The histone deacetylase inhibitor sodium butyrate modulates acquisition and extinction of cocaine-induced conditioned place preference

摘要

Despite decades of research on treatments for cocaine dependence, relapse rates following many behavioral and drug-based therapies remain high. This may be in part because cocaine-associated cues and contexts can invoke powerful drug cravings years after quitting. Recent studies suggest that drugs that promote cognitive function can enhance the formation of memories involving cocaine and other substances. One target of these drugs is facilitating histone acetylation to promote learning by increasing gene transcription that supports memory formation. Here, we investigate the effects of the histone deacetylase (HDAC) inhibitor sodium butyrate (NaBut) on cocaine-induced conditioned place preference (CPP) in C57BL/6 mice. After establishing a graded dose-response curve (2, 5, & 20 mg/kg) for cocaine-induced CPP, we examined the effects of different doses of NaBut (0, 0.3, 0.6, & 1.2 g/kg) on conditioning, extinction, and post-extinction reconditioning of CPP. A high dose of NaBut (1.2 g/kg) enhanced initial acquisition of cocaine CPP, but there were no effects of NaBut on reconditioning of extinguished CPP. Effects of NaBut on extinction were more complex, with a low-dose (0.3 g/kg) facilitating extinction and a high dose (1.2 g/kg) weakening extinction evident by preference at a retention test. These findings suggest that HDAC inhibition may have dose dependent effects on different components of cocaine CPP, with implications for (1) involvement of histone acetylation in context-drug learning, (2) interpretation of acute and chronic drug effects, and (3) the targeting of different types of learning in therapeutic application of HDAC inhibitors.