Increased cocaine-induced conditioned place preference during periadolescence in maternally separated male BALB/c mice: the role of cortical BDNF, microRNA-212, and MeCP2

Abstract

Early life stress is a major risk factor for cocaine addiction; however, the underlying molecular mechanisms remain relatively unexplored. MicroRNA-212 (miR-212) and methyl CpG binding protein 2 (MeCP2) have recently emerged as key regulators of brain-derived neurotrophic factor (BDNF) signaling during the acquisition and maintenance of cocaine-seeking behaviors. We therefore investigated the effect of maternal separation (MS) on cocaine-induced conditioned place preference (CPP) during periadolescence and how this influences miR-212, Mecp2, and Bdnf expressions in the prefrontal cortex. Male BALB/c mice subjected to MS (3h/day) from postnatal day 2 to 15 or normal animal facility rearing (AFR) were tested for CPP at postnatal day 45, or not exposed to experimental manipulations (drug-naïve animals). Cultured primary cortical neurons were used to determine miR-212 expression changes following depolarization by KCL treatment. MS increased cocaine-induced CPP and decreased Bdnf exon IV expression, which correlated with higher CPP scores in such animals. An experience-dependent decrease in miR-212 expression was observed following CPP test. This effect was mimicked in primary cortical neurons in vitro, under activity-dependent conditions. In contrast, increased Mecp2 expression was found after CPP test, suggesting an opposing relationship between miR-212 and Mecp2 expression following cocaine place preference acquisition. However, these effects were not present in mice exposed to MS. Together, our results suggest that early life stress can enhance the motivational salience for cocaine-paired cues during periadolescence, and that altered expression of miR-212, Mecp2, and Bdnf in the prefrontal cortex is involved in this process.