Dopaminylation of Histone H3 in Ventral Tegmental Area Regulates Cocaine-seeking

Vulnerability to relapse during periods of attempted abstinence from cocaine use is hypothesized to result from rewiring of brain reward circuitries, particularly ventral tegmental area (VTA) dopamine neurons. How cocaine exposures act on midbrain dopamine neurons to precipitate addiction-relevant changes in gene expression is unclear. We found that histone H3 glutamine 5 dopaminylation (H3Q5dop) plays a critical role in cocaine-induced transcriptional plasticity in midbrain. Rats undergoing withdrawal from cocaine showed an accumulation of H3Q5dop in VTA. By reducing H3Q5dop in VTA during withdrawal, we reversed cocaine-mediated gene expression changes, attenuated cue-induced dopamine release in nucleus accumbens and reduced cocaine-seeking behavior. These findings establish a neurotransmission-independent role for nuclear dopamine in relapse-related transcriptional plasticity in VTA. Following chronic cocaine vs. saline self administration (extended access), rats were infected intra-VTA with either empty vector (RFP) or H3.3 WT controls vs. H3.3Q5A viruses, followed by a 30 d period of forced abstinence