ERK2 Signaling in the Nucleus Accumbens Facilitates Stress Susceptibility and Cocaine Reinstatement.

BACKGROUND: Second-messenger signaling within the mesolimbic reward circuit plays a key role in the negative effects of stress and the underlying mechanisms that promote drug abuse. Because the nucleus accumbens (NAc) integrates reward valence, we investigated how ERK2 (extracellular signal-regulated protein kinase-2) signaling affects the development of stress-related comorbidities, including negative affect and drug sensitivity. METHODS: We assessed how chronic unpredictable stress influenced the phosphorylation of ERK2-signaling proteins within the NAc of male Sprague Dawley rats. Using a herpes simplex virus, we either upregulated or downregulated NAc ERK2 activation and evaluated behavioral responses to stress-eliciting stimuli (elevated plus maze, open field, forced swim test) and cocaine-seeking behavior (conditioned place preference, self-administration). We also examined ERK2-mediated modifications in spine morphology of medium spiny neurons within the NAc. RESULTS: Chronic unpredictable stress increased the phosphorylation of ERK2-signaling proteins within the NAc. Viral-mediated activation of NAc ERK2 enhanced susceptibility to both depression- and anxiety-related stimuli and increased cocaine-seeking behavior (conditioned place preference and reinstatement). These behavioral changes were associated with an increase in stubby and mushroom spines of NAc medium spiny neurons. Conversely, downregulation of ERK2 activation attenuated affect-related behavioral responses in the forced swim test and blunted cocaine's rewarding effects without influencing NAc spine morphology. CONCLUSIONS: NAc ERK2 contributes to stress-induced behavioral deficits, including anxiety- and depression-like phenotypes, while promoting cocaine-seeking behavior. These findings suggest that ERK2 signaling in the NAc plays a role in the comorbidity of these related syndromes.