R.F. Schlemmer, Jr. and J.M. Davis,     Research Department, Illinois State Psychiatric Institute, 1601 W. Taylor Street, Chicago, Illinois 60612, USA

ABSTRACT

The effect of chronic d-amphetamine and chronic apomorphine treatment on non-human primate social and solitary behavior was compared in the same four selected members of an adult Stumptail social colony. In the first experiment, two monkeys received d-amphetamine, 1.6 mg/kg, in time-release form nasogastrically every 12 hrs. for 12 consecutive days following a two week baseline observation period. Four weeks later, twc previously untreated monkeys received identical amphetamine treatment in a cross-over fashion. One year later, the experiment was repeated substituting apomorphine, 0.5 mg/kg, for amphetamine. Apomorphine was administered intramuscularly twice daily for 12 consecutive days. There were a number of similar behavioral changes induced by these agents. Both drugs induced social withdrawal, increased submissiveness, stereotyped behavior, hypervigilance, and hyperactivity. Only d-amphetamine increased self-grooming, whereas apomorphine increased locomotion more than d-amphetamine. These results demonstrate the important role of dopamine systems in the mediation of primate social and solitary behavior. Also, since some of the behavioral changes induced in monkeys by d-amphetamine and apomorphine resemble changes seen during amphetamine psychosis in humans, these results support the hypothesis for the predominant role of dopamine in the mediation of amphetamine psychosis.

KEYWORDS

d-Amphetamine

apomorphine

primate social behavior

stereotyped behavior

psychosis

amphetamine psychosis

dopamine

CNS stimulant drugs

INTRODUCTION

Dopamine agonist drugs such as amphetamine and cocaine often induce a paranoid psychosis in individuals who receive large, frequent doses (Snyder, 1972). Moreover, certain dopamine agonists dramatically worsen psychotic behavior in acute schizophrenic patients (Janowsky and Davis, 1974). These findings have served as one of the major cornerstones of the dopamine theory of schizophrenia (Meltzer and Stahl, 1976). One of the criticisms leveled against this position has been that the dopamine receptor agonist apomorphine does not induce psychosis or worsen psychoses in psychotic patients (Tamminga and co-workers, 1978). However, this argument is weakened by the fact that large doses of apomorphine have rarely been given to humans because of the potent emetic effect of this drug at higher doses.

Apomorphine does not induce vomiting in non-human primates even at very large doses (Brizzee, Neal, and Williams, 1955; Peng and Wang, 1962). In addition, chronic administration of amphetamine or methamphetamine to selected adult members of primate social colonies induces several behavioral changes which resemble human responses during amphetamine psychosis (Machiyama, Utena, and Kijuchi, 1970; Garver and co-workers, 1975; Haber, Barchas, and Barchas, 1977; Schiørring, 1977; Schlemmer and co-workers, 1978). These behavioral changes include the induction of a variety of stereotypies, social withdrawal, increased submissive behavior, increased checking (hypervigilance), excessive scratching, and general hyperactivity. We have recently reported that acute administration of apomorphine to selected members of Stumptail macaque social colonies induced several dose-dependent behavioral changes which are seen with d-amphetamine treatment (Schlemmer, Narasimhachari, and Davis, 1980).

Therefore, because it is impractical to administer large doses of apomorphine chronically to humans, one approach to examining the apomorphine question would be to compare the effects of chronic d-amphetamine and apomorphine administration on primate social and solitary behavior.

We now report the results of a comparative study of the behavioral effects of chronic d-amphetamine and apomorphine treatment in the same selected members of a primate social colony.

METHODS

The subjects for the study were four members of a stable, adult Stumptail macaque (Macaca arctoides) social colony of five monkeys (1 male, 4 females). The male remained untreated throughout the study. The colony was continuously housed in a 1.75 m × 3.0 m × 5.25 m. home cage in a temperature, humidity, and light controlled room. The colony received a generous supply of food (Purina Monkey ChowR) at the same time each morning and had continuous access to water.

The first experiment examined the effects of d-amphetamine. It began with a 10-day drug-free observation period where baseline behaviors were established. Immediately following baseline, 2 selected females from the colony received chronic administration of d-amphetamine sulfate, 1.6 mg (base)/kg, in time-release form (Dexedrine SpansulesR) every 12 hours for 12 consecutive days. The drug was suspended in SimilacR and administered nasogastrically at 6:00 a.m. and 6:00 p.m. daily. The same two monkeys received sham nasogastric treatment with SimilacR alone at 6:00 am throughout baseline, also. Four weeks after the completion of the first part of the experiment, identical baseline and amphetamine treatment was repeated with the previously untreated females of the colony receiving sham and drug treatment in a cross-over design. Following a one year drug “wash-out” period where the animals were maintained as a colony in the same cage, the second experiment began. Again the experiment began with a 10-day baseline observation period which was followed by a 12-day apomorphine treatment period. During the treatment period, the same two monkeys who had received drug treatment first in the previous experiment received apomorphine HCl, 0.5 mg (base)/kg, intramuscularly twice daily, at 10:30 a.m. (15 min. prior to observation) and at 2:30 p.m., for 12 consecutive days. A sham injection of saline was administered i.m. 15 min. prior to observation to all four females during baseline and to the two untreated females during the drug treatment period. After a 4 week drug “wash-out”, the experiment was then repeated with the two previously untreated females receiving apomorphine in a cross-over fashion as before.

A daily 60 min. behavioral observation session was conducted by the same “blind” experienced primate observer at the same time mid-morning throughout both experients. During that time, the observer quantified and recorded the behavior of each monkey in the colony from a checklist of 48 social, solitary, and abnormal behaiors for this species using the focal sampling technique in the following manner. One monkey in the colony was observed for a 30 sec. interval. All behaviors displayed by the animal during that 30 sec. were recorded on the checklist during the following 30 sec. Then, a second monkey from the colony was observed during the next 30 sec. and that behavior similarly recorded. This process continued in rotation for a total of twelve 30 sec. intervals with each monkey being observed once every 5 min. for 1 hr. A new scoring rotation was determined randomly each day. Scores from the twelve 30 sec. intervals were summed for each behavior for the individual animals and represented the daily score for each monkey.

Statistical analysis was performed using a three-way partially-crossed analysis of variance and the least significant difference method for comparing means within the analysis. Because the behavioral response to chronic d-amphetamine may vary across time, treatment data have been divided into 4 day segments: days 1–4 (early treatment), days 5–8 (mid-treatment), and days 9–12 (late treatment).

RESULTS

Chronic d-amphetamine and apomorphine treatment induced several similar behavioral changes in monkeys. In general, both drugs induced hyperactivity to the same degree throughout treatment (Fig. 1).

Particularly noteworthy were the similar changes induced in important social behaviors. d-Amphetamine and apomorphine both significantly reduced the amount of social grooming initiated by treated monkeys throughout the 12-day treatment period (Fig. 2). At the same time, treated monkeys were more isolated from other monkeys in the colony during amphetamine and apomorphine treatment as reflected by their distancing scores (Fig. 3). The number of submissive gestures given by treated monkeys was significantly increased to the same extent by both drugs particularly during the early days of treatment (Fig. 4) despite the lack of a significant increase in aggressive gestures directed toward these animals during this time. Treated monkeys would often lipsmack (a...