Neuronal development genes are key elements mediating the reinforcing effects of methamphetamine, amphetamine, and methylphenidate

Abstract

Rationale: The molecular mechanisms underlying susceptibility to psychostimulant addiction remain unclear. Searching for commonalities in the effects of addictive drugs on brain gene expression is a prolific approach to determine transcriptional signatures influencing drug abuse. Objective: We explored the common transcriptional responses to the reinforcing effects of psychostimulants methamphetamine, amphetamine, and methylphenidate. We also aimed to identify transcriptional changes that may subserve abuse of these drugs. Methods: Genome-wide transcriptome profiling analyses were performed to identify common prefrontal cortical (PFC) and striatal gene expression profiles in drug-naïve (cohort 1) and stimulant-pretreated (cohort 2) rats, which showed a conditioned place preference to and self-administration of methamphetamine, amphetamine, and methylphenidate. Results: In behavioral studies, stimulant-pretreated rats showed behavioral sensitization characterized by enhanced behavioral response to the rewarding or reinforcing effects of psychostimulants. Inflammation-associated genes (e.g., Alas1, S100a8 and S100a9) were identified as the primary differentially expressed genes (DEGs) in both the PFC and the striatum of cohort 1 rats, while neuronal plasticity (Sgk1)- and brain development (e.g., Bhlhe22, Neurod1, Nr4a2, and Msx1)-associated genes comprised the major upregulated DEGs in the striatum of cohort 2 rats. Furthermore, a meta-analysis of the common striatal DEGs in this study along with morphine-regulated striatal transcriptomes in mice (National Center for Biotechnology Information-Gene Expression Omnibus Database Accession Code GSE7762) suggested similar expression profiles of genes involved in neuronal development (e.g., Bhlhe22, Nr4a2). Conclusion: This study provides evidence that brain development-associated genes mediate the reinforcing effects of methamphetamine, amphetamine, and methylphenidate and that these transcripts may underlie susceptibility to psychostimulant addiction. © 2013 Springer-Verlag Berlin Heidelberg.