Adolescent exposure to psychostimulants cross-sensitizes adults to methamphetamine with a drug and sex specific effect

Abstract

Behavioral sensitization, a hallmark of addiction, is indicative of enduring alterations that result from previous drug exposures. The current study explores the effect of psychostimulants, including d-amphetamine, methylphenidate, methamphetamine, and cocaine, on cross-sensitization to another drug of abuse, methamphetamine. Each of these psychomotor stimulants increases synaptic dopamine, but does so with a distinct mechanism of action. Male and female C57Bl6/J mice were exposed to one of the psychostimulants or saline during adolescence (P22-32) followed by a period without drug exposure (>8 weeks). During adulthood, mice were challenged with a subacute dose of methamphetamine or saline and tested in an open-field chamber to assess changes in locomotor activity. Mice exposed to a stimulant preexposure and methamphetamine challenge exhibited higher total activity than their controls in a drug-specific fashion. Additionally, locomotor activity was altered differently in males and females within drug conditions. Males were more susceptible to amphetamine-induced activity changes while females were more susceptible to methylphenidate-induced changes. These results suggest that adolescent exposure to psychostimulants during the critical developmental window have a lasting neurobehavioral effect into adulthood. The novel drug and sex-specific alterations in locomotion have clinical implications and warrant further investigation to elucidate the molecular mechanisms underlying the observed changes.