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

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Abstract

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.

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Acknowledgments

This work was supported by R01DA026854 from the National Institute on Drug Abuse (NIDA). LF Alcantara was supported by a McKnight Fellowship from the Florida Education Fund, BL Warren by training grant T32MH093311 from the National Institute of Mental Health (NIMH), and SD Iñiguez by a NRSA F31027300 fellowship from NIDA.

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The authors report no conflict of interest.

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Correspondence to Carlos A. Bolaños-Guzmán.

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Alcantara, L.F., Warren, B.L., Parise, E.M. et al. Effects of psychotropic drugs on second messenger signaling and preference for nicotine in juvenile male mice. Psychopharmacology 231, 1479–1492 (2014). https://doi.org/10.1007/s00213-014-3434-4

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