Repeated Pre-exposure to Morphine Inhibited the Amnesic Effect of Ethanol on Spatial Memory: Involvement of CaMKII and BDNF.

Evidence suggested that addiction and memory systems are related, but the signaling cascades underlying this interaction have not been ultimately revealed yet. The importance of Calcium-calmodulin-dependent protein kinase II (CaMKII) and Brain-derived neurotrophic factor (BDNF) in the memory processes and also in drug addiction have been previously established. In this present investigation, we examined the effects of repeated morphine pre-treatment on impairment of spatial learning and memory acquisition induced by systemic ethanol administration in adult male rats. Also, we assessed how these drug-exposures influence the expression level of CAMKII and BDNF in the hippocampus and amygdala. Animals were trained by a single training session of eight trials, and a probe test containing 60 s free-swim without a platform was administered 24 h later. Before training trials, rats were treated with a once-daily subcutaneous morphine injection for three days followed by a 5-day washout period. The results showed that pre-training ethanol (1 g/kg) impaired spatial learning and memory acquisition and down-regulated the mRNA expression of CAMKII and BDNF. The amnesic effect of ethanol was suppressed in morphine (15 mg/kg/day) pre-treated animals. Furthermore, the mRNA expression level of CAMKII and BDNF increased significantly following ethanol administration in morphine-pretreated rats. Conversely, this improvement in spatial memory acquisition was prevented by daily subcutaneous administration of naloxone (2 mg/kg) 15 min prior to morphine. Our findings suggest that sub-chronic morphine treatment reverses ethanol-induced spatial memory impairment which could be explained by modulating CAMKII and BDNF mRNA expressions in the hippocampus and amygdala.