Effects of morphine alone and in combination with naloxone or d-amphetamine on shock-maintained behavior in the squirrel monkey.

Key-pressing behavior in the squirrel monkey was maintained under an 8-min fixed-interval (FI) schedule of electric-shock delivery. The acute i.m. administration of morphine prior to a daily session decreased response rates at doses of 1.0--3.0 mg/kg but had little systematic effect on rate at doses of 0.03-0.3 mg/kg. When naloxone was administered concomitantly with morphine prior to a session, 0.01 mg/kg naloxone required a three-fold increase in the dose of morphine necessary to obtain decreased response rates, 0.1 mg/kg naloxone required a 30-fold increase in morphine, and 1.0 mg/kg required more than a 30-fold increase in morphine. Moreover, the administration of naloxone with morphine resulted in increased rates of responding at certain combinations of doses of the two drugs. The administration of d-amphetamine (0.03 or 0.1 mg/kg) alone increased mean response rates under the FI schedule; when combined with 0.03-0.3 mg/kg morphine the increases in responding were greater than obtained with d-amphetamine alone. The negative slope of the linear regression lines relating the effects of morphine to control rates of responding engendered under the FI schedule was decreased when morphine was combined with naloxone, but not with d-amphetamine. These results show that naloxone, but not d-amphetamine, can antagonize the response-rate decreasing effect of morphine when responding in the squirrel monkey is maintained by response-produced electric shock.

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 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.

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.

The behavioral effects of cocaine: rate dependency or rate constancy.

The behavioral effects of cocaine were studied in squirrel monkeys trained to press a response key under an 8-min fixed-interval (FI) schedule of electric shock presentation. Overall mean rate of responding increased at 0.03--0.3 mg/kg (i.m.) and decreased at 1.0--3.0 mg/kg. Increased responding during the initial and middle periods of the fixed-interval accounted for the increase in overall mean rate; response rate during the final two min of the interval did not increase at any dose. An analysis based on response rate during individual 1-min segments of the 8-min interval showed that the rate during the interval became more uniform, and the pattern of positively accelerated responding became more linear, as dose increased. At 0.3--1.0 mg/kg, response rate was relatively constant and independent of the control, pre-drug rate of responding.

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.

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.

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.

Cardiovascular effects of naloxone, naltrexone and morphine in the squirrel monkey.

Heart rate (HR) and mean arterial blood pressure (BP) were recorded from conscious, chair-restrained squirrel monkeys surgically prepared with chronically indwelling arterial and venous catheters to determine the effects of acute intravenous injections of two opiate antagonists and an agonist. Naloxone (0.3--10.0 mg/kg) or naltrexone (0.3--10.0 mg/kg) had little effect on HR or BP during a 30-minute post-injection period. Morphine (3.0--5.6 mg/kg) produced biphasic effects comprising an initial decrease followed by an increase in HR, and an increase followed by a decrease in BP. Lower morphine doses had lesser effects during a 100-minute post-injection period. Pretreatment with 0.03 mg/kg naloxone attenuated the depressive effect of morphine on HR and BP, but increases in HR and BP due to morphine were enhanced. Pretreatment with 0.3 mg/kg naloxone prevented morphine-induced decreases in HR and BP, yet increases in HR and BP persisted. In previous behavioral studies, morphine in combination with naloxone similarly increased rates of responding in the squirrel monkey. Together, these data suggest an effect of naloxone that goes beyond mere pharmacological antagonism of the effects of morphine.

Contrasting effects of d-amphetamine on affiliation and aggression in monkeys.

Amphetamine has been observed to alter conditioned or learned behavior in individually housed animals, as well as naturally-occurring behavior characteristic of animals living in groups. This study is concerned with the effects of d-amphetamine on affiliative and aggressive behavior in adult male stumptail macaques (Macaca arctoides) living in a large, heterogeneous social group. Using standardized observational techniques, the affiliative and aggressive behaviors initiated by five adult male monkeys were characterized and quantitated in the absence of and following drug administration. Acute administration of a range of doses of d-amphetamine (0.003-0.56 mg/kg) resulted in a monotonically depressive effect on the rate of affiliative behavior initiated by the experimental animals. In contrast, d-amphetamine increased the rate of aggressive behavior initiated by the highest- and lowest-ranking monkeys, and had little or no effect in the mid-ranking monkeys. These results show that d-amphetamine can have qualitatively different effects on affiliative and aggressive behavior in the same subjects. The results also provide evidence that the effects of d-amphetamine can be determined by the hierarchical or dominance position of the subject in the group.

d-Amphetamine induced changes in social interaction patterns.

The behavioral effects of d-amphetamine were studied in a group of stumptail macaques in a large outdoor enclosure. d-Amphetamine altered characteristic patterns of aggressive and affiliative behaviors in adult males that received the drug. Each monkey that received d-amphetamine increased its aggression toward non-adult animals in the group and decreased aggression toward adult members. In subjects for which genealogy was known, d-amphetamine increased aggression toward kin-related members of the group and decreased aggression toward non-kin monkeys. The effects of the drug on affiliative behaviors were less uniform and, therefore, less conclusive. Three subjects decreased affiliation and two increased affiliation toward non-adult monkeys. The results demonstrate that d-amphetamine can alter substantially the behavior of drug-treated members of a group and, in addition, that the drug can indirectly affect specific subsets of the group even though they did not receive the drug.

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.

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.

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.

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.

Responding in the cat maintained under response-independent electric shock and response-produced electric shock.

Key-pressing responses in the cat were maintained under conditions in which brief electric shock was first postponed by responses (avoidance), then periodically presented independently of responses, and finally produced by responses on a fixed-interval schedule of 15 min (FI 15-min). A steady rate of responding occurred under shock avoidance and under response-independent shock; positively accelerated responding was engendered by the FI 15-min schedule. A second experiment studied responding under second-order schedules composed of three FI 5-min components. Responding was suppressed when a stimulus was presented briefly at completion of each FI 5-min component and a shock followed the brief stimulus at completion of the third component. Responding was maintained when each of the first two components was completed either with or without presentation of a brief stimulus and a shock alone was presented at completion of the third FI 5-min component.

Responding in the pigeon under chained schedules of food presentation: the repetition of a stimulus during alternate components.

Key pecking in the pigeon was maintained under chained schedules in which the completion of one schedule component initiated the next component, and food was presented upon completion of a sequence of components. Under the chained schedules studied, a particular key color appeared during more than one component, and different key colors appeared during the other components. When seven 1-min fixed-interval components comprised a chained schedule and the response key was the same color during the first, third, fifth, and terminal components, patterns of positively accelerated responding were maintained during all but the first two components of each sequence. In general, response rates were always lowest during the first one or two components and highest during the terminal component when as few as three and as many as eight components comprised a schedule. Increasing the number of components from three to eight showed that response rate during a component increased when it was no longer one of the initial two components of the schedule, even though its temporal relation to food presentation had not changed. Finally, when seven components comprised a schedule and the response key was one color during the first, third, and fifth and a different color during the last component, response rates were low during the first five components and high during the last two components preceding food presentation.

Magnitude and duration of the effects of cocaine on conditioned and adjunctive behaviors in the chimpanzee.

Characteristic patterns of conditioned key-pressing were maintained in the chimpanzee under a multiple 30-response fixed-ratio, 10-minute fixed-interval schedule of food presentation. Adjunctive drinking occurred with regularity during the fixed-interval schedule and, with less frequency, during 1-minute timeout periods that followed each food presentation; drinking seldom occurred during the fixed-ratio schedule. Cocaine increased key pressing under the fixed-interval schedule at doses between .1 and 3.0 mg/kg, but adjunctive drinking and key pressing under the fixed-ratio schedule did not increase at any dose. Conditioned and adjunctive behaviors were disrupted and suppressed for different durations at 10,0 mg/kg, a dose which induced convulsive seizures within 10 minutes after intramuscular injection. A time-course analysis showed the magnitude and duration of the effects of cocaine on key pressing under the fixed-interval schedule and on adjunctive drinking to be dose-related. Moreover, a given dose of cocaine had diverse effects, depending on the behavior and the time since drug administration.