Concomitant adrenal hormonal stress responses are required for cocaine-induced locomotor sensitization

Abstract

Aims: Cocaine-induced locomotor sensitization is a robust increase in locomotion to a standardized dose of cocaine. The associated neuronal changes that underlie increased behavioral sensitization involve addiction-related plasticity. Strong evidence suggests that the systemic stress response is involved in establishing addiction-related behaviors. We previously reported that the systemic adrenal response is required for escalation of addictionrelated behaviors and that glucocorticoids in particular play a role in facilitating long termneural adaptions that result in these behaviors. Here we examine whether increased levels of the adrenal hormones, corticosterone (cort) and epinephrine (epi), either alone or in concert, are required for establishing locomotor sensitization to cocaine. Methods: Male Sprague-Dawley rats underwent surgical adrenalectomy (ADX) with basal cort replacement and were administered cocaine for 10 days. On days 1 and 10 locomotor sensitization was tested by administration of 15mg/kg, ip cocaine, while sensitization was induced on days 2–9 by administering a high dose of cocaine (30mg/kg, ip×8 days). To test the role of the glucocorticoid receptor (GR) in induction of sensitization, the GR antagonist, RU 486 (12.5mg/kg, sc) was administered prior to cocaine administration. To test whether replacement of the adrenal-secreted stress hormones would rescue sensitization in ADX rats, we replaced normal cort (2mg/kg) and/or epi (0.01mg/kg) during cocaine administration. Results: The induction of sensitization was reduced in rats with ADXor pretreatedwith RU486. In ADX rats, replacement using cort or epi alone did not recover locomotor sensitization but did rescue sensitization when co-administered. Conclusions: These findings demonstrate that coordinated systemic stress signaling from the adrenal gland during cocaine administration is required for cocaine-induced locomotor sensitization and may play a role establishing addiction-related neuroplasticity with chronic cocaine use. Financial support:DA015758 to JRMandDiversity Supplement to DFP.