Attenuated Cocaine Seeking After Adolescent-Onset of Cocaine Self-Administration in Male Rats: Behavior, Environment, and Genes

Recreational drug use peaks in the developmental stage of adolescence in humans. In this dissertation, we used a rodent model of adolescence and behavioral assessments of intravenous (i.v.) cocaine self-administration and reinstatement of cocaine-seeking to explore age differences in these cocaine-related behaviors, and then tested for the influence of environmental enrichment and for correlations between behavior and expression of plasticity genes. Although taking similar amount of cocaine, male rats trained to self-administer cocaine during adolescence (adolescent-onset) showed attenuated cue-induced reinstatement of cocaine seeking compared with adults. This attenuated cue-induced reinstatement did not generalize to a natural reward, sucrose pellets. Then we asked whether the attenuated reinstatement may be due to rapid developmental re-organization of reinforcement circuits (high plasticity) in adolescent-onset groups. To stimulate or inhibit neuroplasticity, subjects experienced environmental enrichment or impoverishment during abstinence. Environmental manipulations had no effect in adolescent-onset groups, whereas the enriched environment attenuated cue-induced reinstatement in adults compared with their impoverished counterparts. Thus, we turned to internal factors that may contribute to age-differences in reinstatement of cocaine seeking. Using in situ hybridization to quantify the mRNA for two neuroplasticity-related genes, activity-regulated cytoskeletal-associated gene (arc) and brain-derived neurotrophic factor (bdnf), we identified that overall, arc expression in the nucleus accumbens (NAc) and bdnf expression in the medial prefrontal cortex (mPFC) was higher in adolescent-onset than in adult groups. Together our data suggest that adolescence in rodents may be a period of relative biological resistance to some long-term drug effects