Supersensitivity to d-amphetamine- and apomorphine-induced stereotyped behavior induced by chronic d-amphetamine administration

Journal of the neurological Sciences, 1975, 25:283-289

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Elsevier Scientific Publishing Company. Amsterdam - Printed in The Netherlands

Supersensitivity to d-Amphetamine- and Apomorphineinduced Stereotyped Behavior Induced by Chronic d-Amphetamine Administration HAROLD L. KLAWANS, DAVID I. MARGOLIN, NAVA DANA ANDPAMELA C ROSSET The Division of Neurology, Michael Reese Hospital and Medical Center, the Department O[ Medicine, University of Chicago, Rush Medical College, Chicago and the University 01"Illinois School Of"Medicine, Chicaoo, HI. (U.S.A.) (Received 5 December, 1974)

INTRODUCTION

The phenomenon of denervation hypersensitivity in the central nervous system has been well studied in animal models and has been implicated in the pathogenesis of tardive dyskinesias (Klawans and Rubovits 1972) and levodopa-induced dyskinesias (Klawans 1973) in humans. The converse state, supersensitivity following the chronic stimulation of specific receptor sites or "innervation" supersensitivity, has received amazingly little consideration. Dyskinesias following chronic levodopa use in Parkinsonism and dyskinesias following chronic amphetamine abuse are felt to be related to the increased activity of dopamine at dopamine receptor sites within the striatum (Klawans 1973; Klawans and Weiner 1974). It is possible that supersensitivity due to excess innervation may well play a role in the pathogenesis of these 2 movement disorders. Amphetamine-induced stereotyped behavior and apomorphine-induced stereotyped behavior in animals have been intimately linked to the action of dopamine at dopamine receptor sites in the corpus striatum (Fog 1972). Therefore it was felt that changes in stereotyped behavior following the chronic administration of amphetamine may act as a model of movement disorders in humans following the chronic use of amphetamine or levodopa. MATERIAL AND METHODS

White male guinea pigs weighing between 250 and 300 g were stored 12 to a cage with This research was supported in part by grants from the United Parkinson Foundation, the Boothroyd Foundation, and the Michael Reese Medical Research Institute. David I. Margolin was supported by a grant from the Northside Ladies' Auxiliary of the United Parkinson Foundation.

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a light-dark cycle of 07.00 to 16.00 hr on and 16.00 to t)7.00 hr off. On the morning of each experiment, animals were removed and placed 4 per wire mesh testing cage and denied access to food or water, d-Amphetamine sulfate (Smith, Klmc and French, Philadelphia, Pa., U.S.A.) was diluted for injection on the morning of use. Apomorphine hydrochloride (Merck) was stored at 4°C and dissolved for injection in distilled water not more than 5 rain prior to injection to minimize the possibility of oxidation. All injections were administered subcutaneously. All animals were observed continuously for the first half-hour following injection and at 15-min intervals thereafter for a maximum of 3 hr, or until stereotypy ceased. Rating of behavior was performed according to the method of Ernst (1967), slightly modified' 0 = N o stereotyped behavior: 1 + = Occasional licking of the grid and exploration ; 2 + = Occasional biting and gnawing at the grid, easily distracted by movement or sound in the room: 3 + Persistent and intense gnawing at one location, without locomotion, disturbed by loud noises only" 4 + = Persistent, continuous gnawing at one location, not distracted by noises. Experimental animals were divided into 2 pre-treatment g r o u p s Group A animals received 7 mg/kg d-amphetamine twice a day for 3 weeks followed by injections of 10 mg/kg day for 2 more weeks. Group B animals received 7 mg/kg d'amphetamine once a day for 2 weeks. The pattern of stereotypy was measured every third day during the course of scheduled injections. On the day following the end of the pretreatment period, testing was begun with 3-4 mg/kg d-amphetamine and 0.154).20 mg/kg apomorphine. Both pretreatment and test doses were based on the animals' weight on the first day of pretreatment. By recording the response of the animals to these drugs at the start of the pretreatment period also, it was possible to utilize animals as their own controls. Since d-amphetamine, in the doses used, elicits fully-developed stereotyped behavior, the development of 4 + stereotypy was used for statistical analysis. Since apomorphine in thedoses used here does not elicit 4 + stereotypy, the development of 3 + or 2 + stereotypy was used for analysis. Analysis of data was accomplished by use of the Fisher exact probabilities test (Siegel 1956). RESULTS

Amphetamine-induced stereotyped behavior (see Table 1) Animals in both pretreatment Groups A and B developed full (4 + ) stereotyped behavior at doses of 3 mg/kg and 4 mg/kg d-amphetamine administered following the pretreatment period. No animals in the control group developed stereotyped behavior on 3 mg/kg or 4 mg/kg of d-amphetamine. Animals in Group B in which daily changes in behavior could be evaluated de. monstrated a progressively decreasing latency for the development of stereotyped behavior (see Fig. 1). While this group required the full 60 min observation period to develop 4+ stereotyped behavior on the first pretreatment day, only 20 min was required on the t4th day.

SUPERSENSITIVITY TO d-AMPHETAMINE- AND APOMORPHINE-INDUCED BEHAVIOR

285

TABLE 1 AMPHETAMINE-INDUCEDSTEREO"?YPEDBEHAVIOR

Pretreatment

Amphetamine dosage (mg/kg)

Maximum stereotypy rating

Control (pretreatment)

4

4+

Control (pretreatment)

4

Control (pretreatment)

3

Control (pretreatment)

3

group

Proportion developing stereotypy within 1 hr

Statistical signilTcance

10/10

A

P < 0.005 0/12

11/11

B

4+

P < 0.005

o/12 lO/lO

A 4+

P< 0.005 0/12

B

11/i1 4+

Day 1 of pretreetment

o

-

0

~

~

10 20 30 40 50 60 Min after injection

Day 7

r~ O0

P< 0.005 0/12

~

'10 2'0 3 ; 4 ; 5 ; 610 Min after injection

Day 4

o~

0

'

'

DaylO

0

0

,

,

10 20 30 4~0 50 60 Min after injection

~

20 30 40 50 60 Min after injection

Day 14

0

10 20 30 40 50 60 Min after injection

Fig. 1. Group B animals. Time course of stereotyped behavior.

Apomorphine-indueed stereotyped behavior (see Table 2) Animals in both pretreatment Groups A and B developed marked (3 + ) stereotyped behavior when given 0.20 mg/kg apomorphine and 2 + stereotyped behavior when given 0.15 mg/kg apomorphine following the pretreatment period. No members of the control group developed stereotyped behavior on either 0.15 mg/kg or 0.20 mg/kg apomorphine.

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H. I.. KLAWANS. 1). I. MARGOLIN, N. I)ANA, P. CROSSE'I TABLI:! 2 APOMORPHINE-INDUCED STEREOTYPED BEHAVIOR

Apomorphine dosage (mg/kg ~

Maximum stereotypv ratimt

Control (pretreatment)

0.20

3+

Control (pretreatment)

0.20

Control (pretreatment)

0.15

Control (pretreatment)

0.15

Pretreatment group A

Proportion depelopinq

Statistical

stereotypy within 1 hr

signillCance

12/12 P < 0.005 0//12

11/1 I P<: 0.005

3+ 0/12 10/10 2 4 0/12

B

P < 0,005

11/I 2+

t ' < 0:005 0/12

DISCUSSION

The results presented above indicate that chronic pretreatment of guinea pigs with amphetamine produces an increased sensitivity to amphetamine-induced stereotyped behavior. The mechanism underlying this increased sensitivity to amphetamine could be presynaptic or postsynaptic. The fact that amphetamine innervates dopamine receptor sites indirectly by releasing dopamine from dopamine neurons and preventing its re-uptake into these neurons (Axelrod 1970)makes it impossible to determine which of the mechanisms is involved. Apomorphine, however, is thought to activate caudate dopaminergic receptor sites directly (Ernst 1967). The fact that a decreased threshold to apomorphine-induced stereotyped behavior was observed in the amphetamine-pretreated animals suggests that a postsynaptic mechanism is responsible for the hypersensitivity observed in these animals. The fact that catecholamine levels are decreased after chronic methamphetamine stimulation in rats (Lewander 1968) and guinea pigs (Lewander 1971), and that the pattern of amphetamine urinary metabolites in rats are unchanged by chronic amphetamine administration (Lewander 1969}, adds additional evidence that the supersensitivity effects of amphetamine pretreatment are due to a receptor site change rather than an alteration in catecholamine or amphetamine metabolism. The data presented here are consistent with the hypothesis that a functional or structural change in the dopamine receptor site resulting in increased sensitivity can be caused by chronic administration of a dopamine agonist, viz., d-amphetamine. This drug-induced alteration could consist of a direct modification of the dopamine receptors themselves or a suppression of some other neuronal mechanism which normally antagonizes stereotyped behavior. Whichever mechanism is operating, the

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response of the cells upon which dopamine acts to elicit stereotypy is increased (supersensitive). A similar agonist-induced hypersensitivity might play a role in the development of the 2 human movement disorders, viz., amphetamine-induced dyskinesias and levodopa-induced dyskinesias.

Amphetamine-induced dyskinesias Abnormalities associated with chronic amphetamine use include dyskinesias, complex stereotyped behavior, and a paranoid psychotic state which is often indistinguishable from acute or chronic paranoid schizophrenia (Connell 1958: Rylander 1972). The involuntary dyskinetic movements are most often observed in the facial and masticatory musculature producing chewing, licking, teeth grinding, and protrusion of the tongue (Rylander 1972). Movements strikingly similar to these, known as lingual-facial-buccal dyskinesias occur in Huntington's chorea and in a number of symptomatic choreas (Klawans and Weiner 1974). Dyskinesias of the trunk and extremities are less common than lingual-facial-buccal movements in amphetamine-induced movement disorders (Rylander 1972) which is also the case in tardive and levodopa-induced dyskinesias (Klawans 1973). Klawans and Weiner (1974) have recently found that the administration of a single low dose of d-amphetamine does not produce dyskinesias in normal controls but is sufficient to exacerbate or uncover chorea in patients with Huntington's chorea. Sydenham's chorea, or chorea associated with systemic lupus erythematosus. Each of these disorders is believed to involve physiologic alterations within the basal ganglia and an increased sensitivity to dopamine (Klawans 1973; Klawans and Weiner 1974). In view of this information, the fact that amphetamine does not usually cause dyskinesias early in the course of abuse but does so after chronic abuse supports the hypothesis that chronic amphetamine administration produces supersensitivity to dopamine by altering the physiology of the basal ganglia. Supersensitivity following chronic agonism demonstrated in guinea pigs therefore appears to be an excellent model for the study of dyskinesias induced by chronic amphetamine abuse.

Levodopa-induced dyskinesias Levodopa-induced dyskinesias are clinically quite similar to tardive dyskinesias with lingual-facial-buccal movements being the most prominent (Klawans and Weiner 1974). The fact that the pathogenesis of Parkinson's disease involves degeneration of the dopamine-containing neurons in the substantia nigra (Greenfield and Bosanquet 1953 ; Forno 1966) and subsequent depletion of this neurotransmitter in the striatum (Hornykiewicz 1966) has led to the suggestion that the appearance of dyskinesias associated with levodopa use in Parkinsonism is due to a denervation hypersensitivity (Klawans 1973). While the concept of denervation hypersensitivity explains the fact that normal persons receiving levodopa experimentally rarely develop dyskinesias while Parkinsonian patients receiving equivalent amounts do so (Mena, Court, Fuenzalidia, Papavasiliou and Cotzias 1970), there are several observations which are not explained by the denervation hypersensitivity hypothesis. Klawans, Crosset and Dana (1975) have noted that in a large number of patients

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H. L. KLAWANS, D. I. MARGOL1N, N. DANA, P. CROS~'qET

the dyskinesias are initially present 1-2 hr after levodopa ingestion, at about the same time as the maximal tevodopa effect on Parkinsonmn symptoms. Later in the course of therapy, these dyskinesias begin within minutes of levodopa ingestion. Secondly, there is a direct relationship between the duration of levodopa therapy and the prevalence of dyskinesias (Klawans and Weiner 1974: Klawans et al. 1975). Few patients experience dyskinesias during the first few months of levodopa therapy, but almost 80~o have such movements by the end of 2 yr of such treatment. The phenomenon ofinnervation supersensitivity as reported here may explain these 2 observations. The decreased latency for the appearance of dyskinesias following chronic levodopa administration parallels the decreased latency for the appearance of stereotyped behavior following chronic amphetamine administration and may be due to a supersensitivity to dopamine rather than to a change m the way the patienl metabolizes levodopa. The direct relationship between the length of levodopa therapy and the incidence of dyskinesias is equivalent to a decreased threshold to this effect of levodopa and parallels the decreased threshold for both amphetamine- and apomorphine-induced stereotyped behavior following chronic amphetamine administration. The development of hypersensitivity following chronic excessive agomsm may explain in part 2 other clinical observations: (1) In many patients there is a direct relationship between the duration of dyskinesias and their severity. The dyskinesias often begin quite mildly and become more severe as they persist. This increase often includes a wider distribution (from solely lingualfacial-buccal movements to involvement of the trunk and/or limbs) as well as an increase in the severity of the individual movements (Klawans et al. 1975). (2) There is often an inverse relationship between the duration of dyskinesias and the dosage of levodopa necessary to elicit the dyskinesias (Klawans et al. 1975). This is evidenced by the recurrence of abnormal movements a few weeks to months after the dosage of levodopa has been reduced and the abnormal movements have disappeared (Barbeau 1970). Both of the previous observations reflect a decreased threshold for the development of levodopa-induced dyskinesias. The innervation supersensitivity model may be invoked to account for this decreased threshold following chronic levodopa use. In summary, the concept of denervation supersensitivity is useful in accounting for the appearance of levodopa-induced dyskinesias m Parkinsonian patients. Several characteristics of the course of these dyskinesias are not accounted for by this simple model, however, and it is useful to adopt the concept ofinnervation or chronic agonist supersensitivity to help explain these characteristics. ACKNOWLEDGEMENTS

The d-amphetamine sulfate was supplied by Smith, Kline and French Laboratories, Philadelphia, Pa., U.SA. SUMMARY

Guinea pigs exhibit an increased sensitivity to both d-amphetamine- andapomorphine-

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induced stereotyped behavior following chronic pretreatment with d-amphetamine. This chronic agonist or "innervation" supersensitivity is believed to be a reflection of an increased sensitivity of dopamine receptor sites within the corpus striatum to dopaminergic agonists. The appearance ofdyskinetic movement disorders in humans following the chronic use of levodopa or amphetamine may be a manifestation of similarly increased dopamine receptor site sensitivity within the striatum. It is suggested that the animal model of "innervation" supersensitivity may be useful in the investigation of these human movement disorders.

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