Adolescent vulnerability to methamphetamine: dose-related escalation of self-administration and cue extinction deficits

Adolescence is the most vulnerable period for developing substance use disorders, with adolescents relapsing more compared to adults even after therapy. Methamphetamine is a widely-used illicit psychostimulant by adolescents that is showing a world-wide increase in its purity. However, how adolescents respond to changing doses of methamphetamine or reinstate use after therapy is poorly understood. Therefore, we examined intravenous self-administration of methamphetamine at varying doses followed by instrumental extinction, cue extinction and cue-induced reinstatement of methamphetamine seeking in adolescent and adult rats. We observed with two different starting doses (0.03 or 0.1 mg/kg/infusion) that naive adolescent and adult rats acquire methamphetamine self-administration similarly in 2-hr daily sessions. However, a higher level of methamphetamine use was observed in adolescents compared to adults when the dose was increased, and this was regardless of the starting dose. Adolescent rats exhibited more persistent methamphetamine seeking behaviors, performing more lever presses when methamphetamine was not available during instrumental extinction. Lastly, adolescent rats still showed significant cue-induced reinstatement after 2 sessions of cue extinction, which was enough to completely prevent cue-induced reinstatement in adult rats. Taken together, our findings identify specific aspects of drug taking and seeking that are affected by methamphetamine use during adolescence compared to adulthood. We suggest that adolescents are vulnerable to methamphetamine use disorder because they are more likely to escalate methamphetamine use when dose is increased and more likely to reinstate to methamphetamine-associated cues after cue exposure therapy.