Kristin R. Carlson

Behavioral evidence for dopaminergic supersensitivity following chronic treatment with methadone or chlorpromazine in the guinea pig.

This study demonstrated the enhancement, as a consequence of prior chronic drug treatment, of two behaviors (stereotyped oral behaviors and open field locomotion) which are thought to depend primarily on the striatel dopamine system. Following a 5-week treatment with methadone (MD), chlorpromazine (CPZ), or saline, the dopamine agonist methamphetamine (MA) elicited more intense stereotypies in the MD and CPZ animals. After chronic treatment with MD, the MA-elicited stereotypies were reduced by an acute dose of MD. Stereotyped oral behaviors elicited by a stressful stimulus (foot shock) were enhanced in the MD animals both during and following chronic drug treatment. MA-elicited open field locomotion, measured 2 weeks following termination of chronic drug treatment, was enhanced in the MD and CPZ animals.

Behavioral supersensitivity to apomorphine following chronic narcotic treatment in the guinea pig

Male albino guinea pigs were treated for 3 weeks with methadone, morphine, haloperidol, or saline. One week and 5 weeks following termination of treatment they were challenged with the directly acting dopaminergic agonist apomorphine. At the week 1 test the haloperidol and saline groups did not differ, but behavioral supersensitivity was apparent in significantly elevated mean stereotypy scores of the methadone and morphine groups relative to the saline group. The source of differences in mean scores was a higher peak score rather than increased duration of action. At the week 5 test the scores of the methadone group were even higher, the morphine groups scores were equivalent to the saline groups, and the haloperidol groups scores were significantly depressed. This study indicates that a 3-week treatment period with methadone or morphine is sufficient to induce dopaminergic supersensitivity and suggests that there may be different time courses for the retention or expression of supersensitivity following these narcotics.

Supersensitivity to apomorphine and stress two years after chronic methadone treatment.

Abstract A rhesus monkey which had been withdrawn from oral methadone 26 months previously, and a control monkey, were challenged with the dopaminergic agonist apomorphine. The former-methadone monkey exhibited an intense and prolonged oral dyskinesia, whereas the control monkey showed milder limb movements. The former-methadone monkeys dyskin- esia was reinstated by the stress of being returned to the test cage 24 and 48 hr. later, but the control monkey did not react to this treatment. These results suggest a long-lasting supersensitivity of the striatal dopamine system induced by methadone.

Dyskinesias in monkeys: interaction of methamphetamine with prior methadone treatment.

Rhesus monkeys with a history of drinking methadone, but presently drug-free, were injected with low doses of methamphetamine (MA). They immediately developed oral dyskinesias resembling the symptoms of tardive dyskinesia in humans, a condition resulting from chronic blockade of striatal dopamine receptors by neuroleptics. Nine of 11 control monkeys failed to develop dyskinesias during prolonged MA administration. A stressful stimulus intensified the MA-elicited oral dyskinesias, an effect analogous to exacerbation of tardive dyskinesias by emotional stress. Control monkeys were then injected with methadone, chlorpromazine, haloperidol, or saline for 45 days. Ten days following this chronic treatment, MA immediately elicted oral dyskinesias in the methadone and chlorpromazine monkeys. Acute administration of the dopaminergic blocking agents chlorpromazine, spiroperidol, and clozapine eliminated MA-elicited dyskinesias, whereas the alpha-adrenergic blocker phentolamine was ineffective. Physostigmine blocked the dyskinesias in 1 of 2 cases. Sedative doses of phenobarbital and diazepam had no effect on oral dyskinesias. These data indicate that chronic treatment with methadone or other dopamine receptor blocking agents leads to receptor supersensitivity to the actions of MA.

A temporary restraint chair for monkeys.

Abstract A device for the rapid and safe restraint of macaque monkeys is described. After minimal training, animals will voluntarily position themselves in the device; no physical contact between animal and experimenter is necessary, and the chairing procedure requires only a few minutes. Various accessories permit using the chair in a variety of experimental situations.

Signal detection analysis of stimulus discrimination in normal and split-brain monkeys.

Abstract Five split-brain and 5 control monkeys were trained to perform a go, no-go discrimination between cutaneous stimulation at two arm locations, and subsequently retrained using the other arm. Cardiac and instrumental response latency data from various periods during training and retraining were analyzed in terms of signal detection theory, with the objective of determining the extent to which behavior is differentially controlled by the discriminative stimuli, uncontaminated by other factors affecting response bias. This analysis revealed that differential stimulus control was minimal early in training, and that its growth and final extent, as reflected by both cardiac and instrumental response latencies, were highly comparable between subjects. Differential stimulus control of both cardiac and instrumental responses reached maximum prior to the time each subject attained a conventional criterion of percentage correct responses; we attribute this discrepancy to the influence of response bias factors. At the beginning of retraining on the opposite body side, all control subjects and the two split-brain subjects trained on the left side and retrained on the right immediately displayed differential stimulus control of both cardiac and instrumental responses, whereas the other 3 split-brain subjects trained in the opposite sequence showed no transfer of differential stimulus control of either response. We conclude that this analysis revealed a functional asymmetry in the direction of information flow within the central nervous system which becomes apparent after callosal section.

Sensitivity to apomorphine in the guinea pig as a function of age and body weight

Male albino guinea pigs aged 4–10 weeks were challenged with 0.1, 0.2, and 0.4 mg/kg apomorphine. Mean stereotypy scores rose significantly as a function of age. Stereotypy scores were better correlated with age than with body weight, suggesting that CNS maturation, rather than weight-related factors, was responsible. Although age and body weight were correlated, there was enough variability to make body weight an unreliable indicator of age.

SUSCEPTIBILITY TO AMPHETAMINE-ELICITED DYSKINESIAS FOLLOWING CHRONIC METHADONE TREATMENT IN MONKEYS*

Eight rhesus monkeys that had drunk subdependence-producing doses of methadone daily for 10-22 months, and had subsequently been drug-free for 2-17 months, were injected with low doses of methamphetamine (MA). They immediately exhibited oral dyskinesias resembling the symptoms of tardive dyskinesia in humans, a condition resulting from chronic blockade of striatal dopamine receptors by neuroleptics. Eleven control monkeys failed to develop dyskinesias during prolonged MA administration. Control monkeys then received parenteral methadone, chlorpromazine, haloperidol, or saline for 45 days. Upon subsequent retest with MA, the methadone and chlorpromazine monkeys immediately displayed oral dyskinesias. Dopaminergic antagonists blocked MA-elicited dyskinesis, whereas neither a noradrenergic blocker nor sedative doses of phenobarbital and diazepam had any effect on dyskinesias. We suggest that receptor supersensitivity is produced by chronic treatment with methadone or other dopamine receptor blockers. Following treatment, stimulation of hypersensitive striatal receptors by the dopamine released by MA results in oral dyskinesias. The clinical implications for methadone maintenance treatment program patients are discussed.

Visual discrimination learning of random figure problems by rhesus monkeys

In a two-choice discrimination learning paradigm, a U-shaped function was found between trials to criterion and the number of sides comprising the random figure discriminanda. These data are consistent with results from human Ss and suggest similar information processing capabilities in the two species. Changing the orientation of the stimulus figures after the discrimination had been learned only partially disrupted subsequent discrimination performance. Any single difference in selected form attributes between the two figures comprising a problem was not a good predictor of learning speed, suggesting that monkeys use a combination of such factors.

Effects of oral methadone consumption on visual discrimination performance of the rhesus monkey

Monkeys which drank small doses, once daily, of methadone mixed with Tang orange drink were trained to perform a series of two-object visual discrimination problems. Their average number of trials to criterion was the same as that of normal monkeys, and they made the same number of errors on test trials in which the orientation of the stimulus objects was changed. Their average choice latencies, however, were significantly longer than those shown by the normal group. In a second experiment, on each trial Ss were given a decision interval to observe the stimulus objects. Latencies, as measured from the end of the interval, were the same for control and methadone-consuming monkeys. These data suggest that the previously elevated latencies were not due to motor or motivational lethargy, but to a drug-induced prolongation of the time necessary to decide which was the correct object.