Michael Lawrence Miller, M.D., Ph.D. - US grants

DESCRIPTION (provided by applicant): Cannabis is pervasively consumed in the United States, especially during adolescence with more than 20% of 12th graders using this drug within the past year. As youngsters increasingly use this substance - and as the debates regarding its safety and legal status ensue - understanding the long-term neurobiological consequences of early cannabis exposure is paramount. Human studies convincingly demonstrate an association between early cannabis exposure and neuropsychiatric diseases ranging from substance abuse disorder (or drug addiction) to schizophrenia. In fact, these diseases are linked with earlier, more frequent consumption suggesting a causal relationship between developmental cannabis exposure and future mental health. Consistent with these epidemiological findings, animals exposed to THC, the main psychoactive component of cannabis, exhibit elevated heroin self-administration. These findings indicate that neurobiological disturbances causally contribute to addiction vulnerability later in life. Alongside these behavioral changes, adolescent exposure to THC induces long-term transcriptional changes in nucleus accumbens (NAc), a region of the ventral striatum that regulates reward and reinforcement. Small non-coding miRNAs regulate gene expression and are themselves persistently impacted by adolescent THC exposure, suggesting that these regulatory mechanisms may contribute to the stable, long-term changes in mRNA expression and behavior. The primary goal of this proposal is to identify miRNAs that impact addiction vulnerability via their interaction with proenkephalin (Penk). a neuropeptide precursor induced by adolescent THC that causally mediates heroin self-administration in rats. Since Penk is enriched in a distinct pathway within the NAc, an innovative yet feasible approach to identify and separate these neurons is proposed, allowing for a focused, hypothesis-driven molecular and behavioral study within the relevant neurons. Adolescent exposure to THC increases Penk mRNA and peptide levels in the NAc medial shell, contributing to addiction vulnerability, and I hypothesize that cell type-specific alternations in miRNA contribute to these persistent transcriptional alternations. I further hypothesize that reversing these miRNA derangements in a cell-type specific manner will reduce heroin self-administration even in at-risk animals exposed to THC during adolescence. Findings based on these proposed experiments will increase our neurobiological understanding of addiction as a developmental process and will bring to focus the health-related consequences of early cannabis exposure.