Neurobiology of Disease Juvenile Administration of Concomitant Methylphenidate and Fluoxetine Alters Behavioral Reactivity to Reward- and Mood-Related Stimuli and Disrupts Ventral Tegmental Area Gene Expression in Adulthood

There is a rise in the concurrent use of methylphenidate (MPH) and fluoxetine (FLX) in pediatric populations. However, the long-term neurobiological consequences of combined MPH and FLX treatment (MPH FLX) during juvenile periods are unknown. We administered saline (VEH), MPH, FLX, or MPH FLX to juvenile Sprague Dawley male rats from postnatal day 20 to 34, and assessed their reactivity to rewardand mood-related stimuli 24 h or 2 months after drug exposure. We also assessed mRNA and protein levels within the ventral tegmental area (VTA) to determine the effect of MPH, FLX, or MPH FLX on the extracellular signal-regulated protein kinase-1/2 (ERK) pathway—a signaling cascade implicated in motivation and mood regulation. MPH FLX enhanced sensitivity to drug (i.e., cocaine) and sucrose rewards, as well as anxiety (i.e., elevated plus maze)and stress (i.e., forced swimming)-eliciting situations when compared with VEH-treated rats. MPH FLX exposure also increased mRNA of ERK2 and its downstream targets cAMP response element-binding protein (CREB), BDNF, c-Fos, early growth response protein-1 (Zif268), and mammalian target of rapamycin (mTOR), and also increased protein phosphorylation of ERK2, CREB, and mTOR 2 months after drug exposure when compared with VEH-treated rats. Using herpes simplex virus-mediated gene transfer to block ERK2 activity within the VTA, we rescued the MPH and FLX-induced behavioral deficits seen in the forced-swimming task 2 months after drug treatment. These results indicate that concurrent MPH FLX exposure during preadolescence increases sensitivity to reward-related stimuli while simultaneously enhancing susceptibility to stressful situations, at least in part, due to long-lasting disruptions in ERK signaling within the VTA.