Efeito da morfina sobre a persistência da memória de medo condicionado contextual em ratos

Abstract

It is established that opioids modulate brain networks involved in learning and memory. Studies using various learning tasks have shown that morphine impairs many forms of memory. A common feature of these studies is that morphine was administered pre- or post-training, in order to determine whether this opioid alters memory consolidation that occurs up to 6 hours after learning. Recent studies in animals have shown that pharmacological manipulations performed 12 hours after training alter memory persistence. However, little is known about the role of morphine in this mnemonic phase. Therefore, the aim of this study was to evaluate the effect of morphine on the persistence of fear memory and investigate its putative mechanism of action. Adult male rats were submitted to contextual fear conditioning task and the memory of this task was measured as percentage of observations of immobility ("freezing") 2, 7 or 14 days after training. Morphine administration (10 mg/kg, i.p.), 12 hours post-training, did not alter freezing to context of rats tested 2 days after training but reduced, at the dose of 10 mg/kg, contextual freezing in the testing session carried seven and fourteen days after training. The decrease of contextual freezing induced by injection of morphine 12 hours post-training was not reverted by the injection of morphine (10 mg/kg, i.p.) before the testing session, indicating that its effect was not due to state dependence. The administration of opioid receptor antagonist, naloxone (1 mg/kg, i.p.) inhibited the decrease of contextual freezing induced by morphine. The intrahippocampal injection of activators of enzymes adenylyl cyclase and cAMP-dependent protein kinase (PKA), forskolin (0.13 μg/site) and 8-Br-cAMP (7.5 μg /site), respectively, also prevented the effect of morphine. The findings suggest that morphine administered 12 hours after training of contextual fear conditioning does not alter the formation of memory, but impairs the persistence of the memory trace by mechanisms mediated by opioid receptors and cAMP/PKA signaling. These findings indicate that opioids have therapeutic potential in preventing psychiatric disorders related to fear memories.