HDAC3 in the Hippocampus is a Negative Regulator of Extinction Memory

Drug-associated memories are the mainspring of drug relapse and brain regions underlying these memories are being studied to determine the mechanisms through which drug-seeking behavior can be inhibited. Further comprehension of this dynamic could provide the key to the prevention of relapse. One potential mechanism involves histone acetylation, which is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs generally increase histone acetylation and promote transcription, whereas HDACs generally decrease histone acetylation and suppress transcription. HDACs have recently been shown to play a critical role in long-term memory and drug-associated memory formation and maintenance.  Malvaez et al. (2013) demonstrated that HDAC3 inhibition plays an important role in extinction—a transcription dependent process through which a previously acquired response is eliminated—of drug seeking behavior by enhancing the expression of genes necessary for long-term memory formation like c-Fos and Nr4a2. However it currently remains unknown which brain regions HDAC3 functions in to modulate extinction. Through the utilization of a cocaine-conditioned place preference (CPP) paradigm, we investigated the effects of two different viruses that target HDAC3 to determine its role in extinction memory in the hippocampus. We hypothesize that the direct manipulation of HDAC3 in the hippocampus will affect extinction of drug-seeking behavior. To address this hypothesis, we used three groups in which, one group of animals received infusions of an HDAC3 point mutant, which blocks the enzymatic activity of HDAC3, into the hippocampus. A second experimental group received intra-hippocampal infusions of wild type HDAC3 in order to study the effect of overexpressing HDAC3 on extinction learning. An empty vector infusion was used as a control. HDAC3 point mutant infused into the hippocampus led to accelerated extinction and thus diminished preference. However, HDAC3 overexpression infused into the hippocampus had a similar effect on the extinction of drug-seeking behavior as the empty vector control, and neither of these groups showed accelerated rates of extinction of drug-seeking behavior. Because extinction is a transcription dependent process, the deactivation of HDAC3 via the point mutation is predicted to increase transcription during consolidation of extinction memory. These results illustrate the importance of HDAC3 in the hippocampus in underlying drug relapse and propose a possible treatment for relapse through extinction therapy.