Effects of psychotropic drugs on second messenger signaling and preference for nicotine in juvenile male mice

Rationale: A common treatment strategy for pediatric attention deficit/hyperactivity disorder (ADHD) and major depressive disorder (MDD) is combined methylphenidate (MPH) and fluoxetine (FLX). This has raised concerns because MPH+FLX treatment may have pharmacodynamic properties similar to cocaine, potentially increasing drug abuse liability. Objectives: To examine the short- and long-term consequences of repeated vehicle, MPH, FLX, MPH+FLX, and cocaine treatment on gene expression in juvenile (postnatal days [PD] 20-34) and adult (PD 70-84) male mice. We further assessed whether juvenile drug treatment influenced subsequent sensitivity for nicotine in adulthood. Methods: Juvenile and adult C57BL/6J mice received vehicle, MPH, FLX, MPH+FLX, or cocaine twice-daily for 15 consecutive days. Mice were sacrificed 24 h or 2 months after the last drug injection to assess drug-induced effects on the extracellular signal-regulated protein kinase-1/2 (ERK) pathway within the ventral tegmental area. Subsequent sensitivity for nicotine (0.05, 0.07, and 0.09 mg/kg) was measured using the place-conditioning paradigm (CPP) 24 h and 2 months after juvenile drug exposure. Results: MPH+FLX, or cocaine exposure in juvenile mice increased mRNA expression of ERK2 and its downstream targets (CREB, cFos, and Zif268), and increased protein phosphorylation of ERK2 and CREB 2 months after drug exposure. Similar mRNA findings were observed in the adult-treated mice. Findings on gene expression 24 h following drug treatment were variable. Juvenile drug exposure increased preference for nicotine when tested in adulthood. Conclusions: Early-life MPH+FLX, or cocaine exposure similarly disrupts the ERK pathway, a signaling cascade implicated in motivation and mood regulation, and increases sensitivity for nicotine in adulthood.