Extracellular signal-regulated protein kinase-2 signaling in the nucleus accumbens facilitates stress-susceptibility and cocaine reinstatement.

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BackgroundSecond 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. Since the nucleus accumbens (NAc) integrates reward valence, we investigated how extracellular signal-regulated protein kinase-2 (ERK2) signaling affects the development of stress-related comorbidities, including negative affect and drug sensitivity. MethodsWe assessed how chronic unpredictable stress (CUS) 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 (MSNs) within the NAc. ResultsCUS 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 MSNs. 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. ConclusionsNAc 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.