31. Neurotoxicity Gene Expression Following Adolescent Amphetamine and Methylphenidate Exposure

Abstract

There is a well-documented increase in the use, misuse, and diversion of prescription stimulants used to treat ADHD, especially for adolescents. Considering the sensitivity of neural development during adolescence, there is a need to investigate the implications of these drug exposures. We previously studied the alteration of dopamine- and neuroplasticity-related gene expressions in the dopaminergic prefrontal cortex (PFC) and striatum (STR) following exposure to clinically relevant doses of amphetamine (Adderall; AMPH) and methylphenidate (Ritalin; MPD). From our findings, we hypothesized that MPD exposure has neurotoxic implications, decreasing gene expression, and AMPH-induced neuroplasticity is coupled with change in neurotoxicity gene expressions. Female and male C57Bl/6J mice were given 1mg/kg of AMPH, MPD, or an equivalent volume of saline during early adolescence (P22-31). After the last injection, the STR and PFC were micro-dissected and the total RNA from each region was isolated. We noted mRNA expression changes of genes using a PCR neurotoxicity-array in several functional domains using quantitative RT-PCR. In both the PFC the STR, drug, drug by sex, and drug by sex by domain differences were noted. With many alterations inducing apoptosis and few inhibiting apoptosis, apoptosis is a candidate for neurotoxic effects in both AMPH and MPD treatments. Overall the genetic expression patterns suggest a greater effect in the male PFC. The drug-induced effects extrapolated provide valuable insight into the susceptibility to drug-induced neurotoxicity during this key developmental window of early adolescence. Such long-term susceptibility to psychostimulant-induced neurotoxicity has many implications to include neuroplasticity, behavioral regulation, and clinical outcomes.