Contributions of prolonged contingent and non-contingent cocaine exposure to escalation of cocaine intake and glutamatergic gene expression.

Similar to the pattern observed in people with substance abuse disorders, laboratory animals will exhibit escalation of cocaine intake when the drug is available over prolonged periods of time. Here, we investigated the contribution of behavioral contingency of cocaine administration on escalation of cocaine intake and gene expression in the dorsal medial prefrontal cortex (dmPFC) in adult male rats. Rats were allowed to self-administer intravenous cocaine (0.25 mg/infusion) under either limited cocaine-(1 h/day), prolonged cocaine-(6 h/day), or limited cocaine-(1 h/day) plus yoked cocaine-access (5 h/day); a control group received access to saline (1 h/day). One day after the final self-administration session, the rats were euthanized and the dmPFC was removed for quantification of mRNA expression of critical glutamatergic signaling genes, Homer2, Grin1, and Dlg4, as these genes and brain region have been previously implicated in addiction, learning, and memory. All groups with cocaine-access showed escalated cocaine intake during the first 10 min of each daily session, and within the first 1 h of cocaine administration. Additionally, the limited-access + yoked group exhibited more non-reinforced lever responses during self-administration sessions than the other groups tested. Lastly, Homer2, Grin1, and Dlg4 mRNA were impacted by both duration and mode of cocaine exposure. Only prolonged-access rats exhibited increases in mRNA expression for Homer2, Grin1, and Dlg4 mRNA. Taken together, these findings indicate that both contingent and non-contingent "excessive" cocaine exposure supports escalation behavior, but the behavioral contingency of cocaine-access has distinct effects on the patterning of operant responsiveness and changes in mRNA expression.