Behavior Of Squirrel Monkeys Research Articles

Modification of overt behavioral effects of cocaine by nicotinic agonists

Nicotinic agonists and muscarinic antagonists previously have been shown to, respectively, mimic and accentuate the discriminative‐stimulus (Sd) effects of monoaminergic (MA) stimulants (e.g., cocaine; COC) that also increase overt scanning‐checking (S‐C) behavior in squirrel monkeys. The present studies were undertaken to examine the ability of cholinergic (ACh) ligands—nicotinic full [nicotine (NIC), (+)‐epibatidine (EPI)], partial [varenicline (VAR), (−)‐cytisine (CYT), DMAB‐anabaseine (DMAB)] agonists, and the muscarinic antagonist atropine (ATR)—to mimic or modify COC‐induced increases in S‐C behavior. Results show that COC (0.032–3.2 mg/kg), but no ACh drugs, produced dose‐related increase in S‐C behavior. Further, NIC, EPI—and, to a lesser extent, VAR and CYT—dose‐dependently attenuated, whereas atropine dose‐dependently enhanced, COC's effects on S‐C; DMAB had no effect. The similar effects of ATR in Sd and S‐C studies are consistent with established pharmacological MA‐ACh muscarinic interactions, whereas the qualitatively inconsistent effects of nicotinic drugs suggest that stimulant‐like Sd effects of nicotinic drugs do not involve prominent MA activity (supported by NIH/NIDA DA026548).

Interactions between the mGluR2/3 agonist, LY379268, and cocaine on in vivo neurochemistry and behavior in squirrel monkeys

Recent evidence indicates that group II metabotropic glutamate receptors (mGluR2 and mGluR3) may play a role in the pathology of cocaine addiction. The purpose of the current study was to determine the effects of the mGluR2/3 agonist, LY379268, on cocaine-induced changes in DA neurochemistry in nonhuman primates. Furthermore, the current study aimed to determine if changes in DA neurochemistry would correlate with LY379268-induced changes in the behavioral effects of cocaine. In vivo microdialysis was conducted in conscious squirrel monkeys ( n = 4) in order to monitor cocaine-induced changes in extracellular DA in the caudate nucleus. Separate groups of subjects were trained on a fixed-interval schedule of stimulus termination ( n = 4) or a second-order schedule of cocaine self-administration ( n = 5) to characterize the behavioral-stimulant and reinforcing effects, respectively. LY379268 significantly attenuated cocaine-induced increases in DA. LY379268 also significantly attenuated cocaine-induced behavioral-stimulant effects following a short pretreatment time, but not following a longer pretreatment time. Cocaine self-administration was significantly attenuated but only at an intermediate pretreatment dose of LY379268. Moreover, reinstatement of previously extinguished cocaine self-administration was not significantly attenuated by LY379268. Hence, drug interactions on neurochemistry did not correlate well with behavioral measures.

Fatty Acid Amide Hydrolase Inhibition Heightens Anandamide Signaling Without Producing Reinforcing Effects in Primates

CB(1) cannabinoid receptors in the brain are known to participate in the regulation of reward-based behaviors. However, the contribution of each of the endocannabinoid transmitters, anandamide and 2-arachidonoylglycerol (2-AG), to these behaviors remains undefined. To address this question, we assessed the effects of URB597, a selective anandamide deactivation inhibitor, as a reinforcer of drug-seeking and drug-taking behavior in squirrel monkeys. We investigated the reinforcing effects of the fatty acid amide hydrolase (FAAH) inhibitor URB597 in monkeys trained to intravenously self-administer Delta(9)-tetrahydrocannabinol (THC), anandamide, or cocaine and quantified brain endocannabinoid levels using liquid chromatography/mass spectrometry. We measured brain FAAH activity using an ex vivo enzyme assay. URB597 (.3 mg/kg, intravenous) blocked FAAH activity and increased anandamide levels throughout the monkey brain. This effect was accompanied by a marked compensatory decrease in 2-AG levels. Monkeys did not self-administer URB597, and the drug did not promote reinstatement of extinguished drug-seeking behavior previously maintained by THC, anandamide, or cocaine. Pretreatment with URB597 did not modify self-administration of THC or cocaine, even though, as expected, it significantly potentiated anandamide self-administration. In the monkey brain, the FAAH inhibitor URB597 increases anandamide levels while causing a compensatory down-regulation in 2-AG levels. These effects are accompanied by a striking lack of reinforcing properties, which distinguishes URB597 from direct-acting cannabinoid agonists such as THC. Our results reveal an unexpected functional heterogeneity within the endocannabinoid signaling system and suggest that FAAH inhibitors might be used therapeutically without risk of abuse or triggering of relapse to drug abuse.

Role of the hypothalamic-pituitary-adrenal axis in reinstatement of cocaine-seeking behavior in squirrel monkeys.

Stress has been suggested to play a role in relapse to cocaine-seeking behavior. An important physiological system activated by stress is the hypothalamic-pituitary-adrenal (HPA) axis; however, evidence for a role of HPA axis activation in cocaine relapse has been contradictory. This study examined the effects of pharmacological stimulation of the HPA axis on reinstatement of drug-seeking behavior and salivary cortisol levels in a non-human primate model of cocaine relapse. In addition, the effect of corticotropin releasing hormone type 1 receptor (CRH-R1) blockade on cocaine priming-induced reinstatement was investigated. Squirrel monkeys were trained to self-administer cocaine under a second-order schedule in which behavior was maintained by IV drug injections and a drug-paired visual stimulus. A period of extinction was then imposed during which saline was substituted for cocaine and the stimulus was omitted. Subsequently, monkeys were tested for reinstatement of cocaine seeking following priming injections of drugs. During reinstatement tests, the drug-paired stimulus was restored. Salivary cortisol levels were determined to measure the effects of drug treatments on the HPA axis activity. Priming with corticotropin releasing hormone (10 and 50 microg/kg), adrenocorticotropic hormone (1 microg/kg), or cortisol (1-10 mg/kg) did not induce significant reinstatement of cocaine seeking. All of these treatments, however, resulted in a significant increase in salivary cortisol. In contrast, priming injections of cocaine (0.1-1.0 mg/kg) dose-dependently induced reinstatement of drug seeking, but did not increase salivary cortisol. The CRH-R1 antagonist CP-154,526 (10 mg/kg, IV) did not modulate cocaine priming-induced reinstatement of drug seeking, but attenuated CRH-induced increases in salivary cortisol. The results suggest that activation of the HPA axis is neither necessary nor sufficient for reinstatement of cocaine-seeking behavior in this non-human primate model of cocaine relapse.

Suppression of cocaine- and food-maintained behavior by the D2-like receptor partial agonist terguride in squirrel monkeys.

The D2-like receptor partial agonist terguride has a profile of behavioral effects in rats that suggests potential benefit as a pharmacotherapy for cocaine addiction. The present study investigated the effects of terguride on cocaine- and food-maintained behavior in squirrel monkeys. Squirrel monkeys were trained to respond on a second-order schedule (FI 10 min, FR 10 or 30:S) of either i.v. cocaine injection or food pellet delivery. Additional monkeys were studied using quantitative observational techniques to construct side effect profiles. Under each procedure, the effects of terguride were compared with those of the reference D2-like receptor antagonist nemonapride and the D2-like receptor full agonist quinpirole. Terguride and nemonapride, but not quinpirole, dose-dependently reduced cocaine-maintained behavior. In animals self-administering food, terguride decreased response rates at doses lower than those required to suppress cocaine-maintained behavior. Effective doses of terguride had no systematic effect on motor activity or muscle rigidity, whereas effective doses of nemonapride virtually eliminated motor activity and induced severe catalepsy. The primary observable effects of terguride were a modest increase in self-directed behavior (a D2-receptor agonist-like effect) at intermediate doses and a small increase in static posture (a D2-receptor antagonist-like effect) at the highest dose tested. The results suggest that terguride has advantages over conventional D2-like receptor antagonists and agonists as a candidate pharmacotherapy for cocaine abuse; however, terguride significantly reduces food-maintained behavior at lower doses than those needed to decrease cocaine-maintained behavior suggesting limitations on the utility of terguride as a medication for cocaine addiction.

Natural conceptual behavior in squirrel monkeys (saimiri sciureus): An experimental investigation

Natural conceptual discriminations have been tested in many different species, including pigeons and a variety of non-human primates. The ability of four male squirrel monkeys (Saimiri sciureus) to learn and use the natural concept ‘squirrel monkey’ was investigated in this study. After a training phase, subjects were presented with novel stimuli in transfer and test trials. All subjects performed at a rate significantly above chance on the first test trial (p<.001), indicating that squirrel monkeys can utilize natural concepts in the laboratory.

Behavioral effects of systemically administered mu and kappa opioid agonists in the squirrel monkey: Peptides versus alkaloids

This study compared the effects of receptor-selective peptide and nonpeptide opioid agonists administered intramuscularly to squirrel monkeys responding under a fixed-interval 3-min schedule of stimulus termination. The mu opioid receptor agonist morphine (0.1–3.0 mg/kg) increased response rate at low doses and decreased it and quarter-life at higher doses. [ D-Ala 2,N-Me-Phe 4, Gly-ol]Enkephalin (DAMGO; 0.3–3.0 mg/kg) reduced quarter-life at the highest dose. The kappa opioid receptor agonist U50,488H (0.1–1.0 mg/kg) elevated response rate transiently and dose-dependently decreased quarter-life. Dynorphin (1–13) (0.3–10 mg/kg), a purported endogenous ligand of the kappa opioid receptor, decreased response rate slightly but significantly at 3.0 mg/kg and had no effect on quarter-life. Thus, the behavior of squirrel monkeys was affected by systematically administered peptide as well as by nonpeptide opioid drugs. The two alkaloids were much more effective than the two peptides, presumably because of greater ability to penetrate the blood-brain barrier. Quarter-life was often a more sensitive measure of drug effects than was response rate.

Shock avoidance but not DRL history reverses the effects of cocaine on punished behavior of squirrel monkeys

A history of responding maintained by a shock-avoidance procedure can alter the effect of psychomotor stimulant drugs on punished responding. This study was designed to evaluate whether another type of historical intervention could also alter the effects of cocaine on punished responding and, as a result, clarify certain variables contributing to this effect. Lever pressing of four squirrel monkeys was suppressed by a punishment procedure consisting of a fixed-interval 5-min schedule of food presentation in which every 30th response also produced a 200-ms 5-mA electric shock. Cocaine (0.03-1.0mg/kg) had no effect on or reduced punished responding. Conditions were then changed and responding was maintained for several sessions by a differential reinforcement of low rate (DRL) schedule in which food was delivered only when one response followed another by at least 25s. The punishment schedule was then reinstated and the effects of cocaine redetermined; the dose-response curve was similar to that initially obtained. The monkeys then responded on a shock-avoidance schedule in which each response postponed the next scheduled shock for 25s; shocks occurred every 5s in the absence of responding. Subsequently, the shock-avoidance schedule was replaced by the punishment schedule and the effects of cocaine were redetermined. In contrast to the initial determination of the effects of cocaine on punished responding, and the effects obtained following training on the DRL schedule, cocaine then produced response rate increases or no change in rate at several doses that formerly reduced responding. These results demonstrate that the rate-decreasing effects of cocaine on punished responding may be reversed by a history of responding on a shock-avoidance schedule and also indicate that a history of responding on a DRL schedule is not sufficient to reverse the effects of cocaine. These data suggest that a history of responding under schedules, such as the DRL, that engender responding that is typically increased by psychomotor stimulant drugs, is not sufficient to reverse the effects of these drugs on punished responding. The reversal of the effects of cocaine on punished responding resulting from a history of avoidance responding appears to be attributable to factors other than the rate-increasing effect of cocaine on responding maintained by avoidance.

Generalization of behavioral history across responses in the reversal of the effects of cocaine and d-amphetamine on the punished behavior of squirrel monkeys

Previous research has demonstrated that the effects of d-amphetamine on punished lever pressing of squirrel monkeys are modified by an avoidance history in which lever pressing postpones shock. In the present experiment generalization of behavioral history across responses was assessed by determining the effects of d-amphetamine and cocaine on punished lever pressing of squirrel monkeys before and after exposure to an avoidance procedure in which a chain-pulling response postponed shock. The punishment schedule consisted of a fixed-interval 5-min schedule of food delivery in which every 30 lever presses produced a 5-mA electric shock. During avoidance sessions each chain pull postponed shock delivery for 25s; in the absence of chain pulling, shocks occurred every 5s. Only a single response manipulandum was present in each phase. Punished lever pressing was initially unaltered or decreased by d-amphetamine and cocaine. Following the chain-pull avoidance history, however, d-amphetamine produced dose-dependent increases in the punished lever pressing of all three monkeys at several doses that formerly did not alter or reduce responding; a similar pattern of results was obtained when cocaine was administered to two of the subjects. The effects of d-amphetamine and cocaine on punished lever pressing were subsequently determined within the context of a multiple schedule of lever-press punishment and chain-pull avoidance, with both manipulanda present simultaneously. The effects of the drugs on punished lever pressing within the multiple schedule were similar to their initial, pre-avoidance effects for the two monkeys whose responding was increased by both drugs in the preceding, post-avoidance phase. Chain pulling during the punishment component was dose-dependently increased, suggesting that chain pulling during punishment reduced the opportunity to exhibit increases in punishing lever pressing. The remaining monkey's punished lever pressing was increased by both drugs within the context of the multiple schedule. This experiment demonstrates that avoidance-dependent upward shifts in the dose-response curves of d-amphetamine and cocaine can occur when the punishment and avoidance responses differ, and that original effects can be partially restored when both responses are available simultaneously. The results suggest that generalization across responses of the effects of a critical behavioral history may be a general property of behavioral history phenomena within behavioral pharmacology. These findings underscore the generality and importance of behavioral history as a modulatory influence on the effects of abused drugs.

Allomaternal vocal behavior in squirrel monkeys.

Three groups of squirrel monkeys, containing 1-3 infants (N = 7) and 4 adult females each, were observed weekly for the first 12 weeks of the infants' lives. Infants received approximately 100 vocalizations, mostly "caregiver" calls, per waking hour from their mothers and the other adult females with whom they were housed (allomothers). Mothers vocalized very little to their own infants during the first few weeks of life, when infants remain on the mother's back full-time. Instead, allomothers (who were often carrying their own dependent infants) vocalized copiously to others' very young infants. Infants responded vocally to these allomaternal caregiver calls as early as Day 1 but were less responsive to mothers. When infants began leaving the mothers' backs, mothers' rates of calling increased five-fold as they used caregiver calls to retrieve separated infants. Early vocalizing to infants involves them in their first social exchanges and is probably performed by allomothers rather than mothers because the infant rides dorsally in this genus.

Interactions between ethanol and pantothenic acid on tremor and behavior in squirrel monkeys.

Ethanol consumption alters the levels and distribution of pantothenic acid and its metabolic products, an effect that can be counteracted by preloading with pantothenic acid. Ethanol also produces significant disturbances in motor function and has a potent tremorolytic activity when administered acutely. To investigate the interaction of pantothenic acid and ethanol, the two substances were administered alone and in combination to three squirrel monkeys trained to perform a response-initiated positioning task that enabled the detection of tremor. Tremor was evaluated using spectral analytical techniques. Ethanol at 1.0 gm/kg produced a tenfold reduction in tremor over control sessions while pantothenic acid alone had no effect on tremor. Pantothenic acid (200 mg/kg, IP or IV) administered before ethanol intubation completely counteracted the tremor-reducing action of ethanol in two monkeys and partially counteracted it in a third. The interaction between pantothenic acid and ethanol was limited to these motor effects; the rate-reducing effect of ethanol was unaffected by pantothenic acid.

Interaction of haloperidol and SCH 23390 with cocaine and dopamine receptor subtype-selective agonists on schedule-controlled behavior of squirrel monkeys

Involvement of D1 and D2 dopamine receptors in the effects of cocaine on schedule-controlled behavior was evaluated in squirrel monkeys responding under a multiple fixed-interval 5-min, fixed-ratio 10 schedule (mult FI FR) of food delivery. Cocaine and the D2 agonist quinpirole increased responding under the F1 at certain doses and disrupted the temporal patterning of behavior. Higher doses of these drugs decreased responding. In contrast, the D1 agonist SKF 38393 was devoid of behavioral activity up to 10 mg/kg where response suppression was obtained without significant modification of the temporal distribution of responding. The D2 antagonist haloperidol (0.001-0.03 mg/kg) did not alter the behavioral effects of cocaine up to doses that had pronounced behavioral effects on their own. However, haloperidol attenuated the behavioral effects of quinpirole. In contrast, the D1 antagonist SCH 23390 partially attenuated the response rate-suppressant effects of cocaine without blocking cocaine-induced disruptions of temporal response patterning. SCH 23390 did not antagonize the behavioral effects of SKF 38393. These results suggest that independent stimulation of either D1 or D2 receptors alone does not play a major role in the effects of cocaine on schedule-controlled behavior of squirrel monkeys.

Effects of serotonin agonists on operant behavior in the squirrel monkey: Quipazine, MK-212, trifluoromethylphenylpiperazine, and chlorophenylpiperazine

The behavior of squirrel monkeys was studied under fixed-interval (FI) schedules with responding maintained either by food presentation or by termination of stimuli correlated with impending electric shock delivery (stimulus-shock termination). The 5-HT agonists m-trifluoromethylphenylpiperazine (TFMPP), m-chlorophenylpiperazine (mCPP), and 6-chloro-2(1-piperazinyl)pyrazine (MK-212) decreased responding under both the food and shock schedules (0.3−5.6 mg/kg). These decreases in responding were blocked by the nonselective 5-HT antagonists methysergide and mianserin (0.3, 1.0 mg/kg), but not by the selective 5-HT 2 antagonists ketanserin (0.3−1.7 mg/kg) or pirenperone (0.001−0.1 mg/kg). Quipazine (0.3−5.6 mg/kg) decreased responding under the food schedule, and this effect was blocked by both the nonselective and selective 5-HT 2 antagonists. This pattern of antagonism suggests that the decreases in responding produced by quipazine involve significant actions at 5-HT 2 sites, whereas those produced by TFMPP, mCPP, and MK-212 do not. In contrast to the decreases in responding seen with the food schedules, quipazine produced moderate increases in responding under the shock schedules. Moreover, these increases in responding were not blocked by methysergide or mianserin, but instead were enhanced. The results with antagonists suggest that certain behavioral effects of quipazine are probably due to actions at 5-HT 2 sites, whereas similar effects of TFMPP, mCPP, and MK-212 are more related to actions at other 5-HT receptor subtypes.

Effects of alcohol on aggressive behavior in squirrel monkeys: influence of testosterone and social context

Social status and reproductive cycle determine the effects of acute, low doses of alcohol on the social behavior of squirrel monkeys. Alcohol produces biphasic effects on the behavior of dominant but not subordinate monkeys, and only during the mating season. The change in alcohol sensitivity measured in dominant monkeys coincides with changes in plasma testosterone levels. In order to directly study the interaction between alcohol, testosterone and aggressive behavior, testosterone propionate (TP, 25 mg/kg/day, SC) was administered to either dominant or subordinate male monkeys belonging to four separate groups, resulting in significantly elevated plasma levels of testosterone (i.e., 905 +/- 43 ng/ml in subordinates; 171 +/- 19 ng/ml in dominants). Two to three weeks after the beginning of testosterone treatment, the monkeys were administered doses of alcohol (0.1-1.0 g/kg). The behavior of subordinate monkeys was unaffected by TP treatment (even after the dominant monkey from each colony was removed and housed separately for 6 weeks). Testosterone treatment altered the sensitivity of subordinate monkeys to alcohol. Low doses of alcohol increased the frequency of threats, grasps, and displacements exhibited by subordinate monkeys with exogenously elevated testosterone. Daily administration of TP to dominant monkeys during the non-mating season did not affect the behavior of the treated animals in the group, although the body weight of TP-treated monkeys was similar to that measured during the mating season. Low doses of alcohol increased the frequency of threats, grasps, and displacements in dominant monkeys maintained on TP. We also tested the role of social context in maintaining high levels of plasma testosterone, and alcohol sensitivity in dominant monkeys.(ABSTRACT TRUNCATED AT 250 WORDS)

Maternal separation alters later consumption of novel liquids in the squirrel monkey

The consumption of novel, fruit-flavored drinks was measured in juvenile squirrel monkeys that had either had their mother removed from the home cage for 2 h on 80 occasions prior to weaning or had not undergone this separation procedure. Among previously separated animals, males drank more than did females during the first 30 min following presentation, whereas there was no difference in the drinking of nonseparated males and females at this time. Further, the amount of liquid consumed during the 20 h following presentation increased across days of exposure in the nonseparated, but not in the previously separated monkeys. These results show that brief maternal separation can affect the later behavior of squirrel monkeys, and are consistent with findings in rhesus macaques that maternal separation alters later exploratory behavior.

Social status as determinant of alcohol effects on aggressive behavior in squirrel monkeys (Saimiri sciureus).

We investigated the behavioral effects of alcohol, especially those on aggression, on members of established groups of squirrel monkeys. A continuous measurement of monkey behavior in groups revealed consistent differences between dominant and subordinate animals. Dominant monkeys aggressed more frequently than subordinate monkeys, and spent less time in stationary postures. Alcohol produced dose-related biphasic changes in the number of threats, grasps, and displacements exhibited by dominant but not subordinate monkeys. Low doses of alcohol (0.1, 0.3, 0.6 g/kg) increased the frequency of aggressive behavior, and high doses (1.0 g/kg) decreased these behaviors. The largest change in behavior was evident in the first 20-40 min after injection, with a return to baseline 60-120 min later. The aggression-enhancing effect of alcohol in dominant monkeys required a stable baseline, which was obtained by daily administration of distilled water. Low levels of aggressive and associative behavior in subordinate monkeys were relatively unaffected at any dose of alcohol. They were associated with and aggressed against more often by untreated members of the group. The status-dependent effects of alcohol may be related to the neuroendocrine and neurotransmitter profiles characteristic of dominant and subordinate monkeys.

Drug history modifies the behavioral effects of pentobarbital.

Behavior of squirrel monkeys, maintained by the termination of stimuli associated with electric shock, was suppressed by response-dependent shock delivery. The effects of pentobarbital on this behavior depended on whether monkeys had previously received morphine. In monkeys without experience with drugs, pentobarbital increased responding. In monkeys with recent experience with morphine, however, pentobarbital resulted in a smaller increase or decrease in responding. The rate-decreasing effects of pentobarbital after a history of morphine administration could be reversed by the administration of d-amphetamine. These findings suggest that the behavioral effects of abused drugs may depend on previous experience with other drugs, even when those drugs are from a different pharmacological class.

Effects of phencyclidine on aggressive behavior in squirrel monkeys

Effects of phencyclidine (PCP) on shock-induced and spontaneous aggression in the squirrel monkey were determined. The delivery of response-independent, fixed-time (4′, S-S interval) electric shock to the tail of a restrained squirrel monkey generated post-shock, hose-bite attack responses and pre-shock lever press non-attack responses. In a separate procedure shock was not delivered and spontaneous aggression responses were measured. A PCP dose response function (0.01–1.0 mg/kg SC) was determined for each procedure. In the shock-induced aggression procedure initial increases in attack were observed but upon a second determination of the dose effect curve this effect decreased and an increase in non-attack was noted. PCP produced increases in non-attack responding at high dosages in the spontaneous aggression procedure.

Antipsychotic drug effects on the behavior of squirrel monkeys differentially controlled by noxious stimuli.

The effects of several antipsychotic compounds were examined on two types of behavioral performances of squirrel monkeys. Both behaviors occurred simultaneously and were maintained separately by different schedules using noxious stimuli. Steady rates of responding were maintained when a chain pulling response postponed electric shock delivery (avoidance schedule). Concurrently, positively accelerated rates of responding were maintained on a lever where the first response after 3 min produced electric shock (fixed-interval 3-min schedule). The effects of the different drugs depended both upon whether the behavior postponed or presented shock and on the particular drug. Chlorpromazine (0.001-0.03 mg/kg), haloperidol (0.001-0.01 mg/kg), molindone (0.001-0.03 mg/kg) and thiothixene (0.001-0.03 mg/kg) increased slightly or had no effect on responding under the shock-postponement schedule at doses that decreased responding maintained by shock presentation. The effects of clozapine, a clinically effective antipsychotic compound, differed markedly from the other antipsychotic drugs. Clozapine (0.01-1.0 mg/kg) increased responding maintained by the presentation of shock at doses that decreased responding under the shock-postponement schedule. Higher doses of these drugs decreased responding under both schedules and, with the exception of clozapine, resulted in increased frequency of shocks under the postponement schedule.

Disruption of primate social behavior by d-amphetamine and cocaine: differential antagonism by antipsychotics.

Psychostimulants lead to withdrawal from social interactions and to a decline of affective behavior in squirrel monkeys. These changes, in addition to motor stereotypies, may be related to stimulant-induced psychosis in humans. In the first of two series of experiments, 1 mg/kg d-amphetamine or 10 mg/kg cocaine, administered orally three times over 24 h to one adult male member of an established group (n = 6-9), engendered stereotyped movements of the head and hands, reduced rest postures, and greatly reduced all forms of social initiatives. Chlorpromazine (0.25-1.0 mg/kg), haloperidol (0.25, 0.5 mg/kg), and physostigmine (0.04, 0.08 mg/kg), administered before the third amphetamine or cocaine injection, blocked the motor stereotypies and hyperactivity. Chlorpromazine, haloperidol, and physostigmine did not reliably antagonize the pronounced reduction in social behavior. The second series of experiments focused on agonistic behavior in the context of resident-intruder confrontations and on affiliative behavior toward group members. d-Amphetamine (3 X 0.5 mg/kg) and, to a lesser extent, cocaine (3 X 10 mg/kg) decreased affiliative and agonistic behavior. Chlorpromazine (0.5, 1.0 mg/kg) and haloperidol (0.1, 0.25 mg/kg) did not block the severe disruption of the affiliative and agonistic behavior in amphetamine-treated monkeys; physostigmine (0.06 mg/kg) reversed the decline in time spent close to the familiar monkey in amphetamine-treated monkeys. By contrast, stimulant-induced stereotypies were effectively antagonized by chlorpromazine, haloperidol, and physostigmine. These results suggest that psychostimulant-induced changes in primate social behavior may be mediated by mechanisms other than those underlying motor stereotypies.