Neural Basis of Behavior: Animal Models of Human Conditions PAUL R. SANBERG’
AND DWAINE
F. EMERICH
SANBERG, P. R. AND D. F. EMERICH. Nrurc~i basis ofhrhnrior: Animcd modeis c?f‘iaumnncondirions. BRAIN RES BULL 25(3) 34745 I. 1990. -A variety of neurological disorders including Alzheimer’s. Parkinson’s, and Huntington’s diseases are characterized hy abnormalities within specific neuroanatomical and/or neurochemical systems. Approaches to the treatment of the,e and other neurological disorders are limited. The development and refinement of animal models which closely mimic human disease states would help elucidate the underlying neurobiological mechanisms of the disease as well as suggest novIe therapeutic strategies for their prevention or alleviation. This symposium presents a variety of animal models that have helped us in understanding the human condition. The present introduction presents some clinically relevant findings obtained from basic ex~rimental studies with animal models of Huntin~t0n.s disease (HD) and Tourette Syndrome (TS). These studies demonstrate that animal models can provide a greater understanding of the symptomatoiogy of disease state\ as well as suggest innovative new treatments. Animal
models
Huntington’s
disease
Tourette
Syndrome
Body weight
Nicotine
Haloperidol
_.-
with animal models of Parkinson’s disease. Dr. Mark Geyer then discussed startle response models of schizophrenia and Dr. David Olton described animal models of human dementia. Next. Dr. Ingram talked about studies on the behavioral analysis of aging. Finally, Dr. George Breese described his work on Lesch-Nyhan disease and Dr. Michael Forster concluded the formal presentations with a discussion of behavioral and neural correlates of autoinlmunity. Brief discussions regarding potential treatments of Huntington’s disease and an animal model of Lesch-Nyhan syndrome were presented by Magda Giordano and H. A. Jinnah respectively. Most basic scientists with a clinical interest are pleased when something discovered in an animal model system can actually lead to improved unde~tanding, diagnosis. or treatment of a particular human disease. This may not happen often. but when it does, it can provide enough reinforcement to continue the basic studies with vigour. This fact may be of increasing importance because of the current pressure from governmental and private agencies to do applied research. and from animal welfare groups to increase the justification for animal research. As examples of basic science areas that have yielded clinically relevant information, we will present research on two animal model systems performed in our laboratory.
A fundam~nt~~l goal of neuroscience is to understand and treat disorders of the central nervous system. Through the cooperation of basic researchers and clinicians we are gaining a better understanding of the relationship between brain function and behavior under both normal and abnormal conditions. However. despite enormous technical and conceptual advances. we are still unable to effectively treat the majority of neurological diseases. A crucial approach for understanding and treating neurological disorders is to develop appropriate animal models. Animal models help to elucidate the underlying neurobiological mechanisms of the disease as well as suggest novel therapeutic strategies for their prevention or alleviation. Ideally, an animal model should meet the following criteria: 1) the model should reproduce the pathophysiology exhibited in the human disease state; 2) the animal should exhibit behavioral alterations analogous to those observed in the human disorder: 3) pharmacological compounds should produce comparable effects in both affected humans and in the animal model; and 4) the model should suggest treatment strategies targeted at preventing or minimizing the behavioral sequelae of the disorder. While only a few models may actually meet successfully all these criteria. most animal models do provide a practical way to explore specific questions concerning the disease being modeled. The present symposium was organized in order to examine some important animal models for human neurological disorders. The first presentation by Dr. Michael Zigmond described his work
‘Requests for reprints
should be addressed to Dr. Paul Sanbcrg, Cellular
HUNTINGTOh’S
Huntington’s
Transplants.
447
Inc.,
DISEASE
disease (HD) is an inherited.
Four Richmond
Square. Providence.
progressive
RI 02906.
neuro-
34x
400 380 360 340 320 300 280 260
/ 0:
400 380 360 340 320 300 280 260 0:
I
18
20
22
D -44
c
p
2
4
6
8
10
12
14 16
IV
24 20
l-
18 20 22
POSTOPERAT
. -
Lx
m
8 E
10
12
14
DAYS
FIG. 1. Mean body weights (A and B) and mean water intake (C and D) for rats with kainic acid-induced
striatal lesions (open circles) and control (solid circles) rats. Upper (A and C) and lower (B and D) panels represent rats injected bilaterally into the striatum with 6 and 3 nmol kainic acid respectively. Body weight was significantly decreased (~~0.05) following kainic acid relative to controls. Error bars represent SEM.
degenerative disorder transmitted by an autosomal dominant gene. The symptomology of HD consists of a progressive dementia coupled with bizarre uncontrollable movements and abnormal postures. From the time of onset of HD, typically 35-45 years of age, an intractable course of mental deterioration begins with death usually occurring within 15 years. Although the neural degeneration in HD is widespread, the basal ganglia is the most severely affected region (33). Moreover, the principle motor symptoms of HD are likely the result of neural degeneration in the basal ganglia, the striatum in particular. Although research has provided considerable insight into the pathophysiology and molecular biology involved in HD (l&20), our understanding of the etiology of the disease as well as our ability to prevent or alleviate it is limited. Accordingly, an important approach for understanding and treating HD is the development of an animal model which mimics the behavioral and neurobiological sequelae of the disease. A variety of approaches have been used to develop animal models of HD [see (11) for a review]. Hyperkinesia resulting from genetic abnormalities, various types of brain lesions and acute pharmacological manipulations of striatal transmitter balance have all been suggested as models for HD. Unfortunately, these models all suffer shortcomings which severely limit their utility. The major drawback with these models is that the movement disorders characteristic of HD are the result of a complex and regionally specific mosaic of striatal degeneration which has been difficult to reproduce in laboratory animals. Recently, however, selective toxic compounds have proven useful for examining specific functional properties of the striatum and for developing animal models of human neurological disorders, such as HD. Considerable interest has been focused on the possibility that an endogenous excitotoxic compound results in the neuronal death found in HD and other human neurodegenerative disorders. Since
the pioneering animal studies of Coyle and Schwartz (8) and McGeer and McGeer (20), evidence has indicated that structural analogues of glutamate such as kainic acid (KA) produce a profile of neuronal degeneration in the rat which bears considerable homology to that described in the striatum of HD patients upon postmortem examination (9, 21, 22). Intrastriatal injections of nanomolar quantities of KA result in the degeneration of local, intrinsic neurons while sparing axons of passage and terminals of extrinsic origin. In addition to the pathological similarities between HD and KA-lesioned rats, KA produces biochemical, pharmacological, and psychological alterations which are reminiscent of HD. Accordingly, the KA rat exhibits alterations in locomotor activity (17,32), profound impairments in learning and memory (10, 26, 28, 29), and altered responsiveness to pharmacological compounds (30,32) which are similar to those observed in HD. During our behavioral analysis of these “Huntington” rats, we noticed that postoperatively all lesioned rats lost body weight and had a short-term aphagia and adipsia (Fig. 1). The animals never gained weight back to control group levels (29). This was very similar to that seen in the lateral hypothalamic syndrome (42). Interestingly, although body weight remained decreased, there were no significant differences in ad lib water or food intake between KA-lesioned and control rats. Unlike lateral hypothahunic-lesioned rats, when they were food deprived for 24 hours, their water intake was significantly greater than controls, representing a profound psychogenic polydipsia (34). Moreover, 24-hour food or water deprivation resulted in the lesioned rats consuming more food than controls during the subsequent 24-hour period. The marked changes seen in body weight and regulatory behavior following striatal destruction led us to investigate whether these changes also occurred in HD patients. A search through the literature revealed only anecdotal comments that HD patients
ANIMAL MODELS
449
tended to be thin and that they were cachectic by the time they died (5, 6, 18). To further investigate whether these significant body weight changes were a characteristic symptom of HD patients as suggested by the animal data, we examined the long-term case histories of 11 hospitalized HD patients and 10 neurological controls matched on variables such as duration of hospitalization, age, diet, height, and drug history (31). While the mean body weights of both groups were comparable at the time of admission, body weight in the HD patients was significantly lower at the end of hospitalization (approximately 9.5 years). This analysis further revealed that only the HD patients reduced their body weight compared with their admission values. While some individuals in both groups tended to increase body weight following admission (presumably due to better care and diet), the HD patients reached their maximum body weight sooner and lost weight thereafter. The weight loss displayed by HD patients was not associated with a decreased appetite or anorexia since nearly 50% of the HD patients were fed very high-energy diets in an attempt to keep their body weight loss to a minimum. Likewise, increased caloric expenditure from hyperkinesis could not explain the continuous weight loss, because it is quite common for the disease to progress towards hypokinesia (5) (Westphal variant) as was seen in some of the patients in these studies. It appears, rather, that the body weight symptomatology in HD may be related to underlying striatal degeneration. More importantly, body weight has proven useful as a diagnostic tool and for evaluating the efficacy of various therapeutic interventions. TOURETTE
SYNDROME
Another disorder characterized by motor abnormalities is Tourette Syndrome (TS) (4,40). TS is a complex disorder characterized by chronic motor tics and involuntary verbalizations. Although the underlying pathology of TS is not well understood. it is generally believed that excess extrapyramidal dopamine neurotransmission plays a significant role in the symptomatology of the disorder (41). Although treatments are limited, TS is most commonly treated by neuroleptic medication, particularly the dopamine receptor blocker haloperidol. Haloperidoi is effective in approximately 70% of all TS cases (13,39), but its utility is questioned by the occurrence of deleterious side effects including decreased concentration, drowsiness, depression, weight gain and decreased attention. In addition. there is a considerable long-term risk of tardive dyskinesia (14). Erenberg (13) reported that the majority of TS patients discontinue neuroleptic medication because of dissatisfaction with the side effects. A pharmacotherapeutic strategy which could potentiate the therapeutic action of haloperidol or other neuroleptics, and possibly reduce the side effects, would therefore be useful for individuals with TS. Moss et al. (24) reported that nicotine potentiated reserpine-induced catalepsy in rats. In examining the data. it was clear that this was one of the most marked potentiation effects of rese~ine-induced catalepsy observed, especially with a low dose of a drug (nicotine) which by itself had no cataleptic effects. Reserpine acts presynaptically to deplete intraneuronal stores of catecholamines and has been used for treatment of hyperkinetic movement disorders (43). Given these results we were interested in whether nicotine could potentiate the effects of (the more commonly used dopamine receptor blocker) haloperidol. If so. then nicotine might also be useful for augmenting the therapeutic effects of neuroleptics in patients with extrapyramidal movement disorders, such as TS. In an initial study, rats were treated with haloperidol alone or in combination with nicotine and tested for catalepsy using the bar test (37). This test has previously been shown to depend on the
TABLE 1 THE EFFECT OF NICOTINE ON HALOPERIDOL-INDUCED CATALEPSY IN RATS
Time After NIC or Vehicle HAL + NIC; HAL only* NIC only Control
2 Hr
721.8 169.2 3.8 2.6
i- 206.9 t 77.8 + 2.8 5 I.1
4 Hr
595.2 138.0 8.3 2.1
r 1x5.4 z!z 37.3 t 6.4 “_ 0.7
Animals received injections ofhalo~~dol(O.3 mg/kg) and nicotine (0.1 mgikgf and were tested for catalepsy (bar test) 2 and 4 hours later. Data presented as the mean catalepsy (bar times) rf~SEM. HAL = haloperidol; NIC = nicotine. *Significantly different from NIC only and Control. piO.05. tsignificantly different from other three groups, p
AND DWAINE
F. EMERICH
SANBERG, P. R. AND D. F. EMERICH. Nrurc~i basis ofhrhnrior: Animcd modeis c?f‘iaumnncondirions. BRAIN RES BULL 25(3) 34745 I. 1990. -A variety of neurological disorders including Alzheimer’s. Parkinson’s, and Huntington’s diseases are characterized hy abnormalities within specific neuroanatomical and/or neurochemical systems. Approaches to the treatment of the,e and other neurological disorders are limited. The development and refinement of animal models which closely mimic human disease states would help elucidate the underlying neurobiological mechanisms of the disease as well as suggest novIe therapeutic strategies for their prevention or alleviation. This symposium presents a variety of animal models that have helped us in understanding the human condition. The present introduction presents some clinically relevant findings obtained from basic ex~rimental studies with animal models of Huntin~t0n.s disease (HD) and Tourette Syndrome (TS). These studies demonstrate that animal models can provide a greater understanding of the symptomatoiogy of disease state\ as well as suggest innovative new treatments. Animal
models
Huntington’s
disease
Tourette
Syndrome
Body weight
Nicotine
Haloperidol
_.-
with animal models of Parkinson’s disease. Dr. Mark Geyer then discussed startle response models of schizophrenia and Dr. David Olton described animal models of human dementia. Next. Dr. Ingram talked about studies on the behavioral analysis of aging. Finally, Dr. George Breese described his work on Lesch-Nyhan disease and Dr. Michael Forster concluded the formal presentations with a discussion of behavioral and neural correlates of autoinlmunity. Brief discussions regarding potential treatments of Huntington’s disease and an animal model of Lesch-Nyhan syndrome were presented by Magda Giordano and H. A. Jinnah respectively. Most basic scientists with a clinical interest are pleased when something discovered in an animal model system can actually lead to improved unde~tanding, diagnosis. or treatment of a particular human disease. This may not happen often. but when it does, it can provide enough reinforcement to continue the basic studies with vigour. This fact may be of increasing importance because of the current pressure from governmental and private agencies to do applied research. and from animal welfare groups to increase the justification for animal research. As examples of basic science areas that have yielded clinically relevant information, we will present research on two animal model systems performed in our laboratory.
A fundam~nt~~l goal of neuroscience is to understand and treat disorders of the central nervous system. Through the cooperation of basic researchers and clinicians we are gaining a better understanding of the relationship between brain function and behavior under both normal and abnormal conditions. However. despite enormous technical and conceptual advances. we are still unable to effectively treat the majority of neurological diseases. A crucial approach for understanding and treating neurological disorders is to develop appropriate animal models. Animal models help to elucidate the underlying neurobiological mechanisms of the disease as well as suggest novel therapeutic strategies for their prevention or alleviation. Ideally, an animal model should meet the following criteria: 1) the model should reproduce the pathophysiology exhibited in the human disease state; 2) the animal should exhibit behavioral alterations analogous to those observed in the human disorder: 3) pharmacological compounds should produce comparable effects in both affected humans and in the animal model; and 4) the model should suggest treatment strategies targeted at preventing or minimizing the behavioral sequelae of the disorder. While only a few models may actually meet successfully all these criteria. most animal models do provide a practical way to explore specific questions concerning the disease being modeled. The present symposium was organized in order to examine some important animal models for human neurological disorders. The first presentation by Dr. Michael Zigmond described his work
‘Requests for reprints
should be addressed to Dr. Paul Sanbcrg, Cellular
HUNTINGTOh’S
Huntington’s
Transplants.
447
Inc.,
DISEASE
disease (HD) is an inherited.
Four Richmond
Square. Providence.
progressive
RI 02906.
neuro-
34x
400 380 360 340 320 300 280 260
/ 0:
400 380 360 340 320 300 280 260 0:
I
18
20
22
D -44
c
p
2
4
6
8
10
12
14 16
IV
24 20
l-
18 20 22
POSTOPERAT
. -
Lx
m
8 E
10
12
14
DAYS
FIG. 1. Mean body weights (A and B) and mean water intake (C and D) for rats with kainic acid-induced
striatal lesions (open circles) and control (solid circles) rats. Upper (A and C) and lower (B and D) panels represent rats injected bilaterally into the striatum with 6 and 3 nmol kainic acid respectively. Body weight was significantly decreased (~~0.05) following kainic acid relative to controls. Error bars represent SEM.
degenerative disorder transmitted by an autosomal dominant gene. The symptomology of HD consists of a progressive dementia coupled with bizarre uncontrollable movements and abnormal postures. From the time of onset of HD, typically 35-45 years of age, an intractable course of mental deterioration begins with death usually occurring within 15 years. Although the neural degeneration in HD is widespread, the basal ganglia is the most severely affected region (33). Moreover, the principle motor symptoms of HD are likely the result of neural degeneration in the basal ganglia, the striatum in particular. Although research has provided considerable insight into the pathophysiology and molecular biology involved in HD (l&20), our understanding of the etiology of the disease as well as our ability to prevent or alleviate it is limited. Accordingly, an important approach for understanding and treating HD is the development of an animal model which mimics the behavioral and neurobiological sequelae of the disease. A variety of approaches have been used to develop animal models of HD [see (11) for a review]. Hyperkinesia resulting from genetic abnormalities, various types of brain lesions and acute pharmacological manipulations of striatal transmitter balance have all been suggested as models for HD. Unfortunately, these models all suffer shortcomings which severely limit their utility. The major drawback with these models is that the movement disorders characteristic of HD are the result of a complex and regionally specific mosaic of striatal degeneration which has been difficult to reproduce in laboratory animals. Recently, however, selective toxic compounds have proven useful for examining specific functional properties of the striatum and for developing animal models of human neurological disorders, such as HD. Considerable interest has been focused on the possibility that an endogenous excitotoxic compound results in the neuronal death found in HD and other human neurodegenerative disorders. Since
the pioneering animal studies of Coyle and Schwartz (8) and McGeer and McGeer (20), evidence has indicated that structural analogues of glutamate such as kainic acid (KA) produce a profile of neuronal degeneration in the rat which bears considerable homology to that described in the striatum of HD patients upon postmortem examination (9, 21, 22). Intrastriatal injections of nanomolar quantities of KA result in the degeneration of local, intrinsic neurons while sparing axons of passage and terminals of extrinsic origin. In addition to the pathological similarities between HD and KA-lesioned rats, KA produces biochemical, pharmacological, and psychological alterations which are reminiscent of HD. Accordingly, the KA rat exhibits alterations in locomotor activity (17,32), profound impairments in learning and memory (10, 26, 28, 29), and altered responsiveness to pharmacological compounds (30,32) which are similar to those observed in HD. During our behavioral analysis of these “Huntington” rats, we noticed that postoperatively all lesioned rats lost body weight and had a short-term aphagia and adipsia (Fig. 1). The animals never gained weight back to control group levels (29). This was very similar to that seen in the lateral hypothalamic syndrome (42). Interestingly, although body weight remained decreased, there were no significant differences in ad lib water or food intake between KA-lesioned and control rats. Unlike lateral hypothahunic-lesioned rats, when they were food deprived for 24 hours, their water intake was significantly greater than controls, representing a profound psychogenic polydipsia (34). Moreover, 24-hour food or water deprivation resulted in the lesioned rats consuming more food than controls during the subsequent 24-hour period. The marked changes seen in body weight and regulatory behavior following striatal destruction led us to investigate whether these changes also occurred in HD patients. A search through the literature revealed only anecdotal comments that HD patients
ANIMAL MODELS
449
tended to be thin and that they were cachectic by the time they died (5, 6, 18). To further investigate whether these significant body weight changes were a characteristic symptom of HD patients as suggested by the animal data, we examined the long-term case histories of 11 hospitalized HD patients and 10 neurological controls matched on variables such as duration of hospitalization, age, diet, height, and drug history (31). While the mean body weights of both groups were comparable at the time of admission, body weight in the HD patients was significantly lower at the end of hospitalization (approximately 9.5 years). This analysis further revealed that only the HD patients reduced their body weight compared with their admission values. While some individuals in both groups tended to increase body weight following admission (presumably due to better care and diet), the HD patients reached their maximum body weight sooner and lost weight thereafter. The weight loss displayed by HD patients was not associated with a decreased appetite or anorexia since nearly 50% of the HD patients were fed very high-energy diets in an attempt to keep their body weight loss to a minimum. Likewise, increased caloric expenditure from hyperkinesis could not explain the continuous weight loss, because it is quite common for the disease to progress towards hypokinesia (5) (Westphal variant) as was seen in some of the patients in these studies. It appears, rather, that the body weight symptomatology in HD may be related to underlying striatal degeneration. More importantly, body weight has proven useful as a diagnostic tool and for evaluating the efficacy of various therapeutic interventions. TOURETTE
SYNDROME
Another disorder characterized by motor abnormalities is Tourette Syndrome (TS) (4,40). TS is a complex disorder characterized by chronic motor tics and involuntary verbalizations. Although the underlying pathology of TS is not well understood. it is generally believed that excess extrapyramidal dopamine neurotransmission plays a significant role in the symptomatology of the disorder (41). Although treatments are limited, TS is most commonly treated by neuroleptic medication, particularly the dopamine receptor blocker haloperidol. Haloperidoi is effective in approximately 70% of all TS cases (13,39), but its utility is questioned by the occurrence of deleterious side effects including decreased concentration, drowsiness, depression, weight gain and decreased attention. In addition. there is a considerable long-term risk of tardive dyskinesia (14). Erenberg (13) reported that the majority of TS patients discontinue neuroleptic medication because of dissatisfaction with the side effects. A pharmacotherapeutic strategy which could potentiate the therapeutic action of haloperidol or other neuroleptics, and possibly reduce the side effects, would therefore be useful for individuals with TS. Moss et al. (24) reported that nicotine potentiated reserpine-induced catalepsy in rats. In examining the data. it was clear that this was one of the most marked potentiation effects of rese~ine-induced catalepsy observed, especially with a low dose of a drug (nicotine) which by itself had no cataleptic effects. Reserpine acts presynaptically to deplete intraneuronal stores of catecholamines and has been used for treatment of hyperkinetic movement disorders (43). Given these results we were interested in whether nicotine could potentiate the effects of (the more commonly used dopamine receptor blocker) haloperidol. If so. then nicotine might also be useful for augmenting the therapeutic effects of neuroleptics in patients with extrapyramidal movement disorders, such as TS. In an initial study, rats were treated with haloperidol alone or in combination with nicotine and tested for catalepsy using the bar test (37). This test has previously been shown to depend on the
TABLE 1 THE EFFECT OF NICOTINE ON HALOPERIDOL-INDUCED CATALEPSY IN RATS
Time After NIC or Vehicle HAL + NIC; HAL only* NIC only Control
2 Hr
721.8 169.2 3.8 2.6
i- 206.9 t 77.8 + 2.8 5 I.1
4 Hr
595.2 138.0 8.3 2.1
r 1x5.4 z!z 37.3 t 6.4 “_ 0.7
Animals received injections ofhalo~~dol(O.3 mg/kg) and nicotine (0.1 mgikgf and were tested for catalepsy (bar test) 2 and 4 hours later. Data presented as the mean catalepsy (bar times) rf~SEM. HAL = haloperidol; NIC = nicotine. *Significantly different from NIC only and Control. piO.05. tsignificantly different from other three groups, p
