Michael A. Nader

A phenomenon involving cocaine use disorders is the “incubation of drug craving” - the drive for the drug increases the longer the abstinence period. The present longitudinal study provided a unique opportunity to test whether an increase in the reinforcing effects of cocaine developed after prolonged abstinence and if early life stress was a risk factor. Fourteen ( N = 6 female, 8 male) adult rhesus monkeys, some ( N = 7) that were maltreated as infants by their mothers (MALT), had previously self-administered cocaine under a fixed-ratio (FR) schedule of reinforcement as adolescents, but had not been studied for >3 years. In Experiment 1, cocaine self-administration dose-response curves were redetermined in adulthood when responding was maintained under the identical FR 20 schedule used during adolescence. In Experiment 2, the reinforcing strength of cocaine was evaluated ( n = 12) under a progressive-ratio (PR) schedule of reinforcement. While there were no statistical differences between male and female monkeys on FR responding in adolescents, when redetermined as adults, MALT monkeys showed higher peak response rates relative to adolescence. No such differences were noted in Control monkeys. Under the PR schedule, peak reinforcing strength was not different between groups or sexes. However, higher total adolescent cocaine intake was significantly associated with higher cocaine breakpoints in adulthood. These findings show that after adolescent cocaine self-administration and a long abstinence period, sensitivity to cocaine reinforcement increased, particularly in monkeys who experienced early life stress. Although early life stress (MALT) did not significantly impact measures of cocaine’s reinforcing strength, higher adolescent cocaine intake did.

Rationale Although ethanol consumption is ubiquitous among individuals who use cocaine, most preclinical work investigating factors that contribute to the development of problematic cocaine use do not incorporate ethanol into their experimental designs. Given that only a subset of individuals who try cocaine go on to develop a cocaine use disorder (CUD) research is needed to identify factors, such as ethanol consumption, that may influence vulnerability to cocaine reinforcement. Objectives Thus, this study aimed to determine how a history of ethanol self-administration and exposure immediately prior to the first experience with cocaine self-administration influenced the potency of cocaine to function as a reinforcer in socially housed male and female cynomolgus monkeys. Methods For these experiments, one group of monkeys (n = 7) was trained to self-administer up to 1.5 g/kg of ethanol prior to cocaine self-administration while another group of monkeys (n = 13) remained ethanol-naïve through the study. Acquisition of cocaine self-administration was studied in both groups of monkeys under a fixed-ratio schedule of reinforcement where ascending doses of cocaine were substituted for food pellets. Cocaine ED50 values from the ascending limb were examined statistically. Results The results showed that subordinate monkeys that self-administered ethanol prior to cocaine self-administration required higher cocaine doses to function as a reinforcer compared with subordinate monkeys not exposed to ethanol. Conclusions One possible explanation for this finding is that ethanol, due to its acute anxiolytic effects, mitigated the effect of chronic stress in subordinate monkeys and thereby blunted the reinforcing effects of initial cocaine exposure. Future research is needed to examine whether variables such as environmental enrichment or treatment with clinically effective anxiolytics in chronically stressed individuals can modify the initiation and continued use of cocaine.

Considerable research has suggested that certain cognitive domains may contribute to cocaine misuse. However, there are gaps in the literature regarding whether cognitive performance before drug exposure predicts susceptibility to cocaine self-administration and how cognitive performance relates to future cocaine intake. Thus, the present study aimed to examine cognitive performance, as measured using automated CANTAB cognitive battery, prior to and following acquisition of cocaine self-administration under a concurrent drug vs. food choice procedure in female and male socially housed cynomolgus macaques. The cognitive battery consisted of measures of associative learning (stimulus and compound discrimination tasks), behavioral flexibility (intradimensional and extradimensional tasks), and behavioral inhibition (stimulus discrimination reversal, SDR, and extra-dimensional reversal tasks). After assessing cognitive performance, monkeys were trained to self-administer cocaine (saline, 0.01–0.1 mg/kg/injection) under a concurrent cocaine vs. food schedule of reinforcement. After a history of cocaine self-administration across 3-4 years, the cognitive battery was re-assessed and compared with sensitivity to cocaine reinforcement. Results showed drug-naïve monkeys that were less accurate on the SDR task, measuring behavioral inhibition, were more sensitive to cocaine reinforcement under the concurrent cocaine vs. food choice procedure. Furthermore, following chronic cocaine self-administration, cocaine intake was a negative predictor of accuracy on the SDR behavioral inhibition task. After cocaine maintenance, monkeys with higher cocaine intakes required more trials to complete the SDR behavioral inhibition task and made more incorrect responses during these trials. No sex or social rank differences were noted. Overall, these findings suggest that cognitive performance may influence vulnerability to cocaine misuse. Also, chronic cocaine may decrease levels of behavioral inhibition as measured via the SDR task in both females and males.