Sensitive periods, development, and substance abuse

Mclean Hospital, Belmont MA

Investigators

Linked publications, trials & patents

Abstract

Sensitive periods, development, and substance abuse There is a fundamental gap in our understanding of the factors that increase the risk 4-fold of a lifelong drug addiction when drug use is initiated during young adolescence compared with late adolescence or adulthood. In adulthood, the progression to addiction with repeated drug use involves the gradual recruitment of brain circuits. This progression culminates in drug cues increasing activity in the habit-related brain region of the dorsolateral striatum while decreasing goal-orientated activity. New evidence, however, suggests that drug cues in young adolescent rats can immediately activate the habit region via a temporary neural pathway that is not found in adults. Understanding how activity within this pathway can fast-track young adolescents to form addictive habits will lead to the discovery of novel targets for interventions to prevent or reduce drug use. The long-term goal of these studies is to identify individuals who are vulnerable to cocaine addiction and intervene before drug use is initiated. The overall objective of this application is to establish how early risk behaviors that are related to the habit region facilitate increased drug addiction in an age- and sex-dependent manner. By learning about the development of neural pathways associated with addiction, the central hypothesis that increased prelimbic cortical activity plays an important role in early adolescent vulnerability by modulating the development of goal-orientated versus habitual behavior will be tested. This hypothesis is based on preliminary and published studies in the applicant's laboratory that implicate the D1 dopamine receptor in this process. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims in males and female rats: 1) Determine the relationship between predictive risk factors in juveniles (novelty and sucrose preferences, working memory) on compulsive cocaine use in adolescence. 2) To establish the structural and functional nature of transient changes in prelimbic projections to the dorsal striatum (medial and lateral) as a function of age, sex, and cocaine exposure. Aim I builds on preliminary data that demonstrates identified risk behaviors are associated with increased dorsolateral striatal activity (habit region) and increased drug taking during early adolescence. Aim II builds upon tract tracing, optogenetics/electrophysiology, and DREADDs data that demonstrate functionality of this pathway and will determine how the of age of drug exposure, sex, and pre-existing risk behaviors modulate pathway structure and function. The approach is innovative in that this pathway has not been previously described and will be explored with state-of-the-art methodologies. Importantly, the significance of these studies will show for the first time that behavioral risk factors that are associated with elevated habit region activity or alternatively, reduced goal-orientated activity, predispose subjects to form an addiction. Understanding the role of this transient habit highway fill a major void in understanding the unique vulnerabilities found in this age group and aid in prevention.