UC Irvine

Adolescence is a sensitive period for development of addiction-relevant brain circuits that regulate cognition, drug reinforcement, and motivation. These processes must be carefully balanced to guide adaptive behavior, yet they are particularly vulnerable to disruption during development. Cannabis is one of the most commonly used illicit substances among adolescents, and early-life exposure to Δ9-tetrahydrocannabinol (THC) is associated with an increased risk for psychiatric disorders and later-life substance use. However, the mechanisms by which adolescent THC (AdoTHC) exposure produces persistent alterations across cognitive and motivational domains remain incompletely understood.Here, I explore whether AdoTHC exposure persistently alters brain circuitry and subsequent behavior across three domains: cognition, drug reinforcement, and motivation. Using a suite of behavioral paradigms assessing decision-making, drug reinforcement, and motivation in rats, combined with cell-type specific chemogenetics and immunohistochemistry approaches, I examine the behavioral and circuit-level consequences of AdoTHC exposure. I demonstrate that 1) AdoTHC potentiates amphetamine-induced risky decision-making independent of stimulation of ventral tegmental area dopamine neurons or their projections to prefrontal cortex, 2) AdoTHC promotes a persistent pro-opioid phenotype, especially in females, as well as region- and network-level changes in the brain contributing to distinct neural profiles under heroin in each sex, and that 3) AdoTHC sex-dependently alters responding to aversive stimuli, stressor-modulated motivation for opioid-drug seeking, and neural activity within the prefrontal cortex under pharmacological stress. Together, these findings support the conclusion that AdoTHC exposure produces enduring alterations in brain circuitry that reshape adult cognitive, motivational, and drug reinforcement processes in male and female rats. By integrating these three domains within a unified framework, this work provides experimental evidence for the causal effects of AdoTHC exposure and offers mechanistic insights into how the convergence of these alterations induced by early-life cannabis exposure may increase vulnerability to addiction in humans.