Histone Deacetylase 5 in Prelimbic Prefrontal Cortex Limits Context-Associated Cocaine Seeking

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 patients with SUD, but the molecular mechanisms that control the formation of these prepotent drug-context associations remain unclear.

In an animal model of intravenous cocaine self-administration (SA), we used male Sprague Dawley rats to examine the role of histone deacetylase 5 (HDAC5) in the prelimbic cortex (PrL) and infralimbic cortex in context-associated drug seeking. To this end, we employed viral molecular tools, chemogenetics, RNA sequencing, electrophysiology, and immunohistochemistry.

In the PrL, reduction of endogenous HDAC5 augmented context-associated but not cue- or drug prime-reinstated cocaine seeking, whereas overexpression of HDAC5 in the PrL, but not in the infralimbic cortex, reduced context-associated cocaine seeking but had no effects on sucrose seeking. In contrast, PrL HDAC5 overexpression following acquisition had no effects on future cocaine seeking. We found that HDAC5 and cocaine SA altered expression of numerous PrL genes, including many synapse-associated genes. HDAC5 significantly increased inhibitory synaptic transmission onto PrL deep-layer pyramidal neurons and reduced the induction of FOS-positive neurons in the cocaine SA environment.

Our findings reveal an essential and selective role for PrL HDAC5 to limit associations formed in cocaine, but not sucrose, SA environments, and that PrL HDAC5 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 SUDs.