Antagonism of endogenous opioids modulates memory processing

The studies reported here demonstrate that opioid antagonism enhances memory in two classes of animals viz. Aves and Mammalia. In mice, immediate posttraining administration of naloxone produces a time-dependent improvement in retention tested one week later. This effect is stereospecific. As naloxone was approximately 1000-fold more potent when administered intracerebroventricularly compared to subcutaneously, it appears that it produces its effect within the central nervous system. Pretest administration of naloxone, at a dose that failed to alter acquisition, also improved test performance, suggesting that naloxone also improved recall. Similar improvement in retention was demonstrated with the more potent opioid antagonist, nalmefene, at a 500-fold lower dose. The dose response to naloxone in both the mouse and the chick and to nalmefene in the mouse had the characteristics of an inverted U, with high doses either being ineffective or suppressing memory retention. In mice, naloxone demonstrated anti-amnestic properties against both anisomycin, a protein synthesis inhibitor, and scopolamine, an acetylcholine receptor blocker. Administration of beta-funaltrexamine (B-FNA) 72 h prior to training did not alter acquisition but did enhance retention. In studies where the mu-opioid receptor was blocked with B-FNA, naloxone was unable to enhance retention. B-FNA failed to impair the memory enhancing properties of arecoline, fluoxetine or clonidine. This demonstrates specificity of the B-FNA ability to prevent naloxone from enhancing memory and suggests that the opioid antagonist effects on memory are mediated by the mu-receptor.