Memory enhancement by unconditioned and conditioned heroin withdrawal: Role of corticotropin-releasing factor in the central amygdala

Abstract

To test the hypothesis that unconditioned and conditioned opioid withdrawal enhance memory consolidation through shared neurobiological mechanisms, the current study focused on the central amygdala (CeA) and local corticotropin-releasing factor (CRF) neurotransmission. In the unconditioned withdrawal experiments, male Sprague-Dawley rats were implanted with subcutaneous osmotic mini-pumps releasing 3.5 mg/kg/day heroin (or sham surgery) and injected with 3 mg/kg naloxone (NLX) to precipitate withdrawal. In the conditioned withdrawal experiments, rats injected with heroin (2 mg/kg x 2 injections) received 3 mg/kg NLX immediately prior to confinement to one compartment (CS+) of a place conditioning apparatus, or vehicle prior to confinement in the alternative compartment (CS-). Using immunohistochemistry, it was established that both precipitated withdrawal and confinement to the withdrawal-paired CS + compartment elevated c-Fos expression within the CeA. More importantly, using the post-training approach to target consolidation of object memory, it was found that intra-CeA infusions of the CRF1 receptor antagonist ANT (0.2–2 μg/inf) blocked the memory-enhancing effects of both precipitated withdrawal and exposure to the withdrawal-paired CS + compartment. These findings indicate that pharmacological and conditioned opioid withdrawal influence memory consolidation through a common CRF-mediated mechanism within the CeA.