Previous exposure to cocaine enhances cocaine self-administration in an alpha 1-adrenergic receptor dependent manner

Noradrenergic transmission is implicated in the biochemical and behavioral effects of cocaine. Recently, we demonstrated that the alpha 1-adrenergic receptor antagonist prazosin attenuates cocaine-induced reinstatement of drug-seeking behavior. We now assessed whether prazosin could counter the effect of previous exposure to cocaine to enhance subsequent self-administration behavior. Rats were pre-exposed to systemic injections of either saline, prazosin ( 0.3 mg/ kg), saline + cocaine ( 10 mg/ kg), or prazosin + cocaine for 5 days. Starting 15 - 18 days after the last pre- exposure injection, rats were trained to self- administer cocaine ( 0.5 mg/ kg/ infusion) under a fixed ratio 3 ( FR3) schedule of reinforcement. Several tests were conducted. First, responding for cocaine under an FR3 schedule was assessed across several doses ( 0.125 - 1.0 mg/ kg/ infusion). Second, responding for cocaine ( 0.5 mg/ kg/ infusion) under a progressive-ratio ( PR) schedule was examined for 6 consecutive days. Finally, responding for cocaine ( 0, 0.5, and 1.0 mg/ kg/ infusion) was determined under the PR schedule of reinforcement. Results showed that cocaine pre- exposed rats self- administer more cocaine compared to saline pre-exposed rats when tested under both the FR and PR schedules. Rats pre- exposed to cocaine plus prazosin did not show enhanced cocaine self- administration. These rats, as well those pre- exposed to prazosin alone, showed levels of cocaine self- administration similar to saline pre- exposed rats. Thus, previous exposure to cocaine enhanced cocaine self- administration, an effect that appears to involve activation of alpha 1-adrenergic receptors. These data, along with several recent studies, show further support for the contribution of noradrenergic transmission in the behavioral effects of cocaine.