Susan H. Nader

Social dominance in monkeys: Dopamine D2 receptors and cocaine self-administration

Disruption of the dopaminergic system has been implicated in the etiology of many pathological conditions, including drug addiction. Here we used positron emission tomography (PET) imaging to study brain dopaminergic function in individually housed and in socially housed cynomolgus macaques (n = 20). Whereas the monkeys did not differ during individual housing, social housing increased the amount or availability of dopamine D2 receptors in dominant monkeys and produced no change in subordinate monkeys. These neurobiological changes had an important behavioral influence as demonstrated by the finding that cocaine functioned as a reinforcer in subordinate but not dominant monkeys. These data demonstrate that alterations in an organisms environment can produce profound biological changes that have important behavioral associations, including vulnerability to cocaine addiction.

PET imaging of dopamine D2 receptors during chronic cocaine self-administration in monkeys

Dopamine neurotransmission is associated with high susceptibility to cocaine abuse. Positron emission tomography was used in 12 rhesus macaques to determine if dopamine D2 receptor availability was associated with the rate of cocaine reinforcement, and to study changes in brain dopaminergic function during maintenance of and abstinence from cocaine. Baseline D2 receptor availability was negatively correlated with rates of cocaine self-administration. D2 receptor availability decreased by 15–20% within 1 week of initiating self-administration and remained reduced by ∼20% during 1 year of exposure. Long-term reductions in D2 receptor availability were observed, with decreases persisting for up to 1 year of abstinence in some monkeys. These data provide evidence for a predisposition to self-administer cocaine based on D2 receptor availability, and demonstrate that the brain dopamine system responds rapidly following cocaine exposure. Individual differences in the rate of recovery of D2 receptor function during abstinence were noted.

Effects of Cocaine Self-administration on Striatal Dopamine Systems in Rhesus Monkeys: Initial and Chronic Exposure

The purpose of this study was to examine the time course of changes in dopamine D1- and D2-like receptor densities in monkeys self-administering cocaine. Experimentally naïve adult male rhesus monkeys (n = 22) were divided into a food reinforcement group (n = 6), in which responding was maintained by food presentation, or into four cocaine self-administration groups (n = 4/group), based on dose (0.03 or 0.3 mg/kg per injection) and duration of exposure (5 or ˜100 sessions). After the last session, monkeys were euthanized, brains were removed, frozen, and coronal sections through the striatum, rostral to the anterior commissure, were processed for D1 ([3H]SCH23390) and D2 ([3H]raclopride) receptor autoradiography. Compared with controls, there was no effect of 5 days of cocaine self-administration on D1 and D2 receptors. In monkeys with extensive cocaine histories, D1 receptor densities were significantly increased relative to controls in some parts of the striatum, while D2 receptor densities were significantly decreased throughout the striatum. These findings demonstrate that chronic cocaine self-administration produces neuroadaptations in dopamine systems, but that these changes do not occur in a parallel fashion.

Chronic cocaine-mediated changes in non-human primate nucleus accumbens gene expression.

Chronic cocaine use elicits changes in the pattern of gene expression within reinforcement‐related, dopaminergic regions. cDNA hybridization arrays were used to illuminate cocaine‐regulated genes in the nucleus accumbens (NAcc) of non‐human primates (Macaca fascicularis; cynomolgus macaque), treated daily with escalating doses of cocaine over one year. Changes seen in mRNA levels by hybridization array analysis were confirmed at the level of protein (via specific immunoblots). Significantly up‐regulated genes included: protein kinase A α catalytic subunit (PKAcα); cell adhesion tyrosine kinase beta (PYK2); mitogen activated protein kinase kinase 1 (MEK1); and β‐catenin. While some of these changes exist in previously described cocaine‐responsive models, others are novel to any model of cocaine use. All of these adaptive responses coexist within a signaling scheme that could account for known inductions of genes(e.g. fos and jun proteins, and cyclic AMP response element binding protein) previously shown to be relevant to cocaines behavioral actions. The complete data set from this experiment has been posted to the newly created Drug and Alcohol Abuse Array Data Consortium (http://www.arraydata.org) for mining by the general research community.

Predictors of social status in cynomolgus monkeys (Macaca fascicularis) after group formation

The purpose of the present study was to determine whether various behavioral and hormonal markers obtained in individually housed monkeys would be predictive of social rank following group housing. Body weight, serum cortisol and testosterone levels, and locomotor activity in an open‐field apparatus were examined in 20 experimentally naive male cynomolgus monkeys (Macaca fascicularis) while they were individually housed. It was hypothesized that eventual subordinate monkeys would have higher cortisol levels and increased locomotor activity scores. These monkeys were then placed in social groups of four (five pens of four monkeys), and social rank was determined based on outcomes of dyadic agonistic encounters. Body weight correlated significantly with eventual social rank. In general, the heavier the monkey the higher the social rank. Locomotor activity in an open‐field apparatus following administration of a low dose of cocaine (0.01 mg/kg, i.v.), which has been shown to increase CNS dopamine, correlated with eventual social rank such that individually housed monkeys with high levels of locomotion were more likely to become subordinate. Serum cortisol and testosterone levels failed to correlate with eventual social rank. Hypothalamic‐pituitary feedback sensitivity and adrenal responsiveness were examined by measuring cortisol levels after administration of dexamethasone and following ACTH challenge. Cortisol responses in these tests were not associated with eventual social rank. These results suggest that, in addition to body weight, the level of reactivity in a novel environment after administration of a low dose of cocaine is a potential trait marker for social rank. This trait is apparently not associated with hormone levels, but may involve other CNS mechanisms. Am. J. Primatol. 52:115–131, 2000.

Effect of Menstrual Cycle Phase on Dopamine D2 Receptor Availability in Female Cynomolgus Monkeys

Sex differences have been reported in a variety of affective and neurodegenerative disorders that involve dysfunctional dopamine (DA) neurotransmission. In addition, there is evidence for differences in sensitivity to the abuse-related effects of psychostimulants across the menstrual cycle which may result from effects of ovarian hormones on DA function. The goal of the present study was to extend previous work examining menstrual cycle-related changes in DA D2 receptor availability in humans to drug-naive female cynomolgus monkeys (n=7) using the selective D2-like receptor ligand [18F]fluoroclebopride (FCP) and a high-resolution microPET P4 scanner. Menstrual cycle phase was characterized by daily vaginal swabs and measurements of serum progesterone levels. PET studies were conducted once during the luteal phase and once during the follicular phase. Regions of interest in the caudate nucleus, putamen, and cerebellum were defined on coregistered MRIs. Distribution volumes were calculated for FCP in each structure and the distribution volume ratio (DVR) for both brain regions relative to the cerebellum was used as a measure of D2 receptor availability. FCP DVRs were significantly higher in the luteal phase compared to the follicular phase in both the caudate nucleus (11.7% difference, p=0.02) and putamen (11.6% difference, p=0.03). These findings extend earlier work in humans and suggest that changes in DA receptor availability may be involved in the variation in symptoms of various neuropsychiatric disorders across the menstrual cycle, including differences in sensitivity to the abuse-related effects of stimulants.

Social Dominance in Female Monkeys: Dopamine Receptor Function and Cocaine Reinforcement

BACKGROUND Brain imaging and behavioral studies suggest an inverse relationship between dopamine (DA) D2/D3 receptors and vulnerability to cocaine abuse, although most research has used males. For example, male monkeys that become dominant in a social group have significant elevations in D2/D3 receptor availability and are less vulnerable to cocaine reinforcement. METHODS DA D2/D3 receptor availability was assessed in female cynomolgus monkeys (n = 16) with positron emission tomography (PET) while they were individually housed, 3 months after stable social hierarchies had formed, and again when individually housed. In addition, PET was used to examine changes in dopamine transporter (DAT) availability after social hierarchy formation. After imaging studies were complete, monkeys received implantation with indwelling intravenous catheters and self-administered cocaine (.001-.1 mg/kg/injection) under a fixed-ratio 30 schedule of reinforcement. Acquisition of cocaine reinforcement occurred when response rates were significantly higher than when saline was self-administered. RESULTS Neither DAT nor D2/D3 receptor availability in the caudate nucleus and putamen was predictive of social rank, but both significantly changed after formation of social hierarchies. DA D2/D3 receptor availability significantly increased in females that became dominant, whereas DAT availability decreased in subordinate females. Dominant female monkeys acquired cocaine reinforcement at significantly lower doses than subordinate monkeys. CONCLUSIONS The relationship between D2/D3 receptor availability and vulnerability to cocaine reinforcement seems, on the basis of these findings, opposite in females and males. These data indicate that the social environment profoundly affects the DA system but does so in ways that have different functional consequences for females than for males.

Behavioral and neurobiological characteristics influencing social hierarchy formation in female cynomolgus monkeys.

Socially housed monkeys have been used as a model to study human diseases. The present study examined behavioral, physiological and neurochemical measures as predictors of social rank in 16 experimentally naïve, individually housed female cynomolgus monkeys (Macaca fascicularis). The two behavioral measures examined were novel object reactivity (NOR), as determined by latency to touch an opaque acrylic box placed in the home cage, and locomotor activity assessed in a novel open-field apparatus. Serum cortisol concentrations were evaluated three times per week for four consecutive weeks, and stress reactivity was assessed on one occasion by evaluating the cortisol response to adrenocorticotropic hormone (ACTH) following dexamethasone suppression. Measures of serotonin (5-HT) function included whole blood 5-HT (WBS) concentrations, cerebrospinal fluid (CSF) concentrations of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) and brain 5-HT transporter (SERT) availability obtained using positron emission tomography (PET). After baseline measures were obtained, monkeys were assigned to four social groups of four monkeys per group. The two measures that correlated with eventual social rank were CSF 5-HIAA concentrations, which were significantly higher in the animals who eventually became subordinate, and latency to touch the novel object, which was significantly lower in eventual subordinate monkeys. Measures of 5-HT function did not change as a consequence of social rank. These data suggest that levels of central 5-HIAA and measures of novel object reactivity may be trait markers that influence eventual social rank in female macaques.

Effects of Varenicline on the Reinforcing and Discriminative Stimulus Effects of Cocaine in Rhesus Monkeys

Varenicline is a low-efficacy, α4β2* subtype-selective nicotinic acetylcholine receptor (nAChR) agonist that has shown success in smoking cessation and promise in preclinical assessments relating to other drugs of abuse. The primary goal of the present study was to examine the effects of varenicline on cocaine self-administration and cocaine discrimination and compare these effects with those of the nAChR agonist nicotine and antagonist mecamylamine. One limitation of agonist treatments is the potential for abuse. Thus, a second goal was to examine the abuse potential of varenicline in rhesus monkeys. In the first experiment, rhesus monkeys (n = 3) were trained to self-administer cocaine (saline, 0.01–0.56 mg/kg) under a progressive-ratio schedule of reinforcement; monkeys also earned all of their food by responding on another lever under a fixed-ratio 50 schedule of reinforcement. Chronic administration of varenicline (0.01–0.56 mg/kg p.o., salt) potentiated the reinforcing effects of cocaine, whereas mecamylamine (0.3–1.7 mg/kg p.o, i.m., i.v., salt) had no significant effects on cocaine self-administration up to doses that disrupted food-maintained responding. Neither varenicline (0.01–0.17 mg/kg, salt) nor nicotine (0.01–0.1 mg/kg, base) functioned as reinforcers when substituted for cocaine. Finally, in monkeys trained to discriminate self-administered 0.3 mg/kg cocaine, varenicline (0.1–0.3 mg/kg i.v.) did not substitute for cocaine but, along with mecamylamine (0.3–1.7 mg/kg i.v.) and nicotine (0.03–0.1 mg/kg i.v.), potentiated the discriminative stimulus effects of cocaine. These results suggest that varenicline has low abuse liability in monkey models of cocaine abuse, but would not be an effective medication for cocaine addiction.

Nonhuman primate models of social behavior and cocaine abuse

RationaleAlthough cocaine is often abused in social situations, very few animal studies examine the effects of cocaine in the context of social behavior.ObjectivesThis review highlights studies investigating the behavioral effects of cocaine in the context of social housing conditions using nonhuman primates. In addition, this review presents recent findings examining the effects of self-administering cocaine on social behavior and the effects of manipulations hypothesized to be stressful or enriching on the interactions between cocaine reinforcement and social rank. The following dependent variables are examined: (1) cocaine-induced changes in social behavior and (2) cocaine self-administration in cynomolgus monkeys of varying social ranks. The independent variables examined include several environmental and pharmacological manipulations.ConclusionsThe studies reviewed here indicate that several variables can differentially affect cocaine self-administration when studied in a social context, rather than in individually housed animals. These variables include the social rank and sex of the individual, drug history, the nature of the “fear”-inducing manipulation, and the reliability of cortisol as an appropriate measure of “stress.” While the inclusion of socially housed animals necessitates larger sample sizes, animal models incorporating social behavior are more homologous to the human condition and should be implemented when possible.