t demonstrated that the muscarinic (acetylcholine) receptor concentration in post-mortem HD brains was decreased relative to control brains. Subsequent investigations have confirmed this finding (Hiley, 1976; Enna et a l , 1976a; 1976b; Wastek et a l , 1976a; 1976b). Thus, i t could be concluded from these studies that drugs which attempt to increase, the acetylcholine levels in the brain or prolong i t s act iv i ty may be of limited value since most patients possess only about 50% of their normal compliment of cholinergic receptors. Enna et a l (1976a; 1976b) have reported that GABA binding sites may be unaltered in HD, however, Lloyd et a l (1976) have reported a 70-80% decrease. Recently, Bird (1976) has stated that i t "would seem reasonable that before one spends a great deal of time in developing methods to increase the GABA concentration of the brain, an effort should be made to determine whether or not the GABA receptors are intact in choreic basal ganglia and s t i l l able to respond to GABA." Although the GABA binding studies are s t i l l controversial and the previous therapeutic t r i a l s have been largely unsuccessful, some means of increasing GABA levels that has not already been tr ied should be found. Recently, Matsui and Deguch (1977) reported the isolat ion of gabaculine. Gabaculine is a potent inhibitor of GABA transaminase, and in their study gabaculine was reported to increase GABA content to about 15 times the control values and to maintain high levels forty hours after administration to mice. Picrotoxin- and thiosemicarbazide-induced convulsions were also completely protected against by gabaculine. Gabaculine seems worth testing in HD patients. 26 As is evident from the preceding section, l i t t l e , . . i f any, success has been experienced in therapeutic t r i a l s in HD. What makes this even more complicated is that most investigators have limited their efforts to trying to al leviate the motor impairments of their patients. But these patients also have intense psychological changes which are in many cases even more debi l i tat ing than their motor symptoms. Thus, ideal ly , any therapeutic approach should take into account a l l aspects of the disease, since as Bruyn (1968) explains, the mental and motor abnormalities are not mutually exclusive but can influence each other to a large degree. The next section gives a brief account of our current understanding of the mental symptoms in HD. Psychopathology George Huntington's (1872) or ig inal description of HD stated that "insanity with a tendency to suicide" was one of the three distinguishing characteristics of the i l lness . The others, of course, were the facts that i t is hereditary and that i t s onset i s in adulthood. Since then investigators have noted several different mental disturbances in these patients. These are dementia (Hallock, 1898), psychotic symptoms (Bruyn, 1968; Dewhurst et a l , 1969), and changes of personality (McHugh and Folstein, 1975). Usually, the psychological symptoms precede the motor disturbances (Bruyn, 1968; Maida and Schnaberth, 1976; James et a l , 1969). Because of this , some investigators have tried to use psychological indices as pre-morbid indicators of HD carriers (James.et a l , 1969; Lyle and Quast, 1976; Lyle and Gottesman, 1977). However, the results are inconclusive. McHugh and Folstein 0-9.75) have suggested that there are three dist inct ive features of the dementia syndrome in HD: "(1) a slowly progressive dilapidation of a l l cognitive powers; (2) a prominent psychic apathy and inert ia that worsens to an akinetic mute state; and (3) an absence of aphasia, alexia, cort ica l blindness, or Korsakov-type amnesia." They further suggest that the combination of these three factors that form this syndrome is only found in disorders with prominent subcortical pathology, such as Parkinsonism and hydrocephalus. Other dementia diseases with definite cort ica l pathology, such as Alzheimer^ disease, do not show this type of syndrome. Thus, they conclude with the proposition that HD is characterized by a "subcortical dementia syndrome." This view is direct ly opposed to the c lass ica l view that the mental changes in HD are a result of the progressive cort ica l atrophy (Barr, 1974; Bruyn, 1968; Pinel , 1976). It is evident that strategies of treatment in HD must take into account the mental symptomatology which u n t i l recently was pract ical ly ignored. The general cachexia,dysarthria and hyperkinesias have served to convey impressions of a greater severity in mental impairment than was actually present. This led most investigators to generalize that HD was just another dementia syndrome which caused the patient to become an eventual "wreck of a human being." Recent neuropsychological testing has given us a better understanding of HD. Most of these findings have supported McHugh and Folstein's (1975) proposition. The general mental changes are summarized in Table 5, while a summary of recent neuropsycho-logical test results are given in Table 6. 28 TABLE 5 Psychopathology of Huntington's Disease* Psychologic findings: - Patients have an insight into their dementia - Severe d i f f i cu l ty with organization, planning, and sequential arrangement of information. - Disturbed by too much input, also easily distracted. - Thought patterns frequently become repetit ive, because continuously interrupted by lack of attention, interpretation, word-finding and increased motor restlessness. - Di f f icul ty with retr ieval of memory on command, and a loss of finely detailed memories. - Failure to spontaneously in i t ia te ac t iv i t i e s , unless strong motivation is presented. - Mental apathy and inert ia present, leading to an akinetic mute state. - Absence of agnosia, aphasia, alexia, apraxia, cort ica l blindness, Korsakov-type amnesia, disturbances of spatiotemporal and personal orientation. - Seemingly loss of psychomotor inhibi t ion. Psychiatric findings: - Increased i r r i t a b i l i t y and anxiety. - Labile effect, with some emotional deterioration. - Delusions and psychotic behaviors, including depression and paranoia - Intense fluctuations of mood - Bad temper, aggression, but also apathetic many times - Mentally restless and feelings of discomfort - General personality change usually occurs. From Bruyn, 1968; Caine et a l , 1978a; McHugh and Folstein, 1975. 29 TABLE 6" Results of Neuropsychological Test Batteries in Huntington's Disease* Test Results Source Wechsler Adult Intelligence Scale Wechsler Memory Scale Wechsler-Bellevue Scale Halstead Neuropsychological Test Battery Minnesota Multiphasic Personality Inventory Bender Visual-Motor Gestalt Test Shipley-Hartford Retreat Scale Short-Term Memory Tests Parietal Lobe Battery Language Performance Test Test of Verbal Fluency Reading and Writing Test Picture Naming Test T r a i l Making Test Tactual Performance Test Low Bol l et al,1974; Butters et a l , 1978; Caine et al,1978a, McHugh & Folstein, 1975; Norton, 1975 Low Butters et a l , 1978 Low Bol l et a l , 1974; Norton, 1975 Impaired Bol l et a l , 1974, Norton, 1975 Impaired Bol l et a l , 1974; Goodman et a l , 19.76. Low Lyle and Quast, 1976 Low Lyle and Gottesman, 1977 Impaired Butters et a l , 1976; 1977; 1978 Relatively Caine et a l , 1978a normal Normal Caine et a l , 1978a Impaired Butters et a l , 1978 Normal Caine et a l , 1978a Normal Butters et a l , 1978 Low Bol l et a l , 1974 Normal Bol l et a l , 1974 Most tests take into account the motor impairments and the possible detrimen-ta l effects they could cause while undergoing each test. Please refer to source papers for information and source about any test. 30 The cognitive deficits of patients with HD do not develop uniformly. Instead, there are certain disorders, such as those concerning memory, which seem to develop f i r s t , preceding the more widespread inte l lectual deterioration (Butters et a l , 1978). Even in advanced cases the pattern of impairment is not diffuse and homogenous, but is characterized by a relative sparing of several higher cort ica l functions (Caine et a l , 1978b). Affective changes are also pronounced in HD (Bruyn, 1968) and have been suggested to cause dynamic disturbances in concentration, intention and "goal tenacity" (Hochhemier, 1936). Behavioral aspects such as these are important to keep in mind when trying to find an animal analog for HD. This is because similar def ic i ts which are characteristic of the "subcor-t i c a l dementia syndrome" must be shown. It is not enough just to try and mimic the motor abnormalities. In fact, only models which demonstrate neuro- and psycho-pathological s imi lar i t ies should be called analogs of HD. The following section examines the efforts of many investigators towards producing such an animal model. 31 Animal Models Based on the preceding review there are essentially five c r i t e r i a which should be reached i f an animal analog or syndrome is to be considered an ideal model of HD. These are: (1) there should be a genetic component involved; (2) neuropathological changes similar to those seen in HD must be present; (3) motor, and (4) behavioral symptomatology of a nature para l le l to HD symptoms should be represented; and (5) the model should show responsiveness to psychotropic drugs in a manner similar to that observed in patients with HD. A l l previous "models" of HD have rarely taken into account more than two of the above c r i t e r i a . A survey through the l i terature reveals that, in fact, c r i t e r i a 3 and 5 are real ly the only ones which are consistently found in animal models. Table 7 l i s t s most of these. As can be seen from this table most of the "models" try to demonstrate motor abnormalities following short-term simulation of some of the neurochemical changes found in HD. Some investigators have even attempted to demonstrate motor abnormali-ties following destruction of various brain areas such as the striatum (Nei l l et a l , 1974). However, this is s t i l l unsatisfactory, in spite of the associated behavioral changes found in these animals (Kirkby and Polgar, 1974; Winocur, 1974). This is because the thermocoagulative techniques used to destroy these structures have also unavoidably damaged supportive tissue, as well as fibers which pass through and terminate in the area. Three years ago, however, a s tart l ing breakthrough was made by Olney and his colleagues (1975), which influenced two laboratories to discover independently the best animal "model" of HD known at present. This model is the subject of the next section and the remainder of this thesis. 32 TABLE .7" ANIMAL MODELS FOR PRODUCING DYSKINESIAS* Peripheral Systemic Administration Dopamine system** Source Amphetamine Apomorphine Levodopa Neuroleptics (Klawans & Rubovits, 1974; Eibergen & Carlson, 1976) (Weiner et a l , 1978; Wolfarth & Kolasiewicz, 1977) (Mones, 1973; Goldstein et a l , 1976) (Sayers et a l , 1975; Paulson, 1976b; Gunne and Barany, 1976) Serotonin system 8,B ' -Iminodipropionitri le (Langlais & Gabay, 1977) Intrastr iatal Administration Dopamine system Dopamine (Cools & van Rossum, 1976; Costal l & Naylor, 1975) Amphetamine (Cools & van Rossum, 1976) Apomorphine (Cools & van Rossum, 1976) 3-Methoxytyramine ( D i l l et a l , 1976) Acetylcholine system ' Acetylcholine ( D i l l et a l , 1968) Carbachol ( D i l l et a l , 1968; Murphey & D i l l , 1972; McKenzie & Viik, 1975) Alcuronium (McKenzie & V i i k , 1975) GABA system PAcrotoxin (Pycock, 1976; Standefer & D i l l , 1978) Al ly lg lyc ine (Pycock, 1976) Bicuculline (Standefer & D i l l , 1978) D-Tubocurarine (McKenzie & V i i k , 1975; McKenzie et a l , 1972) Thiosemicarbazide (McKenzie & V i i k , 1975) Serotonin system 5-Hydroxytryptamine (Cools and van Rossum, 1976) Others Mescaline ( D i l l , 1972) Somatostatin (Razek et a l , 1977) Dyskinesias are defined as stereotyped, choreiform, athetoid, hyperkinesia and epileptoid behavior. Mainly a model of tardive dyskinesia; shown in normal, 6-OHDA, and electro-l y t i c l e s i o n e d s t r ia ta l animals. 33 Str iata l Kainic Acid "Model" In 1975, Olney and his colleagues reported that kainic acid (KA), a structural analog of glutamate, exerted direct toxic effects on neuronal perikarya, while leaving axons, terminals and g l ia re lat ively unaffected, except for the anterograde degenerating axons- of the affected neurons. A proposed mechanism of action for the nerve c e l l death is irreversible ionic shifts caused by extreme excitation of neurons possessing glutamate receptors (Olney, 1975). Recently, Coyle arid Schwarcz (1976) and McGeer and McGeer (1976b) reported that, when small amounts of KA are injected into the striatum of rats, biochemical and morphological changes occur which resemble those in HD. Str ia ta l CAT and GAD ac t iv i t i e s , as well as concentrations of s t r i a t a l ACh and GABA, are s ignif icantly decreased, while TOH act iv i ty and dopamine levels are normal or elevated (Coyle et a l , 1978b). Morpholo-gical ly in the striatum, there is a loss of neurons, shrinkage, ventricular di lat ion and g l ios i s . A summary of the presently known biochemical and morphological s imi lar i t i e s , as reviewed by Coyle et a l (1978b), are shown in Table 8. Histological analyses within the striatum following KA injections have been controversial... Some investigators maintain that KA selectively destroys neuronal c e l l bodies (Coyle, 1978a; 1978b; Mason et a l , 1978b), while others show evidence of non-specific necrosis (Meibach et a l , 1978; Wuerthele et a l , 1978). The differences between these investigators may be a result of inconsistencies in KA administration procedures (McGeer and McGeer, 1978b) and the strain of rat employed (Sanberg et a l , 1978c). Similar controversy exists over the extent of any resulting extrastriatal damage (Coyle et a l , 1978b; Wuerthele et a l , 1978); however, the same explanation may, in part, hold true. 34 The s t r ia ta l KA animals show behavioral responses to psychotropic drugs (summarized in Table 9) which are quite similar to those seen in HD patients. These results are quite important since they demonstrate that this animal model may be a good tool for evaluating the effectiveness of various experimental agents considered for use in HD. The s imi lar i t ies between the s t r i a t a l KA animals and HD support the c r i t e r i a set out in the beginning of this section; (1) while there is presently no. demonstratable inheritance of neurodegeneration in these animals, Sanberg et a l (1978c) have shown that the neurotoxicity of KA in the striatum is indeed genetically influenced; (2) neuropathological changes similar to those seen in HD are present in the animal condition, and (3) the model does show responsiveness to psychotropic drugs in a manner similar to those observed in patients with HD. Recently, HD-like motor (Fibiger, 1978) and behavioral disturbances (Sanberg et a l , 1978a) were reported in s t r i a t a l KA animals. The purpose of the following experiments was to veri fy , extend and .elucidate the nature of these behavioral abnormalities.. The findings reported here f u l f i l l the remaining two criteria' (3 and 4), and give- a further indication that KA s t r i a t a l lesioned rats may indeed'be a viable animal "model" of •Huntington's!. disease.. 35 TABLE 8 A comparison of biochemical and morphological changes in the striatum reported in rats given in tras tr ia ta l injections of kainic acid (KA)„ and Huntington's disease (HD) Neuronal Index Str iata l KA HD Biochemical Indices* G A M a , b , c , d Acetylcholine ^ ' ' Dopamine ' * * „ . b ,c ,d Serotonin Angiotensin Enkephalin Decreased Decreased Normal or Increased Normal Decreased Decreased Decreased Decreased Normal or Increased Normal Decreased Decreased Receptor Binding Muscarinic Serotonin Dopamine Decreased Decreased Not determined Decreased Decreased Decreased Morphology Intrinsic neurons G.lia Afferent terminals Internal capsule Mass Decreased Increased Normal Normal Decreased Decreased Normal or Increased Normal Normal Decreased ^Biochemical indices used for KA striata: Synthetic enzyme act ivi ty transmitter level 'transmitter uptake transmitter release 36 TABLE .9 A comparison of motor response to various pharmacological agents in rats given in tras tr ia ta l injections of kainic acid (KA) and patients with Huntington's disease (HD)* Drugs used and their relation to neurotransmitter system Str ia ta l KA HD Source t Increased dopaminergic act iv i ty d-Amphetamine potentiated Apomorphine (high dose) (low dose) normal normal Decreased dopaminergic act iv i ty Pimozide Haloperidol decreased decreased Decreased cholinergic act iv i ty Scopolamine potentiated exacerbated (Mason et al,1978a,b; Sanberg et a l , 1978b) normal (Mason et al,1978b) normal (Sanberg et a l , 1978b) s l ight ly beneficial (Fibiger, 1978) s l ight ly beneficial (Sanberg, Pisa and Fibiger, in prep.) exacerbated (Sanberg, Pisa and Fibiger, in prep.) potentiated not determined (Sanberg, Pisa and Fibiger, in prep.) not determined s l ight ly beneficial Increased cholinergic act iv i ty Pilocarpine Choline Increased serotonergic act iv i ty Fenfluraminett potentiated not-determined (Sanberg and Fibiger, 1978) Tmipramine not determined potentiated Anesthetics potentiated potentiated (Sanberg, Pisa and Fibiger, in prep. Barbituates The effects on s t r i a t a l KA animals are expressed in terms of similar effects on control animals. For HD the effects are "expressed in 'terms; of amount of. chorea. t Sources are for s t r ia ta l KA results only. Refer to introduction for HD sources. t t Determined on anorexic act iv i ty 37 METHODS Subjects: A total of th ir ty-nine male Wistar albino rats from Woodlyn Farms, Guelph, Ontario were used. Groups 1 and 2 consisted of 21 and 18 rats respectively. Eleven rats in Group 1 and nine rats in Group 2 received KA lesions(KAL) .aridwere maintainedj as described in Appendix I. The remaining rats were used as sham operated controls. Group 1 was employed as experimental subjects for the following behavioral tests; body weight, food and water intake, locomotor act iv i ty , acquisition and extinction of bar-pressing, and step-down passive avoidance. Group 2 was used for the spontaneous alternation, alleyway maze exploration, and the shuttlebox avoidance paradigms. Groups 1 and 2 were operated pn; approximately three months apart. Apparatus: Locomotor act iv i ty: Six photoactometer cages (BRS Foringer #PAC-001) measuring 61 cm in diameter, with 43 cm high walls, a removable top, painted black internally and being transected by six infrared photocell beams were used. Interruption of the beams incremented electromechanical counters located approximately 9 m from the cages. Photocell beam interruptions were cumulated over periods of 10 or 30 minutes and then recorded by an automatic printout counter (BRS Foringer //P0S-112). The environment consisted, in part,; idf white noise, temperatures ranging between 21-24°C, and was illuminated by 4 x 100 watt bulbs located 3.6 m above the act ivi ty cages. Appetitive bar pressing: Four standard Skinner boxes (BRS Foringer #RTC-020) enclosed in soundproof chambers (BRS Foringer //SEC-020) and 38 f i t ted each with a lever (BRS Foringer //RCL-001) and a dispenser (BRS Foringer #PDC-020) of food pellets were used. Digibits modules were assembled in a logical c ircui t controll ing the reinforcement schedule, with 45 mg Noyes pellets being used as reinforcers. Bar presses were recorded on conven-tional electromechanical counters. Step-down passive avoidance: A 27 x 27 x 30 cm box with plexiglass walls, grid f loor, and a 7.5 x 26.7 cm wooden platform shelf which was located to the side, hinged on a microswitch and 9.4 cm above the floor was used. On release of the microswitch, scrambled DC current e lectr i f ied the stainless steel rods of the grid, which were spaced. 1.5 cm apart. Footshock, set at a nominal 2 mA, was supplied by a DC shock generator/scrambler (BRS Foringer #SCS-003). Spontaneous alternation: A gray wooden T maze 14 cm high and 8 cm wide throughout was used. A 27 cm long startbox was separated from a 66 cm long alleyway by a guil lot ine door. The alleyway led to two 39 cm long choice arms which were f i t ted with guil lot ine doors, separating them from the choice point situated at the intersection of the alleyway and the arms. The top of the maze was covered by a galvanized mesh.wirescreen, and was illuminated by a 15 watt Luxo lamp placed 50 cm above the choice point. Alleyway maze exploration: A modified Hebb-Williams.maze as described by Whishaw and Cooper (1970) was used. Essential ly, i t consisted of a square maze measuring 80 x 80 cm with 11 cm high walls. At two opposite corners the walls were removed and a startbox and a goalbox were attached each measuring 30 x 30 cm. The goal box contained a food cup recessed in the floor towards the back. Guil lotine doors separated the startbox from the inside alleyways. The center area consisted of five diagonal alleyways running para l le l to the start and goal boxes. A further fourteen designated areas around the perimeter of the inside section constituted the remaining alleyways. The apparatus was painted gray internally and covered with clear plexiglass over the top. The maze was located in a 2.5 x 2.5 x 2.5 m. wooden soundproof chamber, lined with 1.8 cm thick foam rubber on the inside and covered with aluminum f o i l on the exterior. One 100 watt bulb located 2.3 m above the maze illuminated the interior of the chamber. Shuttlebox avoidance: A wooden box measuring 29 x 70 x 30 cm with a grid floor and a hinged covered top was used. The box was divided into two equal areas across the long axis by a wooden guil lot ine door. The brass rods of the grid floor, which were spaced 1.5 cm apart,, on the left or right side of the apparatus could be e lectr i f ied by a Lafayette AC constant current shock generator and scrambler (Model No. 82404) with the intensity set at a nominal 1 mA. Procedures; Body weight,, water intake and food intake: Post-operatively, a l l animals were housed separately and given free access to.ad l i b food and water, and their body weights were recorded dai ly . A l l lesioned animals were tube-fed intragastrical ly with 10 ml of Soyalac , twice dai ly , unt i l they regained weight to at least 300 gms. Control rats were handled similarly but were not tube fed. When the lesioned animals were a l l free-feeding, gaining weight and had surpassed their pre-operative body weights, graduated (100 ml) volu-metric water feeders (Richter tubes) replaced the water bottles on a l l animals cages and their daily water intake was recorded for one week. Following the measurement of daily water intake a l l animals were food deprived for 24 hrs. Following this time, the amount of food consumed over 20 minutes was recorded. Water intake during the 24 hr food deprivation period was also measured in the Richter tubes. 40 Two-way analyses of variance with Lesion and Days as main factors were used to evaluate the significance of the body weight and daily water intake data. Two-tailed Student's _t tests were used on the food and water tests. Locomotor act iv i ty: The rats were individually placed in the photoactometers at either 10 a.m. or 1 p.m. and their act iv i ty was recorded for 1 hr. They were then injected i . p . with 1 mg/kg of d-amphetamine sulphate and immediately replaced in the same photoactometers for another 2 hrs. KAL and control rats were also assessed for nocturnal locomotor act iv i ty by placing the rats individually in the locomotor cages between 7 p.m. and 9 a.m. Photocell counts were cumulated over 30 min periods. In a l l locomotor studies equal numbers of control and KAL rats were run at the same time. Two-way analyses of variance with Lesion and Periods as main factors were separately conducted on the pre- and post-injection,as well as the nocturnal scores. Acquisition and extinction of bar-pressing: A week after the test of locomotor act iv i ty the food diet of the rats was,, restricted to about 15 gm of Purina Chow dai ly , un t i l they reached 90% of their free-feeding weights, which took about a week. The rats were thereafter maintained at these reduced weights by appropriately adjusting their daily amount of food, to which the rats had access for about 1 hr after training. The animals were f i r s t given 12 acquisition sessions of 30 min each under a continuous reinforcement schedule (CRF). To promote learning., at the onset of Session 1, ten 45-mg Noyes pellets were attached on the bar with cellophane tape and another ten pellets were placed in the food magazine. At the onset of Session 2 five pellets were freely available on the bar. In the 41 following ten sessions only pellets contingent on bar pressing were available. On Sessions 13-17 reinforcement was discontinued. Each of these extinction sessions lasted u n t i l the rats ceased to respond for three consecutive minutes. Both latency and number of responses to the extinction cr i ter ion were recorded. Two-way analyses of variance, with Lesion and Sessions as main factors, were conducted on the responses during acquisition and on both the responses and the latencies during extinction. One lesioned rat was excluded from the analysis of the locomotor and CRF testing because of methodological and control problems in running groups of unequal size. Step-down passive avoidance: At the end of the bar-pressing experiment a l l rats were given free access to food for two weeks. At the onset of the acquisition session a small amount of electrode paste was applied to the paws of each rat. The rat was then placed on the platform. Upon stepping on the grid they received a 2mA footshock, lasting u n t i l they returned onto the platform. Latency to the f i r s t step-down, latency to an avoidance cr i ter ion of three consecutive minutes spent on the platform, and number of descents to cr i ter ion were recorded. One day following the acquisition session, the rats were placed on the platform, and their latencies to step down, measured to a maximum of 3 min, were recorded. Three days after the retention test, footshock detection thresholds were determined. Prior to being placed on the grid f loor, electrode paste was applied to the paws of each rat. The animal was allowed to habituate to the apparatus for 1 min and then presented with a series of inescapable 0.5 sec footshocks of ascending intensities (0.25 mA - 3.0 mA). An intershock interval of 15 sec was used. Threshold intensities of f l inch , 42 jump, and vocalization were determined by the occurrence of the appropriate behavior in at least three out of five presentations at that intensity. After five days the freezing reaction to footshock was determined. The rat was exposed to five 0.5 sec, 2 mA inescapable footshocks at intervals of at least 30 sec. Both latency of the f i r s t movement (except eyeblink) and number of fecal b o l i were recorded. The passive avoidance experiments were, run blind insofar as the investigator did not know the identity of the animals. Two-tailed _t s tat is t ics were used to evaluate the results , except for the avoidance retention data, which were analyzed using. Mann-Whitney U s tat i s t ics (Siegel, 1956). Spontaneous alternation: .Three, weeks following surgery, ten daily spontaneous alternation sessions of three test t r i a l s each were conducted. The f i r s t t r i a l consisted of placing the rat in the startbox, l i f t i n g the door 5 seconds later , and determinating which arm the rat entered, in order to establish i t s position preference. A maximum seven minutes were allowed in this t r i a l for the rat to enter one of the arms. If after 6 min no choice had been made, a small shove was given to the rats ' posterior to help him get on his way. If a rat did not enter any arm within the seven min from the onset of the t r i a l , i t was considered to have fai led to make a choice. After a rat entered one of the arms, the guil lot ine door of that arm was closed and the rat was confined there for 10 sec, afterwhich i t was then transferred to the startbox for the next t r i a l . Tr ia l s 2 and 3, which tested for spontaneous alternation, were conducted exactly as the f i r s t t r i a l , except that a maximum of four minutes were allowed for a choice. Once the animal fai led to make a choice i t was not given any subsequent t r i a l s in that session. A cr i ter ion of obtaining 5 successful sessions in which a choice was made in at least the f i r s t two t r i a l s was used. The rat was not tested on any subsequent sessions upon reaching this cr i ter ion. Mann-Whitney TJ s tat i s t ics were used to determine the s t a t i s t i c a l significance of the data. If any animals did not reach cr i ter ion by the end of the testing sessions a maximum value of 10 sessions was given for the purpose of s ta t i s t i ca l analysis. Alleyway maze exploration: Two weeks following the spontaneous alternation testing, a l l rats were deprived of food for 24 hr and then placed in the startbox of the maze apparatus. A few seconds later the door leading to the alleyways was opened. The time to emerge from the startbox into the alleyways, the number of alleyways entered in seven successive 3-minute periods following emergence,, and the total time spent in the goalbox before consumption of the f i r s t of eight Noyes food pellets present in the food cup were recorded. Before an alley could be considered entered, a l l four paws must have crossed the boundary markings. At the end of the 3-minute testing periods the animal was removed and the maze was wiped clean with a weak vinegar solution. Two-way analyses of variance with Lesion and Periods as main factors,were conducted on the number of alleyways explored. Two-tailed jt s tat i s t ics were used to evaluate the startbox and goalbox latencies. Shuttle-box avoidance: a) Acquisition (one way active avoidance) Two weeks following the alleyway maze testing,each animal was 44 placed in the left side of the box with the center door closed,and after 5 sec a tone (Sonalert, 500 Hz) was sounded (conditioned stimulus, CS) as the door was raised. The CS lasted for a duration of 10 sec after which the left side of the box was e lectr i f ied (unconditioned stimulus, UCS). After the animal shuttled to the right, non-electrified side the door was lowered and the shock terminated. If the animal avoided by shuttling to the safe side during the presentation of the CS, the door was lowered and the CS turned off. Following an i n t e r t r i a l interval of 15 sec the animal was returned.by hand to the-left <side of the apparatus where the next t r i a l commenced 5 sec later. Training occurred within one day with the dependent measure being the total number of t r i a l s required to reach the acquisition cr i ter ion of nine consecutive avoidance responses. Control and lesioned rats were run alternately. b) Retention Three days following the acquisition session, the rats were replaced in the apparatus and the number of t r i a l s required to reattain the cr i ter ion of nine consecutive avoidance responses were determined. The UCS was again presented during this phase. c) Extinction One day after the retention test, the animal was placed in the apparatus as before. During this phase the UCS was never presented. A maximum of 30 t r ia l s were given each day u n t i l an extinction cr i ter ion of three consecutive avoidance failures occurred. d) Retraining One day after the extinction test, a l l animals were retrained exactly as described in the acquisition phase (a). 45 e) Shock-shock confl ict (Passive avoidance) One day later , the rats were replaced in the left side of the apparatus. The t r i a l s were run the same as previously except that now the grid floor of the right side of the box was e lectr i f ied following the termination of the CS. Each t r i a l was terminated when the rat remained in the non-electrified safe compartment by either shuffling back following entry into the shocked side or by remaining in the safe side following the CS termination, thereby successfully avoiding the shocked side. An avoidance fai lure occurred i f the animal was shocked. One t r i a l was given per day and testing continued unt i l the cr i ter ion of three consecutive avoidances occurred. f) Shock threshold About one-week following the completion of the avoidance tests, footshock detection thresholds were determined. The animal was placed in the left side of the apparatus with the door closed and allowed to habituate to i t for 1 min. The rat was then presented with a series of inescapable 0.5 sec footshocks of ascending intensities (0.15 mA - 0.75 mA). An inter-shock interval of 15 sec was used. Threshold intensities of f l inch , jump and vocalization were determined by the occurrence of the appropriate behavior in three out of five presentations at that intensity. Two-tailed _t s tat is t ics were used to evaluate a l l the results. Histology: Following the completion of behavioral testing two control and three KAL rats from group 1 and a l l the rats from group 2 were given an overdose of sodium pentobarbital and perfused intracardial ly with isotonic saline solution followed by 10% Formol saline. Sections were cut from frozen tissue at 50 u, and every third section from group 1 and every second section from group 2 were saved. A l l the mounted sections from 46 group 1 were stained with cresyl v io le t . For group 2 rats , two sets of sections ( i . e . , every forth section) were mounted and one set was stained with cresyl violet and the other set with luxol blue in order to reveal both c e l l bodies and fiber bundles, respectively. Biochemistry: Eight control and eight KAL rats from group 1, were sacrificed by cervical fracture. The act iv i t ies of choline acetyl-transferase (CAT), glutamic acid decarboxylase (GAD), and tyrosine hydro-xylase (TOH), were assayed in samples of the dorsal neostriatum, ventral neostriatum, nucleus accumbens, and cortex of four control and four KAL rats, using the methods of McCaman and Dewhurst (1970),, Chalmers et al(1970), and McGeer et a l (1967)', respectively. The remaining four control and four KAL rats were used to assay noradrenaline (NA) levels in the combined samples of neocortex and hippocampus according to the method of McGeer and McGeer(1962). Student's _t tests were used to evaluate the s ta t i s t i ca l significance of the data. 47 RESULTS Aphagia and Adipsia: During the f i r s t 24 hr after surgery, a l l lesioned animals showed loss of eating and drinking behaviors. This aphagic and adipsic behavior was temporary, lasting from 1-3 (x = 1.8) days. Also during the f i r s t 24 hr period most lesioned animals rejected even palatable pellet mash with sucrose added. For the f i r s t few post-operative days a l l lesioned animals exhibited intense stereotyped behaviors. During this same period approximately 40% of lesioned animals showed peripheral bleeding from their urinary tracts, nasal and visual or i f ices , which stopped after 1-3 days; Force feeding by gastric intubation was required to keep many of the lesioned animals al ive. By the fourth post-operative day a l l animals were free-feeding on ad l i b food and water. Body weight: The results of the mean body weight measurements are shown in Figure 3A. Analysis of variance revealed significant main effects of lesion, F = 16.87, df = 1,18, p_ < .001, and days, F = 198.2, df = 9,162, j> < .0001, as well as the interaction of lesion with days, _F = 8.84, df = 9,162, p_ < .001. This indicates that the KAL animals showed a significant and long lasting depression of body weight relative to controls. Following surgery, the control animals showed a continuous daily body weight gain. On the other hand, the KAL animals displayed an i n i t i a l period of rapid weight loss (during the period of aphagia and adipsia) followed by daily weight gains at r a t e s comparable to controls. As seen in Figure 3A, however, the KAL animals never regained weight to control values, but instead, showed a relat ively permanent reduction in body weight over the course of the study. Although not shown in Figure 3A a significant reduction in body weight was s t i l l present in the KAL animals 75 days after surgery 7 8 9 10 11 12 POSTOPERATIVE DAYS 13 Figure 3. Mean body weights (A) and mean water intake (B) for con t r o l (open'squares') and KA s t r i a t a l lesioned ( f i l l e d squares) f a t s . " E r r o r bars represent standard error of the mean. N = 10 per group. OP = day of operation. V 49 (x controls = 523.3 gms, x'KALS = 499.3 GMS, t ,= 2.11, df • = 18, p < .05). Food and water intake: Figure 3B depicts the' daily mean water intake of control and KAL rats. There were no significant differences found between groups either in the effect of lesion, _F < 1, or the interaction of lesion with days, F_ = 1.04, df = 7,126. As shown in Table ,^10 mean food intake measured after 24 hr of food deprivation also did not differ s ignif icantly, _t < 1. However, as also seen in Table.l'^, mean water intake during the 24 hr of food deprivation (non-prandial drinking) was signif icantly greater in KAL animals when compared with controls, t_ = 2.62, df = 18, _p_ < .02, or with the previous baseline day shown in Figure 3B, _t = 2.53, df = 9, _p_ < .05. There was a tendency for the lesioned animals to consume more ad l i b food and water per gram body weight, but this did not reach significance on any day. Locomotor act iv i ty: The results are depicted in Figure 4. Before d-amphe-tamine administration there were no significant effects of lesion on locomotor act iv i ty , F_ < 1. The significant effect of periods, F = 26.3, df = 5,90, j> < .001, reflected the progressive decrease of act iv i ty of the rats in both groups. After administration of d-amphetamine, however, the KAL rats revealed a s ignif icantly greater increase in act iv i ty than the controls, F = 13',04, df = 1,18, p_ < .005. The KAL animals did show a signif icantly greater increase in nocturnal locomotor act iv i ty than did the controls (Fig-t. .. 5) especially between the hours of 12 and 7 a.m., £ . = 29.65, df = 18, £ < .0005. Appetitive bar pressing: Although the average response rate of the KAL rats during acquisition was s l ight ly lower than that of the controls (Fig. 6), neither the effect of lesion, _F = 2:.55, df = 1,18,' nor; the^ inter-act Lon of lesion with sessions, F 1.03, df - 11,98, reached. TABLE 10 Food intake for 20 minutes following,and water intake during,24 hours food deprivation in ct Kainic Acid Str ia ta l Lesioned Rats Group Food Intake Water Intake Control (n = 10) 4.63 ± 0.77 29.10 ± 2.62 Kainic acid Str iata l (n = 10) 4.77 ± 1.38 51.73 ± 7.71* ct Values are means ± standard error of the mean in grams of food and mis of water. Significantly different from controls, JD < .02 (two-tailed tes 51 Figure 4. Mean locomotor act iv i ty and standard error of the mean of the rats in each group before (left panel) and after (right panel) administra-tion of d-amphetamine (1 mg/kg). F i l l e d c irc les = control rats (n=10); open circles = KA s tr ia ta l lesioned rats (n=10). 52 Figure 5. Mean nocturnal locomotor act iv i ty of the control ( f i l l ed squares) and KA s t r i a t a l lesioned (open squares) rats recorded every 30 minutes between 7 p.m. and 9 a.m. N =10 per group. 53 significant levels . The rel iable effect of sessions, _F = 34.2, df.^ 11,98, £ < .001, reflected the improvement in performance of the rats of both groups. By mistake, the animals were given ad l i b food on the day before Session 10. This accident accounts for the drop in performance on that session. During extinction (Fig. 7) the KAL rats performed more responses and took longer to reach the extinction cr i ter ion than the controls. Analysis of variance of the responses revealed significant effects of lesion, _F = 5.05, df = 1,18, £ < .05, and sessions, F = 11.21, df = 4,72, £ < .01, and a significant interaction effect, F_ = 3.54, £ < .05. Tests of simple main effects (Winery, 1963) showed that the KAL rats responded s ignif icantly more than the controls in both the f i r s t session, _F = 13.3, df = 1,18, £ < .01, and the second session, _F = 6.3, df = 1,18, £ < .05, but not in the subsequent sessions, _p_'s > .05. Analysis of variance of the latencies also revealed significant effects of lesions, F = 10.41, df = 1,18, £ < .01, and sessions, F = 4.36, df = 4,72, £ < .01, with no significant interaction effect, F_ = 1. Tests of simple main effects revealed that the KAL rats took signif icantly longer than the controls to reach cr i ter ion in both the f i r s t and the second session, _F's = 7.95 and 5.51, respectively, df - 1,18, £ < .05, but not in the subsequent sessions, £ ' s > .05. Step-down passive avoidance: The acquisition data are shown in Table ,11. There were no significant differences between groups in latency to the f i r s t step down, _t = 0.1. After footshock the KAL rats showed a significant impairment in terms of both number of step-down responses and latencies to cr i ter ion , _t's = 3.64 and 4.62, respectively, df = 19, £ < .005. The KAL rats were also impaired in the retention test (Table lil) as indicated by their s ignif icantly shorter latency to step off the platform I CRF ACQUISITION 3 0 0 -(0 w (A c o a in a> oc w a> > c «s a> 2 0 0 1 0 0 -Figure 6. Mean responses and standard error of the mean during acquisition of continuously reinforced (CRF) bar pressing. F i l l e d c irc les = control rats; open c irc les = KA s t r i a t a l lesioned rats; s i and s2 = sessions in which shaping procedures were used. CRF E X T I N C T I O N 100 Figure / • Mean responses and standard error of the mean (upper pane] and mean latency to cr i ter ion and standard error of the mean, (lower panel) during extinction of bar pressing. F i l l e d triangles = control rats; open triangles = KA s t r ia ta l lesioned rats. 56 TABLE -11 . E f f e c t of b i l a t e r a l k a i n i c acid lesions of the striatum on ac q u i s i t i o n and retention of step-down passive avoidance . I n i t i a l step-down latency Time to c r i t e r i o n (sees) Number of descents to c r i t e r i o n 24-hr retention: step-down latency (sees) Controls (n=10) 3.58±1.01 298.70±28.73 3.10±0.23 148.20116.67 Kainic acid S t r i a t a l ( n = l l ) 3.78±1.40 502.64±42.84** 6.09±0.58*** 83.50±23.14* Data represents means ± standard error of the mean. *Significantly different from controls. _p_ < .05 (two-tailed test). **p_ < .005 (two-tailed test) ***p_< .0005 (two-tailed test) 57 compared with that of the controls, JJ = 25.5, nl/n2 = 10/11, £ < .05. There were no significant differences between groups in detection thresholds of f l inch , jump, and vocalization, _t's < 1 (Table 12). Also, there were no significant differences between groups in number of bo l i defecated after the 2 mA footshock, _t < 1 (Fig. - S ) . However, the KAL rats showed a signif icantly shorter immobility reaction than the controls, t_ (19) = 3.03, p < .01. Spontaneous alternation: The results are shown in Table 13. The mean number of sessions to reach cr i ter ion was s ignif icantly greater in the KAL rats compared to the controls, U = 11, N 1 / N 2 = 9/9, £ < .02. In fact, six of the KAL rats fa i led to reach cr i ter ion , whereas none of the controls did. The percent of arm entries in the f i r s t t r i a l for the KAL rats was signif icantly lower than the control values U = 11, N 1 / N 2 = 9/9, £ < .02. The KAL rats also fai led to make as many choices in either the second or third t r i a l s compared to the control rats , U's = 0 and 3, N 1 / N 2 = 9/9, £ ' s < .005, respectively. The poor performance of the KAL rats reflected the fact that six of them rarely would leave the startbox, let alone come out to the choice point and choose an arm. When the KAL rats did make choices on either t r i a l s 2 or 3, they did not show any re l iable differences from control rats in regards to alternating spontaneously between arms. Alleyway maze exploration: Figure 9 depicts the latency to depart from the startbox and the total time spent in the goalbox unt i l the f i r s t pellet was consumed. The KAL animals took signif icantly longer to leave the startbox, _t = 3.70, df = 16, £ < .0025, as well as to consume the f i r s t pel let , _t = 2.60, df = 15, £ < .025, than did the control rats. \ TABLE 12 Effect of b i la tera l kainic acid lesions of the striatum.on shock-" ct thresholds of f l inch , jump and vocalization Thresholds (mA) Group Flinch Jump Vocalization Controls (n = 10) 0.95 ± 0.09 1.80 ± 0.11 1.70 ± 0.17 Kainic acid Str iata l (n = 11) 0.86 ± 0.07 1.86 ± 0.15 1.73 ± 0.24 ct Data represents means ± standard error of the mean. Current was supplied by a DC shock generator. 59 14 12 10 CO o z o o LU to 0 F R E E Z I N G f DE F E C A T I ON •n m o > r 2 co O r-C to m to CONTROL LESION CONTROL LESION Figure 8. Freezing time and number of f e c a l b o l i a f t e r , 3 mA footshock i n c o n t r o l (n = 10) and KA s t r i a t a l l e s i o n e d r a t s (n = 11). Data represent means of f i v e t r i a l s . Bars represent standard e r r o r s of the means. * S i g n i f i c a n t l y d i f f e r e n t from c o n t r o l s , p < .01. TABLE -T3 Effect of b i la tera l kainic acid lesions of the striatum on spontaneous alternation' T r i a l l \ - % arm Mean choices for Mean % alternation No. of sessions entries in total sessions for total sessions Group to cr i ter ion total sessions T r i a l 2 T r i a l 3 T r i a l 2 T r i a l 3 Controls"(n=9) 6.56+0.53 86 .00±4 .87 5 . 0 0 ± 0 . 0 0 4 . 7 8 ± 0 . 2 4 7 1 . 1 1 ± 7 . 9 9 8 4 . 4 0 ± 5 . 8 9 Kainic acid s t r i a t a l (n=9) 8 . 7 8 ± 0 . 7 0 * 4 3 . 1 1 ± 1 2 . 3 0 * 2 . 3 3 ± 0 . 7 3 * * 1 .89±0 .86** 7 6 . 8 6 ± 1 4 . 5 4 7 7 . 5 0 ± 1 1 . 9 0 a Data represent means ± standard error of the mean *Significantly different from controls, p_ < .02 (two-tailed test) **P < .001 (two-tailed test) o 61 in •o c o o in > O z LU I-< 9 0 7 5 6 0 4 5 3 0 15 , 0* S T A R T - B O X Depar t u re G O A L - B O X Consume 1 st pellet CON K A L CON KAL Figure 9. Mean latencies to depart from alleyway maze start-box (left panel) and to consume the f i r s t food pellet in goal box for control (n = 9) and KA s t r ia ta l lesioned (KAL; n = 9) rats. , v Signif icantly different from controls, p < .05, **p < .005 62 During alleyway exploration (Fig. 10) neither the effect of lesion _F < 1, df = 1,16, nor the interaction of lesion with periods, F_ = 1.70, df = 6,96, reached significant levels. The re l iable effect of periods, F_ = 9.20, df = 6,96, _p_ < .001, reflected the progressive decrease in act iv i ty of the rats of both groups. Tests for simple main effects showed that the KAL rats explored s ignif icantly less than the controls in the f i r s t period, F^  = 4.50, df = 1,16, _p_ < .05, but not in subsequent sessions, p_'s > .10. Shuttle box avoidance: The acquisit ion, retention and extinction data are shown in Figure 1.1, The KAL animals showed a significant impairment in acquisition in terms of the total number of t r i a l s to cr i ter ion , _t = 2.15, df = 16, p < 0.05. Three day retention did not differ between groups' however, during extinction the KAL animals took more t r i a l s to reach the.extinction cr i ter ion than the control animals, t_ = 2.16, df = 16, p_ < 0.05. Retraining the rats on the one-way active avoidance paradigm 24 hr following extinction did not reveal any differences between groups (Fig. 12). When the shock-shock confl ict procedure was introduced 1 day later, however, the KAL rats took signif icantly longer to acquire this passive avoidance response than did the controls, _t 2.49, df = 16, _p < 0.03 (Fig. 10). No change in the sensit ivi ty to e lectr ic footshock was seen, with the f l inch , jump and- vocalization detection thresholds showing no significant differences between control and KAL rats, _t1s < 1 (Table 14). Histology: Group 1: A representative neostriatal lesion is shown in Figure 13. In a l l three brains sampled for histology the ventricles were enlarged and the neostriatum appeared shrunken b i la t era l l y . The rostra l aspect of the T i m e ( 3 - m i n p e r i o d s ) Figure 10. Mean exploratory act ivi ty of an alleyway maze in control ( f i l l ed circles) and KA s t r ia ta l lesioned (open circles) rats. N = 9 per group. O N E - W A Y A C T I V E A V O I D A N C E c o o o 60 50 40 A c q u i s i t i o n " 30 o 20 o c ? 10 R e t e n t i o n E x t i n e t i o n * C K A L C K A L C K A L Figure 11. Acquisit ion, retention, and extinction of a shuttle-box one-way active avoidance task. C = controls (n = 9); KAL = KA s t r ia ta l lesioned rats (n = 9). Data represents means ± standard errors of the means (bars). *Significantly different from controls, p < .05. o 20 CD o 16 o « 12 o c c CO 8 4 -0 R E T R A I N I N G l-way avoid. C KAL A C Q U I S I T I O N Pass ive avoid. 2 CD 3 O C KAL 4 ™ 3 q <D O 3 Figure 12. Retraining of one-way active avoidance (left panel) and subsequent acquisition of a passive avoidance response in a shuttle-box apparatus. C = controls (n = 9); KAL = KA s t r ia ta l lesioned rats (n = 9). Data represents means ± standard.errors of the means (bars). *Significantly different from controls, p < .03. TABLE 14 Effect of b i la tera l kainic acid lesions of the striatum on shock ct thresholds of f l inch , jump and vocalization ; Thresholds uA  Group Flinch Jump Vocalization Controls (n = 9) 243 ± 12 516 ± 39 525 ± 54 Kainic acid s t r ia ta l (n = 9) 248 ± 15 549 ± 54 459 ± 48 ct Data represents means ± standard error of the mean. Current was supplied by an AC shock generator. 67 neostriatum revealed marked, b i l a t era l loss of neuronal perikarya and dense g l i a l i n f i l t r a t i o n in the space surrounding the facicles of the internal capsule. The fascicles appeared to be more packed than normal tissue, but their size and stain density was not appreciably altered. In two brains the area showing neuronal loss had a diameter of about 0.8 mm. In the third rat the lesion was larger, extending from A9.0 to A6.5. In a l l brains, the ventral neostriatum did not show appreciable damage... ' Additional damage included a sl ight decrease of neuronal density in the layers V and VI of the neocortex at the injection s i te , in a l l three brains. Also, in the brain of the rat with relat ively large neo-s t r i a t a l lesions a decrease in the number of pyramidal cel ls was observed in the CA3 f ie ld of the anterior dorsal hippocampus and in the CAI f i e ld of the posterior dorsal hippocampus. The hippocampal neuronal loss was mostly uni lateral . No other damage to brain areas outside the neostriatum could be detected. Group 2: The s t r ia ta l lesions found in this group of rats was similar in nature to those found in group 1. Ventricular di lat ion and s t r i a t a l atrophy was demonstrated in a l l brains. The mean extent of the lesions, in millimeters, was as follows: For the left side they were: rostro-caudal = 2.0 ± 0.31 (S.E.M.) , dorso-ventral. = 1.86 ± 0.29, and medio-lateral 1.02 ± 0.12. For the right side they were: rostro-caudal = 2.31 ± 0.24, dorso-ventral = 2.08 ± 0.16, and medio-lateral =1.23 ± 0.18. The lesions were confined primarily to the dorsal, and sometimes central, areas of the striatum. Figure 14 gives a' representation of neuronal loss in the striatum, as presented by one brain. 68 In four brains there was slight neuronal rarefaction., in cort ica l layers V and VI overlying the injection s i te . Hippocampal damage was rarely found in any - animals. One brain showed uni lateral pigmentosis in the CAI layer, and in a further two brains the CA3 and CA4 layers appeared to be less densely packed with neurons than in control brains, although the relative number of cellswas the same. No other extrastriatal damage was observed. Biochemistry The results are shown in Table 15. There were no significant differences r between control'and KAL rats in act iv i t ies of CAT, GAD, or TOH in either the cortex or the nucleus accumbens. Also, the animals of the two groups did not differ s ignif icantly in NA. levels in the cortico-hippocampal regions. These results indicate that the injections of kainic acid did not damage cholinergic and GABAergic neurons of the neocortex and the nucleus accumbens, or noradrenergic afferent terminals to the cortex and the hippo-campus . Clear differences between groups were found, however, in the act iv i t ies of s t r ia ta l enzymes. Specif ical ly , both CAT and GAD act iv i t ies in the dorsal striatum were signif icantly lower in the KAL than in the control rats, _t = 2.47 and 3.57, respectively, df = 14, _p_'s < .005. However, the rats of the two groups did not s ignif icantly di f fer either in GAD act ivity in the ventral striatum, _t < 1, or in TOH act iv i ty , both in the dorsal striatum, _t :=,1.56, df = 14, and in the ventral striatum, _t=1.57, df = 14. 69 Figure 13. 1- \Area of s t r ia ta l neuronal loss in a rat treated with in tras tr ia ta l injections of three nmoles of kainic acid. Numbers correspond to frontal planes of Konig and Klippel (1963) atlas. 70 Figure 14. Microphotographs and p i c t o r a l representation of control and kai n i c acid lesioned s t r i a t a . Number corresponds to f r o n t a l planes of Konig K l i p p e l (1963) a t l a s . 71 TABLE 15 Choline acetyltransferase (CAT), glutamic acid decarboxylase (GAD), / and tyrosine hydroxylase (TH) act iv i t ies and noradrenaline levels ct in control and kainic acid lesioned rats Area & group CAT Act iv i ty %* GAD Act iv i ty %* TH Act iv i ty %* Cortex Controls Lesioned Accumbens Control Lesioned Dorsal Control Lesioned Ventral Control Lesioned 15.2+1.95 15.4+3.32 101 4 7 . 3 ± 6 . 5 7 86 40.4+2.85 7 2 . 8 ± 7 . 9 8 4 3 . 3 ± 8 . 8 5 t 60 6 6 . 6 ± 3 . 4 2 4 4 . 7 ± 5 . 5 8 t t 67 7 9 . 5 ± 2 . 1 8 78.613.46 99 1 3 6 . 8 ± 5 . 2 3 1 4 7 . 4 ± 8 . 1 4 108 5 7 . 7 ± 4 . 4 7 3 7 . 7 ± 3 . 3 6 t t 65 7 4 . 2 ± 4 . 0 9 68.916.33 93 0.1210.07 0.13+0.05 9.66+0.99 9.85+0.44 9.4710.31 10.5610.63 9.50+0.34 8.8010.28 108 102 112 93 Control Lesioned Hippocampal and cort ica l noradrenaline levels  Level Percentage* 0.37+0.01 0.3410.02 92 The enzyme data are ex-pressed as nanomoles per milligram of protein per hour. Noradrenaline values are expressed as grams per wet weight of tissue. A l l values respresent means+ standard error of the mean for four control and four lesioned animals. *Percentage of control act ivi ty remaining in kainic acid-lesioned tissue. tSignificantly different from controls, p_ < 0.05 (two tai led Student's _t test) ttp_ < 0.005 (two-tailed Student's _t test) DISCUSSION Neuropathology Confirming the results of previous studies (Mason et a l , 1978a; 1978b) both the histological and biochemical data indicated a loss of s t r i a t a l neurons following injections of KA in the dorsal striatum. It was of interest that a decrease of CAT, but not of GAD activity^ was found in the ventral striatum. One possible explanation of this result is that cholinergic neurons of the ventral striatum are more sensitive to the neuro-toxic action of KA than are GABAergic neurons. However, the histology, showed l i t t l e evidence of neuronal loss in the ventral striatum. There-fore, i t is more l ike ly that the selective decrease of ventral s t r ia ta l CAT act iv i ty resulted from anterograde degeneration of cholinergic interneurons presumably projecting from the dorsal to the ventral striatum. According to Coyle et al.-(1978;a) s t r i a t a l injections of KA result in specific loss of s t r i a t a l perikarya, with no demyelination of fibers of passage, and no loss of extrastriatal neurons, at least in a range of doses of KA including that used in the present study. However, these investigators did observe neuronal loss both in the hippocampal CA3-CA4 f ields and in the neocortex overlying the s t r i a t a l injection site with higher doses of 2-5 yg of KA. Other investigators have reported even more extensive damage with in tras tr ia ta l injections of 2.5 yg of KA, including non-specific necrosis in the striatum and neocortex, demyelination of fibers of passage, necrosis and neuronal degeneration in the amygdala, pyriform cortex, and entorhinal cortex, and selective neuronal loss in the CA3-CA4 hippocampal f ields (Wuerthele, .et "al 1978). 73 With the use of KA injections of 3 nmoles, i . e . 0,63 ug, in the present study, there was no evidence of necrotic phenomena at the site inject ion. The architecture of the internal capsular... bundles passing through the lesioned area appeared intact. In addition, the normal levels of TOH act iv i ty in both the dorsal and the ventral striatum of the lesioned rats indicated sparing of the dopaminergic terminals of the nigrostr iatal bundle. The relat ively normal levels of NA in the cortex also suggested that KA spared noradrenergic fibers in transit through the striatum (Lindvall and Bjo'rklund, 1974; Tohyama et a l , 1974). However, i t is not possible to exclude the occurrence of some fiber demyelination especially near the injection s i te , or an electrophysiologi-cal alteration in the morphologically intact internal capsule. Some extrastriatal damage was present in the brains of the histolo-g ical ly examined lesioned rats . Thus, despite the fact that KA injections did not substantially modify CAT and GAD act iv i ty in cort ica l samples, the histology showed a slight neuronal rarefaction in layers V and VI of the neocortex overlying the injection s i te . Furthermore, some brains also showed neuronal loss in the hippocampus. It therefore appears that even with the relat ively low dose of KA used in the present study, damage may occur to extrastriatal neurons that are especially sensitive to the action of KA. It has recently been demonstrated that the neuro-degenerative effects of KA on the pyramidal layer of the hippocampus may be due to the temporary seizure act iv i ty e l ic i ted during the acute stages, and are not a direct result of KA (Nadler et a l , 197.8). Smaller doses and slower rates of injection of KA as well as pre-treatment with an ant i -convulsant should probably be used in an attempt to minimize any extra-s t r i a t a l damage. The biochemical findings are quite similar to those found in post-mortem brain tissue of HD patients, as has been described extensively by Coyle et al (1978b) and reviewed previously. The histological sequelae are also remarkably similar to that found in HD brains. Shrinkage of the striatum, ventricular d i la t ion , loss of s t r ia ta l interneurons, g l ios i s and even similar extrastriatal damage (although in a much lesser extent in the animal condition) occur in both the human and animal conditions. The neuropathology of HD appears to be unevenly distributed throughout the striatum. McGeer et a l (1973) repeatedly refer to the "patchy loss" within the caudate. Aquilonius et a l (1975) demonstrate that the most severe loss (95%) of CAT act iv i ty is in the rostromedial area of human choreic s t r i a t a l tissue. Although i t is not anatomically possible to determine which area of the rat striatum corresponds to the rostromedial portions of the human caudate these results at least suggest that i t may be the same dorsal region which was damaged in the present studies by KA injections. Body Weight and Regulatory Behaviors Previous research shows that lesions to the la tera l hypothalamus (LH) in animals produce regulatory def ic i t s , such as temporary aphagia and adipsia and lowered body weights compared to sham operated controls (Blundell and Leshem, 1974; Levine and Swartzbaum, 1973; Powley and Keesey, 1970; Teitelbaum and Epstein, 1962). The severe change in body weight produced by LH lesions'has .been suggested to be due to a lesion-induced change in the body weight "set point" (Powley and Keesey, 1970). It has also been shown, however, that selective lesions of the ascending dopaminergic fibers which transverse the LH produce regulatory def ic i ts and decreased body weights similar to those found in LH lesioned animals (Baez et a l , 1977; Fibiger et a l , 1973). The intr ins ic neurons of the striatum receive their dopaminergic innervation from the substantia nigra v ia the NSB (McGeer et a l , 1974). On the basis of these previous findings i t may be reasonable that selective lesions of the neurons post-synaptic to the DA terminals in the striatum result in a syndrome similar to that seen after NSB lesions. Pettibone et a l (1978), Sanberg et a l (1978a) and the present study have shown that these post-synaptic elements, which are characterized in part by cholinergic and GABAergic cel ls and lesioned by KA are also involved in eating and drinking behaviors as well as the maintenance of normal body weight. The long-lasting reduced body weight in the KA s t r i a t a l lesioned animals would suggest that the loss of such s t r i a t a l cel ls causes a reduction in the body weight set point. The present results also show that the KA lesioned rats have quite profound regulatory differences compared to those observed in LH or NSB lesioned rats. In the present study, i t was demonstrated that s t r i a t a l lesioned rats deprived of food increased their consumption of water. These results are direct ly opposed to those reported for both LH and NSB lesioned rats for which large reductions in water intake were found during food deprivation ( i . e . , non-prandial drinking) (Baez et a l , 1977; Fibiger et a l , 1973; Levine and Swartzbaum, 1973; Teitelbaum and Epstein, 1962). "Progressive loss of weight are early symptoms in Huntington's chorea" (Bruyn et a l , 1972). "Most choreic patients lose a considerable amount of weight as their disease progresses" (Barbeau, 1973). Although most references to the gross weight loss symptomatology associated with HD are subjective statements related to c l i n i c a l findings such as " a l l patients were nonobese" (Podolsky and Leopold, 1977), and those cited above, the mean body weights of HD (53 kg) and control (64.5 kg) patients reported in various studies (Keogh et a l , 1976; Phi l l ipson and Bird, 1976), and a previous study by Oepen (1962) based upon findings obtained from 217 postmortem cases also support "the str iking prevalence- of cachexia and marasmus in patients with hereditary chorea": (Bruyn, 1968). In order to evaluate objectively.'the body weight symptoms in HD we have examined the case histories of 11 non-deceased hospitalized HD patients and 11 matched (duration of hospitalization, age, diet and height) non-Huntingtonian control patients (Sanberg and Fibiger, in preparation). This study indicated clearly that loss of body weight was a progressive symptom of HD, which can lead to a marasmic condition in the later stages,, iWspite of being fed double portions of daily meals. Increased caloric expenditure from hyperkinesis cannot explain continuous weight loss in the later stages^,since i t is quite common for the disease to progress towards hypokinesis ' (the Westphal variant) in the ultimate stages (Bruyn, 1968). It is evident that the weight loss is not associated with decreased appetite or anorexia since as Bruyn (1968) best described i t : "His (the patient's) interest in the world narrows down and simple bodily functions become a major focus of interest. The well-known ravenous appetite of choreic patients bordering on gluttony thus too 77 becomes an understandable phenomenon." The continuous hyperkinesis while the patient is awake would explain the need for more caloric intake. It may be that the loss of weight in HD patients is a result of the s t r ia ta l pathology associated with this disease, as has been shown in the KA s t r i a t a l lesioned rats. This is in contrast to the -suggested" relationship between this symptomatic weight loss and the pathology found in the la tera l hypothalamus of post-mortem HD brains (Bruyn, 1973). Original ly , Facon et a l (1957) suggested that the cachexia was a result of degeneration of the dorsal paramedian hypothalamic nucleus. Alternatively, i t has been proposed that these weight changes reflect multifocal damage occurring in HD; including in addition to those above, the cortex, globus pallidus and subthalamic nucleus (Bruyn, 1968; Lange et a l , 1976; Roizin et a l , 1976). These areas have a l l been shown to affect ingestive behavior in animal studies (Kolb and Nonneman, 1975; Morgane, 1961; N e i l l and Linn, 1975; Thompson, 1978). Only a few investigators have attempted to increase the weight or have even measured body weight changes of HD patients following administration of various drugs (Drymoitis et a l , 1976; Hoffer, 1976; Lehnoff, 1973). Conceivably, loss of weight in animals associated with KA lesions of the striatum may be a good tool for evaluating the effectiveness of various experimental agents on restoring the:: weight ' to normal levels. Recently, muscimol (a GABA agonist) was shown to increase food intake when administered to rats (Grandison and Guidotti , 1977). Perhaps drugs, such as muscimol, which would tend to restore the lowered GABA act iv i ty found in both HD patients (Barbeau, 1973; Coyle et a l , 1977) and the KA lesioned animals (Coyle et a l , 1977; McGeer and McGeer, 1976b) may also reverse the consistent weight loss associated with these two conditions. It is possible that the prandial drinking results may have some predictive value for HD patients and in turn augment the use of this animal model as a tool for studying the pathophysiological conditons of HD. Thus, i t would be of great interest to find out i f HD patients also increase their water intake during fasting. The present results would suggest that they may. In support, Refsum in 1938 reported polydipsia as one of the vegetative symptoms in HD (Bruyn, 1968). Motor Behavior The results of previous studies have been replicated (Fibiger, 1978; . Mason et a l 1978a; 1978b; Sanberg et a l , 1978a; 1978b) in showing that KA-induced lesions of the dorsal striatum do not alter daytime locomotor act iv i ty , as measured in photoactometers or the alley-way maze, but greatly enhance the nocturnal and d-amphetamine-induced locomotor response. Similar results were obtained by N e i l l et a l (1974a) following e lectrolyt ic lesions of the striatum. The increased locomotor behavior in the KA s t r ia ta l lesioned rats during their awake cycle (nocturnal act ivity) and the relat ively normal locomotor response during their sleep cycle (day-time activity) can be considered analogous to the biphasic act iv i ty changes in the abnormal involuntary movements of patients with HD. HD patients typical ly show an excerbation of chorea when fu l ly awake or aroused, diminished movements during response and cessation of chorea during sleep (Bruyn, 1968; Shoulson and Chase, 1975). Similarly, the increased response to d-amphetamine of rats with dorsal s t r i a t a l lesions has been considered analogous to the exacerbation of choreic movements induced by d-amphetamine in HD patients (Klawans and Weiner, 1974; 1976) and has been tentatively 79 attributed to interruption of a s tr iato-nigral projection normally inhibit ing the locomotor-inducing act iv i ty of mesolimbic dopaminergic neurons (Mason et a l , 1978a;1978b). Because of i t s robustness and simplicity this pharmacological effect may be used as a preliminary check of the lesioning effectiveness of KA s t r i a t a l injections before using the animals in time consuming behavioral studies. Psychopathology The KA s t r i a t a l lesions ,did not interfere with either rate of acquisition or asymptotic performance of lever-pressing for continuous reinforcement. However, the lesions increased resistance to extinction of the CRF schedule. Similar results have been reported using e lectrolyt ic lesions of the .striatum (Schmaltz and Issacson, 1972). In the latter study i t was found that dorsolateral frontal ablations did not alter resistance to extinction, suggesting that damage to cort ica l connections in transit through the striatum via the internal capsule were not responsible for the perseverative responding of the s tr ia ta l lesioned animals. The present findings support this view, by showing an increased resistance to extinction after KA s t r i a t a l lesions that apparently spare fibers of the internal capsule. The results of the step-down passive avoidance experiment, showing an impairment in both acquisition and retention of the punishment contingency, confirm and extend those of a previous study (Sanberg et a l , 1978a)in which larger doses of KA were used for the s t r i a t a l injections. 80 The dorsal s t r ia ta l lesioned rats were also impaired in the acquisition of the one-way active avoidance paradigm. While their retention in this task was relat ively normal, they did show a greater-resistance to extinction of the punishment contingency. These.results, therefore, broaden the range of reinforcing contingencies . ( i .e . positive and negative).that w i l l e l i c i t resistance to extinction in these animals. In agreement with the step-down passive avoidance results, the lesioned animals were also impaired in the acquisition of passive avoidance requiring the inhibit ion of the previously acquired one-way response. The avoidance results cannot be explained in terms of gross motor def ic i t s , since no significant differences were found between lesioned and control groups on daytime locomotor act iv i ty , as measured in photoactometers and the alleyway maze, or on the i n i t i a l step-down latencies recorded when the rats were f i r s t placed on the platform in the step-down apparatus. -Explaining-'the avoidance impairments in terms of decreased footshock sen-s i t i v i t y is hot practical since the lesioned rats did not re l iably dif fer from controls in shock thresholds of f l inch , c'.vjump and vocalization. The differences obtained, between the two shock, threshold studies were'a result of the different shock generators used for each study. Avoidance impairments and increased resistance to extinction may result from lesions of extrastriatal structures, including the dorsal noradrenergic bundle (Crow and Wedlandt, 1976; Fibiger and Mason, 1978;';' Mason and Iversen, 1978) and hippocampus (Black et a l , 1977; Schmaltz and Issacson, 1967). Since the dorsal s t r i a t a l lesioned rats showed normal levels of cort ica l noradrenaline i t is not l ike ly that their behavioral impairments 81 r e s u l t e d from damaged f o r e b r a i n noradrenergic f i b e r s . Hippocampal damage may have co n t r i b u t e d to the a l t e r e d performance of some les i o n e d r a t s . However, the r a t s without hippocampal damage showed s i m i l a r impairments to those w i t h demonstratable hippocampal l e s i o n s , i n d i c a t i n g that a s e l e c t i v e l o s s of d o r s a l s t r i a t a l neurons was at l e a s t i n part r e s p o n s i b l e f o r the observed b e h a v i o r a l d e f i c i t s . In a d d i t i o n , l e s i o n e d r a t s who completed the a l t e r n a t i o n task d i d not show any d e f i c i t i n t h e i r a b i l i t y to a l t e r n a t e between arms spontaneously. In c o n t r a s t , hippocampal l e s i o n e d r a t s g e n e r a l l y perseverate on one arm and thus f a i l to a l t e r n a t e spontaneously (Kirkby et a l , 1967; Stevens and Cowey,1973). S i m i l a r avoidance r e s u l t s have been reported using e l e c t r o l y t i c l e s i o n s of the s t r i a t u m (Kirkby and Polgar, 1974; Mitcham and Thomas, 1972; Rothman and G l i c k , 1976; Studelska and Beatty, 1978; Winocur and M i l l s , 1969). There i s general agreement that d o r s a l e l e c t r o l y t i c caudate l e s i o n s produce d e f i c i t s i n passive avoidance r e q u i r i n g e i t h e r the i n h i b i t i o n of an untrained response (Rothman and G l i c k , 1976) or the i n h i b i t i o n of a p r e v i u s l y acquired response (Mitcham and Thomas, 1972; Win'oc'ur and M i l l s l 9 6 9 ) . However, the e f f e c t s of d o r s a l s t r i a t a l l e s i o n s on one-way avoidance are not yet c l e a r . Winocur and colleagues (1969;1974) observed no impairment i n the a c q u i s i t i o n of the one-way avoidance task f o l l o w i n g such l e s i o n s , whereas Kirk b y and Polgar (1974) found that d o r s a l s t r i a t a l l e s i o n s d i d produce s i g n i f i c a n t impairments. Recent evidence using e l e c t r o l y t i c l e s i o n s (Studelska and Beatty, 1978), as w e l l as the present r e s u l t s * s u g g e s t that the l a t t e r f i n d i n g i s c o r r e c t . 82 The present spontaneous alternation results are at variance with those reported by-other: investigators using e lectrolyt ic s t r i a t a l lesions (Potegal and Squire, 1974). The latter study found a signif icant, though small, spontaneous alternation def ic i t in rats with s t r i a t a l lesions. Wg-th the use of KA-induced lesions in the present study,no significant effects were found on spontaneous alternation. It is possible that the low number of rats completing the alternation task in the present study may have minimized the poss ibi l i ty of obtaining significant differences, i f present. This appears unlikely, however, since the present results have been confirmed by Pisa et a l , (1978 ) . One explanation of the observed behavioral changes in KA s tr ia ta l lesioned rats might be that the lesions interfere with associative and memory processes (Kirkby and Polgar, 1974; Mitcham and Thomas, 1972; Rothman and Glick, 1976; Sanberg et a l , 1978a; Thompson and Mettler, 1963; Winocur, 1974). The results of the lever pressing experiment, however, indicated that these lesions did not have any significant effect on learning of an appetitive instrumental response, thus arguing against the hypothesis of a generalized associative impairment. Also, in the step-down passive avoidance task, the finding that the rats with s t r i a t a l lesions showed a much longer step-down latency during retention than before any footshock experience suggests that their amnesia for the punishment contingency was at least incomplete. This is further supported by the finding that lesioned rats were not impaired in the retention of the one-way avoidance punishment contingency. An alternative explanation-of both the increased resistance to extinction and the impairment in suppression of punished responses might be an 83 interference of dorsal s t r i a t a l lesions with inhibitory control of voluntary movements (Divac, 1972; Kirkby, 1969; N e i l l , 1976; N e i l l et a l , 1974b; Schmaltz and Issacson, 1972). The finding that the rats with lesions showed a shorter immobility reaction to footshock in the step-down passive avoidance apparatus than control rats might be taken in support of this hypothesis. The relat ively normal spontaneous locomotor act iv i ty and pre-shock step-down latency in rats with s t r i a t a l lesions, however, appear to confl ict with this view. Previous findings with e lectrolyt ic lesions of the striatum in rats , demonstrate locomotor hyperactivity after food deprivation, at night, or in brightly illuminated environments, i . e . , in conditions presumably involving high levels of arousal (Kirkby, 1973; N i e l l et a l , 1974). Thus, Kirkby (1973) has suggested that dorsal s t r ia ta l lesions interfere with inhibitory control of arousal reactions. The present findings that KA-induced dorsal s t r i a t a l lesions result in nocturnal locomotor hyperactivity and an increased locomotor response to d-amphetamine also support this proposed r o l e . An exagerated arousal reaction either to lack of expected re in-forcement or to the occurrence of aversive stimuli might therefore account at least in part for the abnormally high levels of responding of the lesioned rats after extinction and punishment, respectively. Also evident in the KA s t r i a t a l lesioned rats was the poss ibi l i ty of an enhanced fear of novelty or neophobia. As previously discussed these rats do not show gross changes in day-time locomotor act iv i ty , especially when i t is measured in homogenous environments l ike the photoactometers and the center section of the alleyway maze. However, in conditions involving locomotion from one place to another, such as the start and goal areas of the T and alley-way mazes, the s t r i a t a l lesioned rats show a marked decrease in act iv i ty . Furthermore, during the alley-way maze testing, the greater latency found in the lesioned rats compared to controls - in . consuming the small food pel lets , which were both novel in themselves and in a novel environment, also support the view of an increased fear of novelty. • Taken-together these findings suggest a possible' v"'role of the striatum in the control of emotional reactions. Recently, much attention has been given to the neuropsychological features of HD. As previously reviewed, the cognitive impairments found in HD patients include marked def ic i ts in information processing, learning, memory (short-term, long-term and episodic) and judgement. Caine et a l (1978b) however, recently found that the "the Huntington's disease pattern of cognitive impairment is not i n i t i a l l y diffuse and homogenous, but characterized by a relative. , : sparing of several higher cort ica l functions." In the KA s t r i a t a l lesioned animals, psychological deficits have also been shown, such as impaired learning and memory of an avoidance response. Concomitantly, however, the present study also demonstrated.that such def ic i ts are not "diffuse and homogenous", since the animals' were not impaired in the learning of a l l behavioral tests employed ( i . e . , learning of a bar-pressing response and memory of one-way avoidance). Changes of affect and emotion are quite pronounced in HD patients. While these have been reviewed previously, the chief symptoms are emotional ins tab i l i ty , increased i r r i t a b i l i t y , and intense fluctuations of mood. These can lead , among other things, to an inab i l i ty to maintain a steady train of thought and lack of concentration on the task at hand. A few investigators have suggested that altered arousal levels probably contribute to the cognitive and motor disorders of patients with HD (Bertha and Kolmer, 1940; Baruyn, 1968; Hocheimer, 1936; Kehrer, 1940). In fact, as far back as sixty years ago, Morgue (1919) suggested that the mental symptoms of HD were a result of a basic defect in cort ica l psychomotor inhibi t ion. Such analysis of the mental symptoms of HD are consistent with the present view that altered arousal levels also contribute to the behavioral disorders of KA s t r i a t a l lesioned rats. An interesting point of note shown by Caine et a l (1978b) was that HD patients demonstrated a pronounced fai lure to in i t ia te act iv i t ies spontaneously. A similar feature was seen in the KA s t r i a t a l lesioned rats. On many occasions these rats fai led to leave the start box of the T-maze and would remain there for the duration of the testing, seemingly quite content. In addition, the relat ively normal performance of these rats in alternating between the T-maze arms is quite similar to the relative absence of any disturbances of spatiotemporal and personal orientation in HD patients*1 even in far-advanced cases (Bruyn, 1968). Tradit ional ly , the psychological features of HD have been attributed to the presence of progressive cort ica l neuronal atrophy (Barr, 1974; Bruyn, 1968, Pinel , 1976). The present studies with animals and those of previous investigators (Divac, 1972; Divac et a l , 1978; Kirkby and Polgar, 1974; Mitcham and Thomas, 1972; Rothman and Glick, 1976; Sanberg et a l , 1978a; Thompson and Mettler, 1963; Winocur, 1974) demonstrate, however, that these symptoms may be direct ly related to the pathology which has been identif ied in the striatum of these patients. The fact that the striatum receives afferents from v ir tua l ly the entire neocortex (Kemp and Powell, 1968) as well as from thalamic and several mesencephalic nuclei (Anden et a l , 1964; Mi l ler et a l , 1975; Nauta et a l , 1974) would appear to make i t well suited to be a substrate for complex psychological, integrative and emotional processes. 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Schweizer  Archives of Neurology and Psychiatry 64, 448.457. 106 APPENDIX I PROCEDURE FOR INTRASTRIATAL KAINIC ACID INJECTIONS A l l rats were housed in groups of six before surgery and in individual stainless steel cages afterwards. with free access to food.(Purina Rat Chow) and water (tap water). The colony room had a temperature of 22 -25°C, humidity of 45-55%, and a 12 hr light-dark cycle. ' Seven days after their arr iva l in the laboratory, the rats were randomly assigned to either a control or a kainic acid lesioned group. The rats were anesthetized with sodium pentobarbital (50 mg/kg), their heads shaven, and positioned on a Kopf stereotaxic instrument with the incisor bar adjusted at 4.2 mm below the interaural l ine . Two holes were dr i l l ed in the skull and 3 nmoles of kainic acid (Sigma Chemical) dissolved in 0.5 y l of a phosphate buffered isotonic saline solution, pH 7.2, were b i la tera l ly injected over a 3-minute period, through a 10 y l Hamilton syringe, at the following coordinates: 9.6 mm rostral and 4.5 mm dorsal to the interaural l ine , ± 2.8 mm latera l to the sagittal suture. In p i lot experiments these coordinates were shown to correspond approximately to AP 8.4 mm, DV 0.8 mm and ML ± 2.2 mm of the Konig and Klippel (1963) atlas. After the injection^ the cannula (34 gauge) was left in place for 5 minutes to allow for diffusion of the drug solution from the t ip . The control rats underwent: similar surgery,but were b i la tera l ly injected with 0.5 y l of the vehicle solution only. Following suturing the rats were removed from the stereotaxic instrument and placed under a heat lamp to prevent hypothermia while under the anesthetic. When awaken the rats were replaced in their home cages. PUBLICATIONS Sanberg, P. R. "Neural Capacity" in Mimosa Pudica: A review. Behavioral  Biology, 1976, 17, 435-452. Sanberg, P. R. and Glass, L . D. The invis ib le leash: A pract ica l appl i -cation of the self-stimulation phenomenon. The Journal of Biological  Psychology, 1976, 18, 33-36. Sanberg, P. R. and Ossenkopp, K. P. Effects of taurine on some open-field behaviors in the rat . Psychopharmacology, 1977, _53, 207-209. Sanberg, P. R. and Ossenkopp, K. P. Paleopsychology and the new archeology. Psychology: A Journal of Human Behavior, 1977 , 3-4_, 59-60. Sanberg, P. R. and Singh, V. K. Bird song as a transfer experiment? A short commentary. The Journal of Biological Psychology, 1977, 19_, 33-34. Sanberg, P. R. and Ossenkopp, K. P. Kindling rats in Wistar rats: An analysis of individual differences. Physiology and Behavior, 1978, 20, 205-207. Mason, S. T . , Sanberg, P. R. and Fibiger, H. C. Amphetamine-induced locomotor act iv i ty and stereotypy after kainic acid lesions of the striatum. Li fe  Sciences, 1978, 22, 451-460. Sanberg, P. R., Lehmann, J . and Fibiger, H. C. Impaired learning and memory after kainic acid lesions of the striatum: A behavioral model of Huntington's disease. Brain Research, 1978, 149, 546-551. Mason, S. T . , Sanberg, P. R. and Fibiger, H. C. Kainic acid lesions of the striatum dissociate amphetamine and apomorphine stereotypy: Similarit ies to Huntington's chorea. Science, 1978, 201, 352-355. Sung, S. C , Sanberg, P. R. and McGeer, E . G. Cholinergic systems in muscle and brain in vitamin E-deficient rats . Neurochemical Research, 1978, in press. Sanberg, P. R. , Lehmann, J . and Fibiger, H. C. The sedative action of apomorphine and an animal model of Huntington's disease. Archives of  Neurology, 1978, in press. Sanberg, P. R., Staines, W. and McGeer,vE. G. Chronic taurine effects on various neurochemical indices in control and kainic acid-lesioned neostria-tum. Brain Research, 1978, in press. Sanberg, P. R. and Fibiger, H. C. Impaired learning and memory following chronic ingestion of taurine. Psychopharmacology, 1978, in press. Sanberg, P. R. , Pisa, M. and Fibiger, H. C. Avoidance, operant and locomotor behavior in rats with neostriatal injections of kainic acid. Pharmacology, Biochemistry and Behavior, in press. PRESENTED PAPERS AND ABSTRACTS Sanberg, P. R. , Lehmann, J . and Fibiger, H. C. The effect of kainic acid induced neostriatal lesions on learning and memory. Canadian Psychological  Association Conference, June, 1977, Vancouver, B. C. Sanberg, P. R. , Lehmann, J . and Fibiger, H. C. Impaired learning and memory after kainic acid lesions of the striatum: A behavioral model of Huntington's disease. Society for Neuroscience Annual Meeting, November, 1977, Anaheim, C a l i f . Neuroscience Abstracts, 1977, _3, 45. (Abstract) Fibiger, H. C , Mason, S. T. and Sanberg, P. R. S tr ia ta l kainic acid lesions as behavioral model of Huntington's disease. American College  of Neuropsychopharmacology Conference, December, 1977, San Juan, Puerto Rico. Sanberg, P. R. An animal model for Huntington's chorea: Pharmacological and behavioral s imi lar i t i e s . B. C. Neuroscience Academic Day, March 3, 1978, New Westminster, B . C . Sanberg, P. R. and Fibiger, H. C. The effect of kainic acid induced neo-s t r ia ta l lesions on acquisition and extinction of an operant response. Canadian Psychological Association Conference, June, 1978, Ottawa, Ontario. Pisa, M. A . , Sanberg, P. R. and Fibiger, H. C. Locomotor act iv i ty , spontaneous alternation and reinforced alternation in rats with experi-mental degeneration of the neostriatum. Canadian Psychological Associa- tion Conference, June, 1978, Ottawa, Ontario. Staines, W., Sanberg, P. R. , McGeer, E . G. and Fibiger, H. C. Neostriatal cysteinesulfinic acid decarboxylase. Canadian Federation of Biological Societies 21st Annual Meeting, June, 1978, London, Ontario. Proceedings  of the Canadian Federation of Biological Societies, 1978, 21, 53. (Abstract). Sanberg, P. R. , Pisa, M. and Fibiger, H. C. Locomotor ac t iv i ty , explora-tion and neophobia in rats with kainic acid-induced degeneration of the neostriatum. Society for Neuroscience Annual Meeting, November, 1978, St. Louis, Missouri, Neuroscience Abstracts, 1978, 4_, 49. (Abstract) Pisa, M . , Sanberg, P. R. and Fibiger, H. C. Learning impairments in rats with experimental degeneration of the neostriatal neuropil. Society for Neuroscience Annual Meeting, November 1978, St. Louis, Missouri, Neuroscience Abstracts, 1978, 4_, 48. (Abstract) Sanberg, P. R., Pisa, M. , Mason, S. T. and Fibiger, H. C. An animal model of Huntington's disease: Behavioral and pharmacological effects of neostriatal lesions induced by kainic acid. Second International  Huntington's Disease Symposium. San Diego, Cal i fornia , November 1978. 

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