Identifying Changes in Protein Signaling that Regulate Substance Use Vulnerability, Craving, and Relapse.

Overview: My laboratory continues to work with the Yale/NIDA Neuroproteomics Center to identify changes in protein phosphorylation that regulate many aspects of the addiction cycle: 1) Vulnerability -- we have determined the effects of adolescent stress on the adult amygdala phosphoproteome, and have plans to perform similar studies that directly investigate the effects of adolescent sleep disruption and circadian misalignment on protein expression and phosphorylation in corticolimbic circuits. This latter project is part of a resubmission of a NIDA P50 Center grant (PI Colleen McClung). 2) Acute intoxication – we were funded by NIAAA to perform phosphoproteomic analysis of what proteins are regulated by low dose alcohol exposure. We examined effects in the nucleus accumbens after acute administration of varying doses of alcohol to identify what molecules may be involved in the acute intoxicating/rewarding effects of alcohol. These results can be compared to other drugs of abuse in future studies. 3) Craving and relapse – we have performed several studies to investigate dynamic changes in protein phosphorylation after a cocaine-associated memory is retrieved, which is thought to trigger a craving-like response and compared these results to effects after that cue memory has been extinguished. We have examined two brain regions and validated several identified targets. We have recently submitted a renewal of our R01 to continue these studies. We also plan to look at other protein post-translational modifications in future collaborations with the Center, particularly addiction-associated changes in histone methylation and acetylation.