Rationale Cocaine use has been associated with cognitive impairments that may contribute to poor treatment outcomes. However, the degree to which these deficits extend into periods of abstinence has not been completely elucidated. Objectives This study tested whether prior experience self-administering cocaine affected acquisition of two cognitive tasks in 16 adult female cynomolgus monkeys. Seven monkeys had previously self-administered cocaine but had not had access to cocaine for two months at the start of this study. Methods After monkeys were trained to respond on a touchscreen, associative learning and behavioral flexibility were assessed using a stimulus discrimination (SD) and reversal (SDR) task from the CANTAB battery. Performance on this task was monitored over the subsequent three months. Additionally, working memory was assessed with a delayed match-to-sample (DMS) task. Results Cocaine-naïve monkeys required fewer total trials and made fewer errors and omissions before acquiring the SD and SDR tasks compared to monkeys who had previously self-administered cocaine; two monkeys in the latter group did not acquire the task. However, this cognitive impairment dissipated over several months of exposure to the task. The number of sessions for touch training and delays required to establish a performance-based curve on the DMS task did not differ between groups. Conclusion Results suggest that cocaine exposure can impair the ability to learn a novel task requiring behavioral inhibition and flexibility, even after an extended period of abstinence. However, this deficit did not extend to maintenance of the task or to acquisition of a working memory task.

Preclinical studies have demonstrated that cognitive function may be influenced by estradiol (E2) and progesterone (P4) concentrations, although few cognition studies involve normally cycling females. The present study examined cognitive performance in normally cycling female cynomolgus macaques (n=14), a species with similarities to humans in brain organization and a nearly identical menstrual cycle to women. Initial assessments compared cognitive measures to circulating concentrations of E2 and P4 (n=12). Once a relationship was characterized between hormones and cognitive performance, the menstrual cycle was divided into 4 distinct phases: early follicular (EF), late follicular (LF), early luteal (EL) and late luteal (LL), verified by the onset of menses and serum concentrations of E2 and P4. Concentrations of E2 were highest during the LF phase and P4 concentrations peaked during the EL phase. All monkeys were trained on two cognitive tasks: reversal learning, involving simple discrimination (SD) and reversal (SDR), which measured associative learning and behavioral flexibility, respectively (n=3–4 per phase) and a delayed match-to-sample (DMS) task which assessed working memory (n=11). P4 concentrations were positively correlated with number of trials and errors during SD performance, but not during acquisition of the SDR task or maintenance of the reversal-learning task. Across the menstrual cycle, significantly fewer errors were made in the SDR task during the LF phase, when E2 concentrations were high and P4 concentrations low. Working memory, assessed with the DMS task, was not consistently altered based on previously characterized menstrual cycle phases. These findings demonstrate a relationship between P4, E2 and cognitive performance in normally cycling cynomolgus monkeys that is task dependent. Knowledge of these interactions may lead to a better understanding of sex-specific cognitive performance.

Physiological and behavioral differences between dominant and subordinate monkeys have been useful in preclinical models investigating numerous disease states. In captivity, it has been inferred that subordinate monkeys live in a context of chronic social stress and may be at risk for a variety of dysfunctions; however, the factors that influence eventual rank are not entirely known. The goal of the present study was to first evaluate several phenotypic characteristics as potential trait markers for eventual social rank and then to determine the consequences of social hierarchy on these measures (i.e., state markers). Baseline estradiol, progesterone, cortisol and testosterone concentrations were obtained from 16 pair-housed female cynomolgus monkeys before and after introduction into new social groups (n = 4/group). Furthermore, effects of the initial week of social rank establishment on outcome measures of cognitive performance and homecage activity were examined. Baseline body weight and mean serum estradiol concentrations were the only statistically significant predictors of eventual rank, with future subordinate monkeys weighing less and having higher estradiol concentrations. During initial hierarchy establishment, future subordinate monkeys had increased morning and afternoon cortisol concentrations, increased locomotor activity and impaired cognitive performance on a working memory task. After 3 months of social housing, subordinate monkeys had blunted circulating estradiol and progesterone concentrations. These findings demonstrate differential effects on gonadal hormones and cortisol as a function of social context in normally cycling female monkeys. Furthermore, disruptions in cognitive performance were associated with subordinate status, suggesting strong face validity of this model to the study of factors related to the etiology and treatment of human diseases associated with chronic stress. Am. J. Primatol. 78:402-417, 2016. © 2015 Wiley Periodicals, Inc.

Nonhuman primate social groups, which represent a continuum of experiences from environmental enrichment in dominant monkeys to chronic social stress in subordinates, have been used to study susceptibility and resilience to human diseases. We have shown that social rank influences sensitivity to cocaine and other dopaminergic drugs. However, it is not clear what biological and environmental factors determine what rank an individual monkey will attain. In females, novel object reactivity and CSF concentrations of 5‐HIAA predicted social rank; these factors did not change after hierarchies stabilized. The present studies examined whether other variables, including cognitive function (using CANTAB touchscreen software) and activity (using Actical monitors), predict eventual social rank and change after social hierarchies stablized. Prior to social housing 4 monkeys per pen, performance on a cognitive task was not different in eventual dominant and subordinate monkeys. After stable hierarchies were formed, subordinate monkeys demonstrated cognitive impairments. Furthermore, future subordinates had higher activity during the day which remained higher after hierarchies stabilized, and preliminary results suggest rank differences in nighttime activity. Additionally, the relationship between these behaviors and cocaine reinforcement is being investigated. Understanding behavioral phenotypes and individual differences in response to environmental manipulations, such as attainment and occupation of social ranks, and the relationship to cocaine self‐administration will aid in the development of behavioral and pharmacological treatment strategies for drug addiction. Grant Funding Source: Supported by DA017763

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