Gene Expression Alterations Following Adolescent Amphetamine and Methylphenidate Exposure in C57BI/6J Mice

Abstract

There is a well-documented increase in the use, misuse, and diversion of prescription stimulants used to treat ADHD, especially for adolescents. Given the sexually dimorphic, neural maturation during this developmental time frame, there is a need to investigate the long-term implications of these drug exposures. We previously demonstrated that exposure to clinically relevant doses of amphetamine (Adderall; AMPH) and methylphenidate (Ritalin; MPD) during early adolescence in C57BI/6J mice leads to sex- and drug-specific behavioral alterations in adulthood. This altered psychomotor response is indicative of an increased susceptibility to addiction. We hypothesize that altered gene regulation in dopaminergic regions following adolescent MPD and AMPH is the underlying mechanism of these long-term, sex- and drug-specific behavioral alterations. The striatum (STR) and prefrontal cortex (PFC), which are dopaminergic regions involved in addictive behaviors, were examined. Female and male mice were given 1mg/kg of AMPH, MPD, or an equivalent volume of saline during early adolescence. After the last injection, the STR and PFC were micro-dissected and the total RNA from each region was isolated. We evaluated mRNA expression of dopamine genes (D1, D2, DAT, VMAT2) and plasticity genes (TrKB and BDNF) using quantitative RT-PCR. Sex by drug analyses indicate a potential role for altered expression of these genes in behavioral sensitization. These results will provide insight into the underlying sexually dimorphic effects of prescription stimulants on normal brain development as well as to inform clinical practice and novel therapeutic approaches in consideration of the noted increased susceptibility to addiction.

Key words: neuroplasticity, methylphenidate, amphetamine, adolescence, addiction, mRNA expression