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Brain imaging studies using positron emission tomography (PET) have shown that long-term cocaine use is associated with lower levels of dopamine (DA) D2/D3 receptors (D2/D3R); less consistent are the effects on DA transporter (DAT) availability. However, most studies have been conducted in male subjects (humans, monkeys, rodents). In this study, we used PET imaging in nine drug-naïve female cynomolgus monkeys to determine if baseline measures of DAT, with [ 18 F]FECNT, and D2/D3R availability, with [ 11 C]raclopride, in the caudate nucleus, putamen and ventral striatum were associated with rates of cocaine self-administration and if these measures changed during long-term (~13 months) cocaine self-administration and following time-off (3-9 months) from cocaine. Cocaine (0.2 mg/kg/injection) and 1.0 g food pellets were available under a multiple fixed-interval (FI) 3-min schedule of reinforcement. In contrast to what has been observed in male monkeys, baseline D2/D3R availability was positively correlated with rates of cocaine self-administration only during the first week of exposure; DAT availability did not correlate with cocaine self-administration. D2/D3R availability decreased ~20% following cumulative intakes of 100 and 1000 mg/kg cocaine; DAT availability did not significantly change. These reductions in D2/D3R availability did not recover over 9 months of time-off from cocaine. To determine if these reductions were reversible, three monkeys were implanted with osmotic pumps that delivered raclopride for 30 days. We found that chronic treatment with the D2/D3R antagonist raclopride increased D2/D3R availability in the ventral striatum but not in the other regions when compared to baseline levels. Over 13 months of self-administration, tolerance did not develop to the rate-decreasing effects of self-administered cocaine on food-reinforced responding, but number of injections and cocaine intake significantly increased over the 13 months. These data extend previous findings to female monkeys and suggest sex differences in the relationship between D2/D3R availability related to vulnerability and long-term cocaine use., (© 2023. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Identifying neurobiological characteristics that predict the development of cocaine use disorder would be of great value in prevention efforts. Because of their importance in mediating the abuse-related effects of cocaine, brain dopamine receptors are logical candidates for investigation. We analyzed data from two recently published studies that characterized availability of dopamine D2-like receptors (D2R) with [ 11 C]raclopride PET imaging and dopamine D 3 receptor (D 3 R) sensitivity with quinpirole-induced yawning in cocaine-naïve rhesus monkeys who subsequently acquired cocaine self-administration and completed a cocaine self-administration dose-effect curve. The present analysis compared D2R availability in several brain areas and characteristics of quinpirole-induced yawning, both acquired when monkeys were drug-naïve, with measures of initial sensitivity to cocaine. D2R availability in the caudate nucleus was negatively correlated with the ED 50 of the cocaine self-administration curve, although the significance of this relationship was driven by an outlier and was not present after the outlier was removed. No other significant associations were observed between D2R availability in any examined brain region and measures of sensitivity to cocaine reinforcement. However, there was a significant negative correlation between D 3 R sensitivity, represented by the ED 50 of the quinpirole-induced yawning curve, and the dose at which monkeys acquired cocaine self-administration. We also report no change from baseline D2R availability when a second PET scan was conducted after completion of the dose-effect curves. These data suggest the utility of D 3 R sensitivity, but not D2R availability, as a biomarker for vulnerability and resilience to cocaine. The well-established relationships between dopamine receptors and cocaine reinforcement in cocaine-experienced humans and animals may require extensive cocaine exposure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Previous studies in humans and in animals have shown dramatic effects of cocaine on measures of brain function that persist into abstinence. The purpose of this study was to examine the neurobiological consequences of abstinence from cocaine, using a model that removes the potential confound of cocaine cues. Adult male rhesus monkeys self-administered cocaine (0.3 mg/kg/injection; N = 8) during daily sessions or served as food-reinforcement controls (N = 4). Two times per week, monkeys were placed in a neutral environment and presented with a cartoon video for ~30 min, sometimes pre- and sometimes post-operant session, but no reinforcement was presented during the video. After ~100 sessions and when the cocaine groups had self-administered 900 mg/kg cocaine, the final experimental condition was a terminal 2-[ 14 C]-deoxyglucose procedure, which occurred in the neutral (cartoon video) environment; for half of the monkeys in each group, this occurred after 1 day of abstinence and for the others after 30 days of abstinence. Rates of local cerebral glucose metabolism were measured in 57 brain regions. Global rates of cerebral metabolism were significantly lower in animals 1 day and 30 days post-cocaine self-administration when compared to those of food-reinforced controls. Effects were larger in 30- vs. 1-day cocaine abstinence, especially in prefrontal, parietal and cingulate cortex, as well as dorsal striatum and thalamus. Because these measures were obtained from monkeys while in a neutral environment, the deficits in glucose utilization can be attributed to the consequences of cocaine exposure and not to effects of conditioned stimuli associated with cocaine., (© 2021. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Recent positron emission tomography (PET) studies of kappa opioid receptors (KOR) in humans reported significant relationships between KOR availability and social status, as well as cocaine choice. In monkey models, social status influences physiology, receptor pharmacology and behavior; these variables have been associated vulnerability to cocaine abuse. The present study utilized PET imaging to examine KOR availability in socially housed, cocaine-naïve female and male monkeys, and peripheral measures of KORs with neuron-derived extracellular vesicles (NDE). KOR availability was assessed in dominant and subordinate female and male cynomolgus macaques (N = 4/rank/sex), using PET imaging with the KOR selective agonist [ 11 C]EKAP. In addition, NDE from the plasma of socially housed monkeys (N = 13/sex; N = 6-7/rank) were isolated by immunocapture method and analyzed for OPRK1 protein expression by ELISA. We found significant interactions between sex and social rank in KOR availability across 12 of 15 brain regions. This was driven by female data, in which KOR availability was significantly higher in subordinate monkeys compared with dominant monkeys; the opposite relationship was observed among males, but not statistically significant. No sex or rank differences were observed for NDE OPRK1 concentrations. In summary, the relationship between brain KOR availability and social rank was different in female and male monkeys. This was particularly true in female monkeys. We hypothesize that lower [ 11 C]EKAP binding potentials were due to higher concentrations of circulating dynorphin, which is consistent with greater vulnerability in dominant compared with subordinate females. These findings suggest that the KOR is an important target for understanding the neurobiology associated with vulnerability to abused drugs and sex differences, and detectable in peripheral circulation., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Most individuals with cocaine use disorder also use alcohol; however, little is known about the behavioural and pharmacological mechanisms that promote co-abuse. For example, although studies in humans and animals have documented that chronic use of either alcohol or cocaine alone decreases D2-like receptor (D2R) availability, effects of co-abuse of these substances on dopamine receptor function have not been characterized. These studies examined the effects of long-term cocaine self-administration in 12 male rhesus monkeys who also consumed either ethanol or an ethanol-free solution each day (n = 6 per group). Specifically, all monkeys self-administered cocaine (0.1 mg/kg per injection) 5 days per week in the morning. In the afternoon, six monkeys consumed 2.0 g/kg ethanol over 1 h to model binge drinking and six monkeys drank an ethanol-free solution. Assessment of D2R availability using positron emission tomography (PET) and [ 11 C]raclopride occurred when monkeys were drug-naïve and again when monkeys had self-administered approximately 400-mg/kg cocaine. D 3 R function was assessed at the same time points by determining the potency of the D 3 R-preferring agonist quinpirole to elicit yawns. Chronic cocaine self-administration decreased D2R availability in subregions of the basal ganglia in control monkeys, but not those that also drank ethanol. In contrast, D 3 R sensitivity increased significantly after chronic cocaine self-administration in ethanol-drinking monkeys but not controls. These results suggest that co-use of ethanol substantially changes the effects of chronic cocaine self-administration on dopamine receptors, specifically implicating D 3 R as a target for medications in these individuals., (© 2022 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Cocaine use disorder has been reported to cause transgenerational effects. However, due to the lack of standardized biomarkers, the effects of cocaine use during pregnancy on postnatal development and long-term neurobiological and behavioral outcomes have not been investigated thoroughly. Therefore, in this study, we examined extracellular vesicles (EVs) in adult (~12 years old) female and male rhesus monkeys prenatally exposed to cocaine (n = 11) and controls (n = 9). EVs were isolated from the cerebrospinal fluid (CSF) and characterized for the surface expression of specific tetraspanins, concentration (particles/mL), size distribution, and cargo proteins by mass spectrometry (MS). Transmission electron microscopy following immunogold labeling for tetraspanins (CD63, CD9, and CD81) confirmed the successful isolation of EVs. Nanoparticle tracking analyses showed that the majority of the particles were <200 nm in size, suggesting an enrichment for small EVs (sEV). Interestingly, the prenatally cocaine-exposed group showed ~54% less EV concentration in CSF compared to the control group. For each group, MS analyses identified a number of proteins loaded in CSF-EVs, many of which are commonly listed in the ExoCarta database. Ingenuity pathway analysis (IPA) demonstrated the association of cargo EV proteins with canonical pathways, diseases and disorders, upstream regulators, and top enriched network. Lastly, significantly altered proteins between groups were similarly characterized by IPA, suggesting that prenatal cocaine exposure could be potentially associated with long-term neuroinflammation and risk for neurodegenerative diseases. Overall, these results indicate that CSF-EVs could potentially serve as biomarkers to assess the transgenerational adverse effects due to prenatal cocaine exposure.

It has been shown that exposure to cocaine can result in neuroinflammatory responses. Microglia, the resident CNS immune cells, undergo a transition to an activated state when challenged. In rodents, and possibly humans, cocaine exposure activates microglia. The goal of this study was to assess the extent and magnitude of microglial activation in rhesus monkeys with an extensive history of cocaine self-administration. Male rhesus monkeys (N = 4/group) were trained to respond on a fixed-interval 3-min schedule of food or 0.3 mg/kg/injection cocaine presentation (30 reinforcers/session) for 300 sessions. At the end of the final session, monkeys were administered 2-[ 14 C]deoxyglucose intravenously and 45 min later euthanized. Brain sections were used for autoradiographic assessments of glucose utilization and for microglia activation with [ 3 H]PK11195, a marker for the microglial 18-kDa translocator protein. There were no group differences in gray matter [ 3 H]PK11195 binding, while binding was significantly greater in cocaine self-administration animals as compared to food controls in 8 of the 11 white matter tracts measured at the striatal level. Binding did not differ from control at other levels. There were also significant increases in white matter local cerebral glucose utilization at the striatal level, which were positively correlated with [ 3 H]PK11195 binding. The present findings demonstrate an elevation in [ 3 H]PK11195 binding in forebrain white matter tracts of nonhuman primates with a prolonged history of cocaine self-administration. These elevations were also associated with greater cerebral metabolic rates. These data suggest that white matter deficits may contribute to behavioral, motivational, and cognitive impairments observed in cocaine abusers.

Background: A major goal of treatments for cocaine addiction is to reduce relapse-associated cravings, which are typically induced by environmental stimuli associated with cocaine use and related to changes in dopamine neurotransmission., Methods: The present study used an animal model of cocaine seeking to determine functional consequences of cue exposure using fluorodeoxyglucose positron emission tomography and to relate findings to juvenile levels of dopamine transporter and D 2 -like receptor availabilities determined before any drug exposure. Adult male rhesus monkeys (N = 11) self-administered cocaine (0.2 mg/kg per injection) under a second-order schedule of reinforcement, in which responding was maintained by conditioned reinforcers. Positron emission tomography scans assessing glucose utilization, a marker of functional activation, were conducted during cocaine-cue responding and food-reinforced responding in a context where cocaine was never available., Results: Compared with the noncocaine condition, we found significant functional activation in the medial prefrontal cortex, anterior cingulate, precuneus region of the parietal cortex, and striatum-findings similar to those reported in humans who abuse cocaine. Furthermore, these functional activations in the prefrontal, cingulate, and parietal cortex measured during cocaine-cue responding were significantly correlated with juvenile measures of dopamine transporter availability, whereas no significant relationship with prior D 2 -like receptor availability was observed in any brain region., Conclusions: The similarity between the present findings and findings in humans who use cocaine supports the use of this model for examination of factors that affect the development and intensity of cue-induced drug seeking and provides evidence for potential biomarkers for the evaluation of potential treatments (behavioral and pharmacologic) for cocaine abuse., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

There are several case reports of nonmedicinal quetiapine abuse, yet there are very limited preclinical studies investigating quetiapine self-administration. The goal of this study was to investigate the reinforcing effects of quetiapine alone and in combination with intravenous cocaine in monkeys. In experiment 1, cocaine-experienced female monkeys (N = 4) responded under a fixed-ratio (FR) 30 schedule of food reinforcement (1.0-g banana-flavored pellets), and when responding was stable, quetiapine (0.003-0.1 mg/kg per injection) or saline was substituted for a minimum of five sessions; there was a return to food-maintained responding between doses. Next, monkeys were treated with quetiapine (25 mg, by mouth, twice a day) for approximately 30 days, and then the quetiapine self-administration dose-response curve was redetermined. In experiment 2, male monkeys (N = 6) self-administered cocaine under a concurrent FR schedule with food reinforcement (three food pellets) as the alternative to cocaine (0.003-0.3 mg/kg per injection) presentation. Once choice responding was stable, the effects of adding quetiapine (0.03 or 0.1 mg/kg per injection) to the cocaine solution were examined. In experiment 1, quetiapine did not function as a reinforcer, and chronic quetiapine treatment did not alter these effects. In experiment 2, cocaine choice increased in a dose-dependent fashion. The addition of quetiapine to cocaine resulted in increases in low-dose cocaine choice and number of cocaine injections in four monkeys, while not affecting high-dose cocaine preference. Thus, although quetiapine alone does not have abuse potential, there was evidence of enhancement of the reinforcing potency of cocaine. These results suggest that the use of quetiapine in cocaine-addicted patients should be monitored., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)

Cocaine users exhibit a wide range of behavioral impairments accompanied by brain structural, neurochemical and functional abnormalities. Metabolic mapping studies in cocaine users and animal models have shown extensive functional alterations throughout the striatum, limbic system, and cortex. Few studies, however, have evaluated the persistence of these effects following cessation of cocaine availability. The purpose of this study, therefore, was to assess the functional effects of re-exposure to cocaine in nonhuman primates after the discontinuation of cocaine self-administration for 30 or 90 days, using the quantitative autoradiographic 2-[14C]deoxyglucose (2DG) method. Rhesus monkeys self-administered cocaine (fixed interval 3-min schedule, 30 infusions per session, 0.3 mg/kg/infusion) for 100 sessions followed by 30 (n=4) or 90 days (n=3) during which experimental sessions were not conducted. Food-reinforced control animals (n=5) underwent identical schedules of reinforcement. Animals were then re-exposed to cocaine or food for one final session and the 2DG method applied immediately after session completion. Compared to controls, re-exposure to cocaine after 30 or 90 day drug-free periods resulted in lower rates of glucose utilization in ventral and dorsal striatum, prefrontal and temporal cortex, limbic system, thalamus, and midbrain. These data demonstrate that vulnerability to the effects of cocaine persists for as long as 90 days after cessation of drug use. While there was some evidence for recovery (fewer brain areas were affected by cocaine re-exposure at 90 days as compared to 30 days), this was not uniform across regions, thus suggesting that recovery occurs at different rates in different brain systems., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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.

Rationale: Studies in rodents have demonstrated that increased access to cocaine can result in increases in drug intake per unit time., Objectives: The present studies characterized long-term changes in cocaine self-administration associated with quantitatively and qualitatively different conditions of cocaine availability in monkeys., Materials and Methods: Separate groups of rhesus monkeys (n = 6/group) self-administered cocaine (0.2 mg/kg per injection) under a fixed ratio (FR) 30 schedule for 3 h twice daily for two consecutive days each week for 1 year, or responded under a second-order FR 10 (fixed interval 3-min:S) schedule of 0.2 mg/kg per injection cocaine during daily sessions. After 18 weeks, probe sessions were conducted once per week, in which responding was maintained under a fixed interval (FI) 30-min schedule in the presence of distinct stimuli., Results: Weekly cocaine intakes under the FR schedule were stable in three subjects, but increased progressively in three monkeys over 1 year. In contrast, response rates under the second-order schedule were low and stable over time. Responding under the FI 30-min schedule was higher for monkeys in the FR group and pattern of responding was not indicative of FI performance, perhaps due to experimental history., Conclusions: These data suggest that increases in cocaine intake can be observed under ratio schedules in monkeys. The use of an FI 30-min "probe" to assess changes in "drug seeking" appeared to be influenced by experimental history. These data may aid in the development of behavioral models of cocaine abuse, which focus on the compulsive nature of drug taking.

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 approximately 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.

The purpose of this study was to examine the time course of changes in dopamine D(1)- and D(2)-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 approximately 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 D(1) ([3H]SCH23390) and D(2) ([3H]raclopride) receptor autoradiography. Compared with controls, there was no effect of 5 days of cocaine self-administration on D(1) and D(2) receptors. In monkeys with extensive cocaine histories, D(1) receptor densities were significantly increased relative to controls in some parts of the striatum, while D(2) 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.

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 organism's environment can produce profound biological changes that have important behavioral associations, including vulnerability to cocaine addiction.

Select Drug Category Stimulants Topic Imaging Abstract Detail Preclinical - In Vivo Abstract Category Original Research There remains no FDA-approved pharmacotherapy for cocaine use disorder (CUD). The kappa opioid receptor (KOR) and its endogenous ligand, dynorphin, are implicated in the neurobiological regulation of stress and CUD. Using positron emission tomography (PET) imaging with the KOR agonist [11C]EKAP in socially housed drug-naïve cynomolgus monkeys, we found significant interactions between sex and social rank in KOR binding potential (BP) that correlated positively with social rank in males and negatively in females (Johnson et al., 2023). The present study extended the investigation of the dynorphin/KOR system using a homologous nonhuman primate model of CUD, involving cocaine self-administration (SA), social behavior, and PET imaging (n=8/sex). Utilizing a longitudinal, within-subject design, starting in drug-naïve monkeys, Experiment 1 examined how chronic cocaine SA affected KOR BPs. Following total cocaine intakes of ~100 mg/kg, KOR BP increased (13.0%±1.4%) across all 15 brain regions of interest (ROI) in males; the relationship between baseline BP and cocaine-induced changes correlated positively in 10/15 ROIs. There were no social rank differences observed. In females, the effect of chronic cocaine SA on KOR BP was influenced by social rank, such that cocaine increased KOR BP in dominant females (52%±11%, n=2) and decreased KOR BP in subordinate (-12%±1.6%, n=3) females across all ROI. The second experiment assessed the neural plasticity of KOR system following protracted time-off from cocaine, by allowing monkeys to respond for 1.0 g food pellets instead of cocaine. Monkeys were rescanned with [11 C]EKAP after ~30- and ~100-days off from cocaine. Rate of recovery of KOR BP varied across monkeys and, in some, did not return to baseline after ~100 days off from cocaine. Future studies will examine how sex and social rank differences in cocaine-induced changes in KOR neurobiology, influence pharmacological interventions, such as KOR antagonists on cocaine-food choice and KOR agonists on punished cocaine SA. [ABSTRACT FROM AUTHOR]

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. © 2000 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Abstract 2 beta- Propanoyl-3beta-(4-tolyl)-tropane (PTT) is a cocaine analog which has been shown in rhesus monkeys to have cocaine-like discriminative stimulus effects and a long duration of action (>8 h), yet does not function as a reinforcer when substituted for cocaine in monkeys responding under a fixed-interval 5-min schedule (Nader et al. 1997). The purpose of the present study was to evaluate the reinforcing effects of PTT under a fixed-ratio (FR) schedule and to determine if decreasing the inter-injection interval would influence the reinforcing effects of PTT. Male rhesus monkeys (n = 3) were trained to respond under a multiple FR 30 food-drug-food schedule. When responding was stable, cocaine (0.003-0.3 mg/kg per injection) or PTT (0.001-0.03 mg/kg per injection) was available during the drug component for at least five consecutive sessions and until stable responding was observed. To investigate whether the inter-injection interval would influence PTT-maintained response rates, the time-out (TO) following PTT injections was reduced from 180 or 300 s to 10 s for at least five consecutive sessions. Cocaine-maintained response rates were characterized as an inverted-U shaped function of dose, with peak rates maintained by 0.03 mg/kg per injection cocaine. PTT (0.001-0.03 mg/kg per injection) maintained response rates significantly higher than rates maintained by the PTT vehicle, but significantly lower than cocaine-maintained response rates; PTT intake increased with dose. A reduction of the TO following PTT injections to 10 s did not alter PTT-maintained response rates or total session intake. Self-administered PTT was more potent than cocaine at decreasing food-maintained responding. These results suggest that for long-acting... [ABSTRACT FROM AUTHOR]