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. Nevertheless, the potential association between early onset of drug use and higher rates of addiction in adulthood has not been thoroughly studied. In this series of experiments, 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. Male rats were trained to self-administer cocaine during either adolescence (adolescent-onset groups) or adulthood (adult-onset groups), and reinstatement of drug-seeking induced by cocaine or cocaine-associated cues was assessed after various durations of abstinence from cocaine intake. First, although taking similar amounts of cocaine during self-administration, adolescent-onset groups surprisingly exhibited attenuated time-dependent increases in cue-induced reinstatement compared with adults. On the other hand, time-dependent increases in cue-induced reinstatement of sucrose-seeking were similar across age groups, suggesting that age differences in reinstatement of cocaine seeking depend on specific effects of cocaine, not a compromised ability among younger rats to associate cues with rewards. 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 and impoverishment during abstinence. Environmental manipulations had no effect in adolescentonset groups, whereas the enriched environment attenuated cue-induced reinstatement in adultonset groups compared with their impoverished counterparts. Last we tested age differences in basal or cocaine-related expression of two neuroplasticity-related genes, activity-regulated cytoskeletal-associated gene (arc) and brain-derived neurotrophic factor (bdnf). Age differences in gene expression after self-administration or cue-induced reinstatement were brain region specific. 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 may be a period of relative biological resistance to some longterm drug effects. INDEX WORDS: Ontogeny, Addiction, Relapse, Neuroplasticity, Enrichment, Gene ATTENUATED COCAINE SEEKING AFTER ADOLESCENT-ONSET OF COCAINE SELF-ADMINISTRATION IN MALE RATS: BEHAVIOR, ENVIRONMENT, AND GENES