Cocaine self-administration in adult female and male rhesus monkeys: longitudinal comparison with adolescent behavior and role of early life stress

Abstract

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.

Fig. 1. Average cocaine response rates at peak dose and dose-response curves in Control and MALT monkeys across adolescence and adulthood.

A Average cocaine response rates (resp/sec), irrespective of sex, at the peak of the cocaine dose-response curve in Control and MALT monkeys during the initial determination in adolescence (white bars) and during the second determination in adulthood (black bars). B Averaged dose-response curves, irrespective of sex, as a function of group (Control on the left, MALT on the right). Data represent the mean ± the standard error of the mean. N = 14 (n = 7 Controls, n = 7 MALT).

Fig. 2. Average cocaine dose producing peak response rates and dose-response curves irrespective of group and sex in adolescence and adulthood.

A Irrespective of group and sex, average cocaine dose (mg/kg) at the peak of the self-administration dose-response curve during the initial determination in adolescence and during the second determination in adulthood. B Averaged dose-response curves across sex and group. Data represent the mean ± the standard error of the mean. N = 14 (n = 7 Controls, n = 7 MALT).

Fig. 3. Average cocaine BPs and dose-response curves in Control and MALT monkeys during adulthood.

A Average peak cocaine BPs (maximum number of injections) during adulthood as a function of group. B Averaged cocaine dose-response curves as a function of group. Data represent the mean ± the standard error of the mean. N = 12 (n = 6 Controls, n = 6 MALT).

Fig. 4. Relationship between adolescent cocaine intakes and peak cocaine breakpoints in adulthood.

Regression plot depicting a regression line between peak cocaine BPs (maximum number of injections) during adulthood and cumulative cocaine intakes (mg/kg) during adolescence. The doses used on the abscissa were individually determined. Adolescence cocaine intake was a significant predictor of peak cocaine BP during adulthood. N = 12 (n = 6 Controls, n = 6 MALT).