Taking rapid and intermittent cocaine infusions enhances both incentive motivation for the drug and cocaine-induced gene regulation in corticostriatal regions

Abstract

ABSTRACTA goal in addiction research is to distinguish forms of neuroplasticity that are involved in the transition to addiction from those involved in mere drug taking. Animal models of drug self-administration are essential in this context. Here, we compared in male rats two cocaine self-administration procedures that differ in the extent to which they evoke addiction-like behaviours. We measured both incentive motivation for cocaine using progressive ratio procedures, and cocaine-induced c-fos mRNA expression, a marker of neuronal activity. Rats self-administered intravenous cocaine (0.25 mg/kg/infusion) for seven daily 6-hour sessions. One group had intermittent access (IntA; 6 minutes ON, 26 minutes OFF x 12) to rapid infusions (delivered over 5 seconds). This models the temporal kinetics of human cocaine use and produces robust addiction-like behaviour. The other group had Long access (LgA) to slower infusions (90 seconds). This produces high levels of intake without promoting robust addiction-like behaviour. LgA-90s rats took twice as much cocaine as IntA-5s rats did, but IntA-5s rats showed greater incentive motivation for the drug. Following a final self-administration session, we quantified c-fos mRNA expression in corticostriatal regions. Compared to LgA-90s rats, IntA-5s rats had more cocaine-induced c-fos mRNA in the orbitofrontal and prelimbic cortices and the caudate-putamen. Thus, a cocaine self-administration procedure (intermittent intake of rapid infusions) that promotes increased incentive motivation for the drug also enhances cocaine-induced gene regulation in corticostriatal regions. This suggests that increased drug-induced recruitment of these regions could contribute to the neural and behavioural plasticity underlying the transition to addiction.