Combined Methylphenidate and Fluoxetine or Cocaine Exposure during Adolescence Alters ERK2-Related Signaling in the VTA and Increase Sensitivity to Nicotine Reward in Adulthood

The most common treatment strategy for adolescents with attention deficit/hyperactivity disorder (ADHD) and major depressive disorder (MDD) is combined methylphenidate (MPH) and fluoxetine (FLX). This has raised concerns because combined MPH+FLX treatment may have pharmacodynamic properties similar to cocaine, potentially increasing drug abuse liability. Chronic exposure to cocaine results in very distinct patterns of gene expression and it is important to know if combined MPH+FLX results in the same pattern of expression. To this end, adult (PD 70-84) and adolescent (postnatal days [PD] 21-34) male mice were exposed to vehicle, MPH, FLX, MPH+FLX, or cocaine treatment twice daily for 15 days. Mice were sacrificed 24 h or 2 months after the last drug injection to assess the effect of drug treatment on the extracellular signal-regulated protein kinse-1/2 (ERK) pathway within the ventral tegmental area (VTA), a brain region known to be key in mediating the reinforcing properties of reward. Sensitivity for nicotine (0.07 mg/kg) was assessed as measured by the place-conditioning paradigm (CPP) 24 hours and 2 months after adolescent drug pretreatment. MPH+FLX and cocaine exposure during adolescence increased mRNA expression of ERK2 and its downstream targets cAMP response element-binding protein (CREB), c-Fos, and early growth response protein (Zif268), and also increased protein phosphorylation ERK2 and CREB 2 months after drug exposure when compared to vehicle-treated controls. Adolescent drug pretreatment increased preference for nicotine when tested in adulthood. These results indicate that combined MPH+FLX and cocaine exposure during adolescence have a similar profile: disrupt the ERK pathway, a signaling cascade implicated in motivation and mood regulation, within the VTA, while increasing sensitivity for nicotine in adulthood.