Epigenetic function during heroin self-administration controls future relapse-associated behavior in a cell type-specific manner.

Opioid use produces enduring associations between drug reinforcement/euphoria and discreet or diffuse cues in the drug-taking environment. These powerful associations can trigger relapse in individuals recovering from opioid use disorder (OUD). Here, we sought to determine whether the epigenetic enzyme, histone deacetylase 5 (HDAC5), regulates relapse-associated behavior in an animal model of OUD. We examined the effects of nucleus accumbens (NAc) HDAC5 on both heroin- and sucrose-seeking behaviors using operant self-administration paradigms. We utilized cre-dependent viral-mediated approaches to investigate the cell-type-specific effects of HDAC5 on heroin-seeking behavior, gene expression, and medium spiny neuron (MSN) cell and synaptic physiology. We found that NAc HDAC5 functions during the acquisition phase of heroin self-administration to limit future relapse-associated behavior. Moreover, overexpressing HDAC5 in the NAc suppressed context-associated and reinstated heroin-seeking behaviors, but it did not alter sucrose seeking. We also found that HDAC5 functions within dopamine D1 receptor-expressing MSNs to suppress cue-induced heroin seeking, and within dopamine D2 receptor-expressing MSNs to suppress drug-primed heroin seeking. Assessing cell-type-specific transcriptomics, we found that HDAC5 reduced expression of multiple ion transport genes in both D1- and D2-MSNs. Consistent with this observation, HDAC5 also produced firing rate depression in both MSN classes. These findings revealed roles for HDAC5 during active heroin use in both D1- and D2-MSNs to limit distinct triggers of drug-seeking behavior. Together, our results suggest that HDAC5 might limit relapse vulnerability through regulation of ion channel gene expression and suppression of MSN firing rates during active heroin use.

Histone deacetylase 5 in prelimbic prefrontal cortex limits context-associated cocaine seeking.

Background: Repeated cocaine use produces neuroadaptations that support drug craving and relapse in substance use disorders (SUDs). Powerful associations formed with drug-use environments can promote a return to active drug use in SUD patients, but the molecular mechanisms that control the formation of these prepotent drug-context associations remain unclear. Methods: In the rat intravenous cocaine self-administration (SA) model, we examined the role and regulation of histone deacetylase 5 (HDAC5) in the prelimbic (PrL) and infralimbic (IL) cortices in context-associated drug seeking. To this end, we employed viral molecular tools, chemogenetics, RNA-sequencing, electrophysiology, and immunohistochemistry. Results: In the PrL, reduction of endogenous HDAC5 augmented context-associated, but not cue-or drug prime-reinstated cocaine seeking, whereas overexpression of HDAC5 in PrL, but not IL, reduced context-associated cocaine seeking, but it had no effects on sucrose seeking. In contrast, PrL HDAC5 overexpression following acquisition of cocaine SA had no effects on future cocaine seeking. We found that HDAC5 and cocaine SA altered the expression of numerous PrL genes, including many synapse-associated genes. HDAC5 significantly increased inhibitory synaptic transmission onto PrL deep-layer pyramidal neurons, and it reduced the induction of FOS-positive neurons in the cocaine SA environment. Conclusions: Our findings reveal an essential and selective role for PrL HDAC5 to limit associations formed in cocaine, but not sucrose, SA environments, and that it alters the PrL excitatory/inhibitory balance, possibly through epigenetic regulation of synaptic genes. These results further position HDAC5 as a key factor regulating reward-circuit neuroadaptations that underlie common relapse triggers in SUD.