Sex differences in cocaine self-administration behaviour under long access versus intermittent access conditions

Abstract

Studies in humans suggest that women progress more rapidly from initial cocaine use to addiction. Similarly, female rats can show more incentive motivation for cocaine than male rats do. Most preclinical studies on this issue have used self-administration procedures that provide continuous cocaine access during each session ("long-access" or LgA and "short-access"). However, intermittent access (IntA) cocaine self-administration better models the intermittency of human cocaine use. Here, we compared cocaine use in female and male rats that received ten, daily 6-hour LgA or IntA sessions. Cocaine intake was greatest under LgA, and female LgA rats escalated their intake. Only IntA rats (both sexes) developed locomotor sensitization to self-administered cocaine, and sensitization was greatest in females. Five and 25 days after the last self-administration session, we quantified responding for cocaine (0.083-0.75 mg/kg/infusion) under a progressive ratio (PR) schedule, a measure of motivation for drug. Across conditions, females earned more cocaine infusions than males under the PR schedule. Across sexes, IntA rats earned more infusions than LgA rats, even though IntA rats had previously taken much less cocaine. Cumulative cocaine intake significantly predicted responding for cocaine under the PR schedule in male LgA rats only. In IntA rats, the extent of locomotor sensitization significantly predicted responding under the PR schedule. Thus, LgA might be appropriate to study sex differences in cocaine intake, whereas IntA might be best suited to study sex differences in sensitization-related neuroadaptations involved in cocaine addiction. This has implications for modelling distinct features of cocaine addiction in preclinical studies.

Keywords: cocaine self-administration; intermittent access; long access; progressive ratio schedule; psychomotor sensitization; sex differences.