Impact of cocaine-associated cues and contexts on adolescent relapse

PROJECT SUMMARY Adolescence is a critical juncture when initiation of drug use intersects with profound developmental and structural changes in the brain. It is well known that adolescent drug use increases the risk to develop substance use disorders (SUDs) later in life, but the mechanisms that confer this vulnerability are not understood. SUDs are defined by cycles of use, abstinence, and relapse. Intense craving during drug-free periods is often triggered by cues and environmental contexts associated with previous use. In adolescents, there is a gap in knowledge on the fundamental brain and behavioral changes occurring during abstinence. We established an abbreviated model of Coc-SA (ABRV Coc-SA) that permits us to examine relapse during adolescence. We find that adolescent rats show incubation of craving in a previous cocaine-paired context, whereas adults do not. Our data suggest that adolescent rats are more sensitive to cocaine-related contextual stimuli compared to adults, which contrasts with their reduced reactivity to cocaine-paired cues (i.e. conditioned stimuli- CS). Our overall goal is to provide a comprehensive understanding of the distinct cocaine-associated stimuli that trigger craving and relapse in adolescent rats. Aim 1 will test the working hypothesis that context-induced incubation of cocaine seeking in adolescent rats results from earlier onset of incubation compared to adults. Adolescent and adult male and female rats will receive ABRV Coc-SA in an context with diffuse background stimuli, lever extinction in a second context (no reward). After 1, 15 or 30 days of abstinence, Relapse tests will occur in the previous cocaine context. Aim 2 will test the working hypothesis that incubation of cocaine seeking in adolescent rats is specific to contextual stimuli rather than cocaine-paired CSs. Adolescent and adult male and female rats will receive ABRV Coc-SA, with cocaine infusion paired with CS, lever extinction will occur in the same context (no reward, no CS). After 1, 15 or 30 days of abstinence, Relapse Tests will occur with response-contingent presentation of cocaine-paired CS. Our proposal will establish foundational knowledge about the unique triggers of craving in an adolescent rat model. This knowledge is critical to inform improved behavioral interventions targeted to reduce relapse in human adolescents.