Histone H3 dopaminylation in ventral tegmental area underlies heroin-induced transcriptional and behavioral plasticity in male rats

• DOI: 10.1038/s41386-022-01279-4
• Publication Date: 2022-01-29T09:02:58Z
• Authors: Sasha L. Fulton; Swarup Mitra; Ashley E. Lepack; Jennifer A. Martin; Andrew F. Stewart; Jacob Converse; Mason Hochstetler; David M. Dietz; Ian Maze
• Keywords: Heroin; Histones; Male; 0301 basic medicine; Cocaine-Related Disorders; 0303 health sciences; 03 medical and health sciences; Cocaine; Ventral Tegmental Area; Animals; Self Administration; Article; Rats

Persistent transcriptional events in ventral tegmental area (VTA) and other reward relevant brain regions contribute to enduring behavioral adaptations that characterize substance use disorder. Recent data from our laboratory indicate aberrant accumulation of the newly discovered histone post-translational modification (PTM), H3 dopaminylation at glutamine 5 (H3Q5dop), contributes significantly cocaine-seeking behavior following prolonged periods abstinence. It remained unclear, however, whether this is important for relapse vulnerability context drugs abuse, such as opioids. Here, we showed H3Q5dop plays a critical role heroin-mediated plasticity midbrain regions, particularly VTA. In rats undergoing abstinence heroin self-administration (SA), found acute persistent Attenuation during induced changes gene expression programs associated with neuronal signaling dopaminergic function led reduced heroin-seeking behavior. Interestingly, observed molecular pathways after SA significant yet reversed overlap same genes altered cocaine SA. These findings establish an essential H3Q5dop, its downstream consequences, heroin-induced functional