Larry D. Byrd

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.

Consequences of Opiate-Dependency in a Monkey Model of AIDS

In 1898, Cantacuzene (1) reported that rodent phagocytes exposed to morphine had reduced phagocytic and chemotactic activity in both in vitro and in vivo experimental systems. This work was carried out in the laboratory of the father of cell-mediated immunology, Elie Metchnikoff, and represents the first rigorous scientific study aimed at characterizing the immunological effects of opiates. About 10 years later, Archard et al., (2) corroborated the findings of Cantacuzene (1). By 1928, evidence indicating the immunomodulatory potential of opiates was reviewed by Terry and Pellens (3).

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

Abstract 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

Abstract 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, quipa- zine, 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 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.

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.

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 Parkinsons disease.

Physiological effects of cocaine in the squirrel monkey

Abstract Doses of cocaine that have previously been shown to have behavioral effects produced dose-related increases in arterial blood pressure, heart rate and core temperature in unanesthetized squirrel monkeys ( Saimiri sciureus ). The pressor effect was immediate, but heart rate increased more gradually after cocaine injection. The onset of hyperthermia was substantially delayed. The squirrel monkey may be a good animal model of the physiological concomitants of cocaine abuse in humans.

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.

Prenatal Exposure to Cocaine

Publisher Summary Cocaine has been the focus of considerable scientific attention in recent years due to its increased use in North America. In the United States, it is estimated that more than 30 million people have tried cocaine, and up to 8 million use it regularly. The amount of exposure that a fetus may receive when the mother uses cocaine is critical in assessing whether there may be significant risks. Many of the lifestyle and socio-economic factors that are correlated with the use of cocaine may produce gestational effects on their own, or interact with cocaines effects on gestation. A considerable number of epidemiological studies are conducted that attempt to ascertain more directly the role of cocaine exposure during pregnancy. Long-term learning deficits and changes in unlearned behaviors following utero exposure to multiple daily doses of cocaine during different exposure periods and maternal plasma cocaine concentrations have been elucidated in this chapter. An advantage of using nonhuman subjects is that the Central Nervous System (CNS) structure and function can be observed more directly through various invasive techniques.