Extended access self-administration of methamphetamine is associated with age- and sex-dependent differences in drug taking behavior and recognition memory deficits in rats

Individuals who begin drug use during early adolescence experience more adverse consequences compared to those initiating later, especially if they are female. The mechanisms for these age and gender differences remain obscure, but studies in rodents suggest that psychostimulants may disrupt the normal ontogeny of dopamine and glutamate systems in the prefrontal cortex (PFC). Here, we studied Sprague-Dawley rats of both sexes who began methamphetamine (METH, i.v.) self-administration (SA) in adolescence (postnatal [P] day 41) or adulthood (P91). Rats received seven daily 2-h SA sessions with METH or saccharin as the reinforcer, followed by 14 daily long access (LgA; 6 h) sessions. After 7 and 14 days of abstinence, novel object (OR) or object-in-place (OiP) recognition was assessed. PFC and nucleus accumbens were collected 7 days after the final cognitive test and NMDA receptor subunits and dopamine D1 receptor expression was measured. We found that during LgA sessions, adolescent-onset rats escalated METH intake more rapidly than adult-onset rats, with adolescent-onset females earning the most infusions. Adolescent-onset rats exhibited modest deficits in OiP compared to adult-onset rats, but there was no sex difference in this effect and no groups differed in OR. We found no group differences in D1 and NMDA receptor expression, suggesting no long-lasting alteration of ontogenetic expression profiles. Our findings suggest that adolescent-onset drug use is more likely to lead to compulsive-like patterns of drug-taking and subsequent dysfunction of PFC-dependent cognition.