Effects of morphine on T-cell recirculation in rhesus monkeys.

A 2-yr study on effects of morphine on lymphocyte circulation in rhesus monkeys (Macaca mulatta) showed that, over time, a well-maintained morphine-dependency caused biphasic depressive effects on circulating lymphocyte levels. Depression of T cell circulation by opiates actually was a relative effect. Morphine exposure basically stabilized T cell circulation in the context of concurrent increases in controls. Biphasic effects of morphine were attributable to distinctions in circulation kinetics of CD4+/CD62L (+ & -) T cells. That is, levels of CD4+/CD62L+ T cells were selectively depressed by opiates through the first 32wk after initiation of drug, and levels of CD4+/CD62L- T cells were selectively depressed thereafter. Regression analyses also showed that morphine stabilized lymphocyte recirculation. Circulating levels of resting and activated-memory types of T cells were positively correlated in opiate-exposed monkeys during the first 32wk after opiate exposure--an effect not seen with control monkeys. Considerations of changes in the types of experimental stressors extant during the study suggested that temporally differential effects of opiates on T cell recirculation were connected with changes in the stress environment and the ability of morphine to modulate these changes. Thus, morphine, and by inference the endogenous opioid system, are involved in homeostasis of lymphocyte recirculation, probably through effects on central mediation of the stress axis.

Fetal development in rhesus monkeys exposed prenatally to cocaine.

Using a timed-breeding protocol, one group of female rhesus monkeys was implanted subcutaneously with osmotic minipumps containing 0.3 mg/kg/h cocaine (N=18) or saline (N=18) from day 24 postconception through gestation. Another group received cocaine (N=12) or saline (N=8) from conception through day 42 of gestation. Mean levels of cocaine in maternal serum were approximately 150 ng/ml during pregnancy. A total of 56 pregnancies were documented in 42 adult monkeys, and 39 pregnancies completed full-term. Maternal food consumption and body weight increased during pregnancy, and there were no significant differences among experimental groups. Although both groups with a history of cocaine exposure had lower survival rates compared to pair-fed controls, of the fetuses that survived, fetal heart rate, fetal biparietal diameter, and mean gestational length were in the normal range for all experimental groups. Similarly, body weight, biparietal diameter, body length, and modified Apgar scores at birth did not differ significantly among experimental groups. The results indicate that surviving fetuses exhibited normal growth.

Behavioral evaluation of hemiparkinsonian MPTP monkeys following dopamine pharmacological manipulation and adrenal co-graft transplantation.

Bradykinesia and rigidity are the symptoms that most directly correlate with loss of striatal dopamine in Parkinson's disease. In the hemiparkinsonian (HP) monkey, this is represented by paucity of movement as measured by coli puterized movement analysis, diminished manual dexterity on clinical examination, and diminished performance on operant behavioral tasks. The present study used an MPTP-induced HP model in rhesus monkeys to evaluate the effectiveness of adrenal medullary and peripheral nerve co-grafts in diminishing parkinsonian symptoms. Unoperated controls (N = 4), surgical controls with caudate lesioning (N = 4), and caudate co-grafted (N = 4) HP monkeys demonstrated diminished movement in the home cage following MPTP. This behavior persisted in unoperated controls, but improved in both surgical control and co-grafted monkeys. Functional hand dexterity evaluations demonstrated similar impairment in all three groups but only surgical controls and co-grafted monkeys demonstrated improvement. In general, rotational behavior in response to apomorphine was consistent with recovery of function in surgical controls and co grafted monkeys, but marked between-subject variability precluded group statistical analyses. None of the monkeys could perform the operant task using the affected limb following MPTP. However, the performance of two co-grafted animals demonstrated partial recovery. L-dopa improved operant performance, demonstrating a dopaminergic component to the task. The results demonstrate recovery of behavioral function after surgical treatment, with adrenal co-grafted monkeys showing the greatest degree of improvement.

Serotonergic modulation of the discriminative-stimulus effects of cocaine in squirrel monkeys.

In order to investigate the potential modulatory role of serotonin on the discriminative-stimulus effects of cocaine, two groups of squirrel monkeys were trained to discriminate 0.3 mg/kg or 1.0 mg/kg cocaine and saline under a two-lever drug-discrimination procedure. Substitution of a range of cocaine doses (0.03-1.7 mg/kg) occasioned orderly, dose-dependent increases in cocaine-lever responding. When administered alone, the non-selective serotonin direct agonist, quipazine, also occasioned increases in cocaine-lever responding which were more pronounced in subjects trained with the lower cocaine dose. When quipazine was administered in combination with cocaine, there was an increase in cocaine-lever responding, indicating an additive effect. The serotonin uptake inhibitor, fluoxetine, occasioned saline-lever responding when administered alone. However, in combination with cocaine, fluoxetine enhanced the discriminative effects of cocaine in subjects trained at the lower cocaine dose. The 5-HT2-selective antagonists, ketanserin and ritanserin, did not occasion cocaine-lever responding when administered alone. In combination with cocaine, ketanserin attenuated the discriminative effects of cocaine in most subjects, and ritanserin attenuated the discriminative effects of cocaine in subjects trained at the higher dose. These results indicate that the discriminative-stimulus effects of cocaine may be increased by direct- and indirect-acting serotonin agonists and attenuated by serotonin antagonists in squirrel monkeys.

Pharmacological interactions between serotonin and dopamine on behavior in the squirrel monkey.

The behavioral effects of GBR 12909, a selective dopamine uptake inhibitor, were determined in squirrel monkeys trained to respond under a fixed-interval (FI) schedule of stimulus termination and a second-order schedule of IV drug self-administration. Intermediate doses of GBR 12909 increased FI response rate markedly, and the highest dose decreased response rate below control values. The 5HT uptake inhibitors, alaproclate and fluoxetine, and the 5HT agonist, quipazine, attenuated the behavioral-stimulant effects of GBR 12909, whereas the 5HT2A/2C antagonist, ritanserin, enhanced the behavioral-stimulant effects of the lowest dose. GBR 12909 reliably maintained self-administration, and ritanserin increased response rate maintained by the highest dose. The dopamine agonist, quinpirole, increased FI response rate in only one of three subjects, and ritanserin enhanced the behavioral-stimulant effects of quinpirole in that subject. The dopamine agonist, apomorphine, only decreased FI response rate, and ritanserin did not alter its behavioral effects. The pharmacological profile of GBR 12909 administered alone and in combination with selective 5HT drugs in the present study was similar to that obtained previously with cocaine, further demonstrating that 5HT can reliably modulate the behavioral effects of psychomotor stimulants with prominent dopaminergic actions.

Serotonergic modulation of the behavioral effects of cocaine in the squirrel monkey.

The behavioral effects of cocaine (0.03-3.0 mg/kg) and several selective serotonin (5HT) uptake inhibitors, direct agonists and antagonists were determined in squirrel monkeys trained to respond under a fixed-interval (FI) schedule of stimulus termination and a second-order schedule of i.v. drug self-administration. Intermediate doses of cocaine increased fixed-interval response rate markedly, and higher doses decreased response rate below control (nondrug) values. The i.v. self-administration of cocaine (0.025-1.0 mg/injection) maintained schedule-appropriate responding over a range of doses, and response rate under the second-order schedule was a function of drug dose. In contrast, none of the 5HT uptake inhibitors (alaproclate, clomipramine and fluoxetine) or direct agonists ((+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane, (+/-)-8-hydroxy-2-(di-N-propylamino) tetralin and quipazine) increased fixed-interval response rate, nor did the 5HT uptake inhibitors maintain self-administration. In drug interaction studies, the 5HT uptake inhibitors and quipazine produced an insurmountable attenuation of the behavioral-stimulant effects of cocaine, whereas the 5HT antagonists (ketanserin, mianserin and ritanserin) with high affinity for 5HT2 binding sites enhanced the behavioral-stimulant effects of low or intermediate doses of cocaine. Additionally, administration of ritanserin increased response rate for i.v. for self-administration of cocaine over a range of cocaine doses. The pharmacological profile of effects of selective 5HT uptake inhibitors and direct agonists indicates that the behavioral-stimulant and reinforcing effects of cocaine do not depend on inhibition of 5HT uptake, whereas the drug interactions suggest that the serotonergic system can modulate specific behavioral effects of cocaine.

Effects of CGS 15943, a nonxanthine adenosine antagonist, on behavior in the squirrel monkey.

The behavioral effects of CGS 15943 (0.1-3.0 mg/kg), a nonxanthine adenosine antagonist lacking phosphodiesterase (PDE) inhibitory effects, and caffeine (1.0-30.0 mg/kg), a xanthine adenosine antagonist with PDE inhibitory effects, were compared in squirrel monkeys trained to lever-press under fixed interval (FI) schedules of food presentation or stimulus termination. Both adenosine antagonists increased FI response rates after i.m. or i.v. administration, with CGS 15943 being more efficacious and approximately 3 to 10 times more potent than caffeine. Moreover, the rate-increasing effects of caffeine were enhanced by CGS 15943 (0.3 and 1.0 mg/kg) pretreatment. In contrast, rolipram (0.01-0.1 mg/kg), a potent PDE inhibitor lacking adenosine-antagonist effects, only decreased response rates. The nonselective adenosine agonist, 5'-N-ethylcarboxamidadenosine (0.003-0.03 mg/kg), the A1-selective adenosine agonists, N6-cyclopentyladenosine (0.1-1.0 mg/kg) and N6-cyclohexyladenosine (0.1-1.0 mg/kg) and the A2-selective adenosine agonist, CGS 21680 (0.03-0.3 mg/kg), produced dose-dependent decreases in response rates that were attenuated by CGS 15943 and caffeine. The potency difference between CGS 15943 and caffeine as antagonists of 5'-N-ethylcarboxamidadenosine, N6-cyclopentyladenosine and N6-cyclohexyladenosine corresponded to the potency difference of the two drugs for increasing FI response rates. In contrast, CGS 15943 and caffeine were approximately equipotent as antagonists of CGS 21680. The similarity of the effects of CGS 15943 and caffeine supports and extends previous findings suggesting that the behavioral-stimulant effects of caffeine and other xanthines are mediated through adenosine-antagonist actions rather than inhibition of PDE activity.

In utero exposure to cocaine: a review.

Cocaine is now regarded as one of the most dangerous illicit drugs available today. A disturbing trend in the pattern of cocaine use is that groups long considered unlikely to be involved in drug use, including women of childbearing age, pregnant women, the pediatric age group, fetuses, and neonates, are showing an alarming increase in cocaine exposure. Substantial data have been derived from clinical observations, clinical studies, and animal studies indicating that prenatal exposure to cocaine may have detrimental short-term and possibly long-term effects on the mother, the developing fetus, and the neonate. The effects attributed to cocaine may, however, be due to other substances (eg, alcohol) ingested by the drug-using woman, to prematurity, or to the environmental chaos in which the infant must develop. Prospective controlled studies are needed to define further the effects of cocaine as distinct from other negative influences having an impact on the developing fetus, the newborn, or the infant.

Enhanced sensitivity to the behavioral effects of cocaine after chronic administration of D2-selective dopamine antagonists in the squirrel monkey.

The behavioral effects of cocaine (0.03-3.0 mg/kg i.v.) were determined in squirrel monkeys (Saimiri sciureus) trained to respond under a fixed-interval 300-sec schedule of stimulus termination. A session consisted of 13 consecutive fixed-interval components, each followed by a 60-sec timeout. Graded doses of cocaine were injected during selected timeout periods using a cumulative-dosing procedure. Subsequently, two dopamine D2-selective antagonists, spiperone and raclopride, and a D1-selective antagonist, SCH 23390, were administered chronically for a 2-week period. Due to pronounced time course differences, raclopride and SCH 23390 were infused continuously via osmotic minipump, and spiperone was administered i.m. twice per week. Spiperone and raclopride markedly suppressed responding during the 2-week period. When the effects of cocaine were redetermined 3 days after spiperone or 1 day after raclopride administration was terminated, there was a parallel leftward shift in the dose-effect curve, indicating enhanced sensitivity to cocaine. Three days later, sensitivity to cocaine had changed and was similar to that obtained before chronic drug administration. In contrast, SCH 23390 did not alter sensitivity to cocaine after chronic administration was terminated, even though it did attenuate the behavioral effects of cocaine as effectively as spiperone and raclopride. Chronic administration of spiperone did not alter sensitivity to nisoxetine, a norepinephrine uptake inhibitor, or quipazine, a serotonin agonist. The acute administration of spiperone in combination with cocaine also differed markedly from nisoxetine and quipazine. The pronounced rate-decreasing effect of spiperone was attenuated by cocaine in a dose-dependent manner, but not by nisoxetine or quipazine.(ABSTRACT TRUNCATED AT 250 WORDS)

A method for quantitating motor deficits in a nonhuman primate following MPTP-induced hemiparkinsonism and co-grafting.

This report describes a nonhuman primate model of MPTP-induced hemiparkinsonism and the recovery of motor function following co-grafting of adrenal medullary tissue and peripheral nerve into the lesioned area of the brain. A rhesus monkey (Macaca mulatta) trained to perform a complex, discrete-trial, operant task served as the subject. After behavioral performance on the task had stabilized and a high level of accuracy was maintained, 0.4 mg/kg MPTP was infused acutely via the left carotid artery to produce a marked impairment of movement of the right arm. Eighteen weeks later, medullary tissue from the left adrenal gland was grafted along with peripheral nerve into the left caudate nucleus. During the original baseline training condition, right- and left-hand performances were comparable on all dependent measures. However, right-hand performance was severely impaired following unilateral MPTP treatment, and left-hand performance was unaffected. Right-hand performance recovered only after adrenal medullary tissue was transplanted with peripheral nerve into the brain. Neuroanatomical analysis of brain tissue showed the anticipated neuronal loss in the left substantia nigra due to MPTP administration and evidence of adrenal medullary cell survival in the area of the co-graft. The data demonstrate that the rhesus monkey and the behavioral task developed during this study can be efficacious in characterizing the effects of MPTP on psychomotor function and in assessing the outcome of new strategies for treating Parkinson's disease.

Characterization of the effects of cocaine and GBR 12909, a dopamine uptake inhibitor, on behavior in the squirrel monkey.

The behavioral effects of cocaine and GBR 12909, a highly selective dopamine uptake inhibitor, were compared in squirrel monkeys trained to respond under a fixed-interval schedule of stimulus termination and a second-order schedule of drug self-administration. Both drugs exhibited similar pharmacological profiles; intermediate doses increased response rates markedly and higher doses decreased response rates below control values. The magnitude of the rate-increasing effect was similar for cocaine and GBR 12909, although cocaine was approximately 3 times more potent. In contrast, the direct-acting dopamine agonists, SKF 38393 and quinpirole, produced only decreases in response rates. When cocaine and GBR 12909 were studied in combination with dopamine antagonists, the effects of either on fixed-interval performance were attenuated in a similar manner by a D1-selective antagonist (SCH 23390) and a D2-selective antagonist (spiperone), indicating the involvement of both D1 and D2 receptor subtypes. In contrast, an alpha 1-selective antagonist (prazosin) did not alter the dose-effect curve for cocaine or GBR 12909 in a manner that indicated a pharmacological antagonism. When doses of cocaine were administered in combination with GBR 12909, the effects on behavior were additive. However, the combined effects of cocaine and SKF 38393 or cocaine and quinpirole were more complex and did not appear to be additive. When the cocaine or GBR 12909 was self-administered under a second-order, fixed-interval schedule of drug injection, schedule-appropriate responding was maintained and the potency difference between the two drugs was comparable to that observed under the stimulus-termination schedule.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of dominance rank on d-amphetamine-induced increases in aggression.

Previous research has suggested that certain social factors, e.g., dominance rank, can determine the behavioral effects of drugs in individual members of a social group. In the present experiment, the effects of d-amphetamine were studied in two adult male monkeys with dominance rankings that changed during a reorganization of the social hierarchy in a captive group of stumptail macaques (Macaca arctoides). A range of doses of d-amphetamine was administered to each subject, and dose-effect curves were determined before and after group reorganization and stabilization. The data revealed drug effects which were dependent upon dose and the social rank of the animals. When either subject occupied the highest ranking or alpha position within the dominance hierarchy, rate of aggressive behavior initiated by the subject was several times greater than when that monkey occupied a lower position within the dominance hierarchy. Moreover, for either subject, the dose-effect curve was shifted to the right when the monkey was highest in the dominance hierarchy. Finally, aggression initiated by the drug-treated subject was directed more frequently toward adult members of the group when the subject was highest in the hierarchy and toward nonadult animals when the subject was lower in the hierarchy. These data support the hypothesis that the dominance position of an animal in a group can be a determinant of the behavioral effect of certain drugs.

Differential effects of cocaine and pentobarbital on fixed-interval and random-interval performance.

Reports have indicated that the behavioral effects of a drug can be related to the nondrug control rate of behavior in the absence of the drug. To investigate the purported relationship between control rate and drug rate, squirrel monkeys were trained under a fixed-interval 300-s schedule of stimulus-shock termination, a procedure that engendered a wide range of response rates. A light illuminated the experimental chamber during the fixed interval, and the first lever press after 300 s had elapsed terminated the light for 30 s and precluded an electrical stimulus to the tail. Following acute intramuscular administration of cocaine (0.03-0.56 mg/kg), overall rate increased and different control rates of responding, during different parts of the fixed interval, converged toward a common rate. Subsequently, the schedule was changed to a multiple fixed-interval 300-s random-interval 300-s schedule; performance during the random-interval component was characterized by steady responding at a uniformly high rate. Analysis of fixed-interval and random-interval performances following acute cocaine administration revealed convergence of response rates toward a common, uniform rate. Pentobarbital (0.3-10.0 mg/kg) only decreased overall rate, and different control rates of responding during the fixed interval did not converge toward a common rate. The results indicate that this type of analysis can be useful in comparing pharmacological agents from different classes and that the rate at which responding becomes uniform can provide a quantitative behavioral end point for characterizing drug effects on behavior.

Behavioral effects of phencyclidine and ketamine alone and in combination with other drugs.

The behavioral effects of phencyclidine (PCP) and ketamine administered alone and in combination with naloxone, atropine, methyl atropine, chlorpromazine and d-amphetamine were studied in squirrel monkeys trained to press a response lever under a fixed-ratio 30 schedule maintained by the termination of a stimulus associated with electric shock presentation. Under non-drug conditions, a period of high-rate responding in the presence of the stimulus associated with shock presentation was followed by a period of no responding during a 40-s timeout scheduled between fixed-ratio components. Mean rates of responding during fixed-ratio components decreased monotonically as PCP dose increased from 0.1 to 0.56 mg/kg, and doses of 3.0 and 5.6 mg/kg ketamine produced decreases in mean response rate comparable to doses of 0.3 and 0.56 mg/kg PCP. The dose-effect functions revealed that ketamine was approximately one-tenth as potent as PCP. The present data also characterized the time-course effects of PCP and ketamine, with the former having effects that were slower in onset yet more persistent in time. None of the drugs studied in combination with PCP and ketamine provided evidence of a pharmacological antagonism of the behavioral effects of the latter two drugs. Rather, the data indicated an enhancement of behavioral effects when certain drug combinations were studied.

Extracellular dopamine in rat striatum following uptake inhibition by cocaine, nomifensine and benztropine.

A microdialysis/smallbore chromatographic system was used to monitor changes in extracellular dopamine concentration in the striatum of the rat following administration of drugs that block catecholamine uptake. Analysis of 0.5 microliter of dialysate every 5 min showed dose-dependent elevations in extracellular dopamine following systemic administration of nomifensine (1 and 10 mg/kg), benztropine (5 and 25 mg/kg) and cocaine (3, 10 and 30 mg/kg). The order of potency in vivo was nomifensine greater than cocaine greater than benztropine. The short sampling interval allows accurate temporal profiles following pharmacological manipulations to be acquired.

Effects of phencyclidine and ketamine on cardiovascular activity and temperature in the squirrel monkey.

Heart rate (HR), mean arterial blood pressure (BP) and core temperature (TEMP) were recorded from chair-restrained squirrel monkeys surgically prepared with chronically indwelling arterial and venous catheters to determine the effects of acute intravenous (i.v.) injections of phencyclidine and ketamine and intramuscular (i.m.) injections of ketamine. Phencyclidine (0.03-3.0 mg/kg) and ketamine (0.3-30.0 mg/kg) i.v. increased BP and decreased TEMP, and the changes in BP and in TEMP were greater in magnitude and duration after phencyclidine. Heart rate also increased monotonically after 0.03-0.3 mg/kg phencyclidine or 0.3-10.0 mg/kg ketamine, but the effects of higher doses of either drug were biphasic with decreases followed by increases in HR. When either of two doses of ketamine (10.0 and 30.0 mg/kg) was injected i.m., the effects were qualitatively similar to those observed after i.v. administration although of much less magnitude, and there was no evidence of a biphasic change in HR. The data show that these two dissociative anesthetics differ in duration of action and in magnitude of effect on cardiovascular activity and core temperature in the squirrel monkey, and that phencyclidine is approximately ten times as potent as ketamine.

Similarities in the rate-altering effects of white noise and cocaine.

The effects of white noise and cocaine on squirrel monkeys' fixed-interval responding were compared to determine whether the presentation of an exteroceptive stimulus could produce rate-altering effects of the type typically observed following drug administration. To investigate the relationship between control response rate and response rate in the presence of drug or noise, the monkeys were trained under a fixed-interval 300-s stimulus-shock termination schedule in order to generate a wide range of local response rates. A light illuminated the experimental chamber during the interval and, after 300 s elapsed, a lever press during a 3-s period terminated the light and precluded the occurrence of a harmless electrical stimulus that otherwise was delivered at the end of the 3-s period. Each interval was followed by a 30-s timeout during which the chamber was darkened and responses had no consequences. Following intramuscular administration of cocaine, different rates of responding characteristic of control performance converged toward a common rate and, at an appropriately high dose, response rate during the fixed interval became more uniform. When white noise was presented continuously during a given session, different response rates also converged toward a common rate and, at an appropriate intensity, response rate became more uniform. Interactions were obtained when cocaine and white noise were presented together, indicating the possibility of a common behavioral mechanism of action. The results suggest that rate-altering drug effects may be, in part, a result of the ability of drugs to produce nonspecific stimulus effects similar to those observed for exteroceptive stimuli.

Effects of d-amphetamine on grooming and proximity in stumptail macaques: differential effects on social bonds.

An experiment was conducted to determine the effects of d-amphetamine on the expression of certain social behaviors, i.e., grooming and proximity, initiated by adult male stumptail macaques living in a large group comprised of both sexes and all ages. Traditionally, grooming behavior and proximity behavior have been considered indicators of social affinity. Under the non-drug conditions of the present study, the two types of behaviors were initiated in greatly different proportions toward individual members of the group. The acute administration of d-amphetamine (0.01-0.3 mg/kg IM) resulted in marked increases in the rate of self-grooming, i.e., the number of self-grooming bouts initiated per hour, for all subjects and in decreases in the rate at which subjects groomed other monkeys, but the drug appeared to have no effect on the rate at which a subject positioned itself near another monkey (proximity). Consequently, the drug had different effects on the two relationships represented by grooming behavior and proximity behavior. Drug administration also produced changes in the distribution of grooming and proximity initiated by the subjects toward various classes of interactants in the group. Furthermore, the changes were not of the same magnitude for the two behaviors. These data provide additional evidence that different group members receive differential behavioral interactions from drugged subjects.