Parise Lyonna F, Iñiguez Sergio D, Warren Brandon L, Parise Eric M, Bachtell Ryan K, Dietz David M, Nestler Eric J, Bolaños-Guzmán Carlos A
Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
Department of Psychological and Brain Sciences, Texas A&M University, College Station, Texas.
Biol Psychiatry Glob Open Sci. 2024 Nov 12;5(2):100416. doi: 10.1016/j.bpsgos.2024.100416. eCollection 2025 Mar.
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.
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.
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.
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.
中脑边缘奖赏回路中的第二信使信号传导在应激的负面影响以及促进药物滥用的潜在机制中起关键作用。由于伏隔核整合奖赏效价，我们研究了细胞外信号调节蛋白激酶2（ERK2）信号传导如何影响与应激相关的共病的发展，包括负面影响和药物敏感性。
我们评估了慢性不可预测应激如何影响雄性Sprague Dawley大鼠伏隔核内ERK2信号蛋白的磷酸化。使用单纯疱疹病毒，我们上调或下调伏隔核ERK2的激活，并评估对应激诱导刺激（高架十字迷宫、旷场试验、强迫游泳试验）的行为反应以及觅可卡因行为（条件性位置偏爱、自身给药）。我们还检查了ERK2介导的伏隔核内中等棘状神经元树突棘形态的改变。
慢性不可预测应激增加了伏隔核内ERK2信号蛋白的磷酸化。病毒介导的伏隔核ERK2激活增强了对抑郁和焦虑相关刺激的易感性，并增加了觅可卡因行为（条件性位置偏爱和复吸）。这些行为变化与伏隔核中等棘状神经元的短粗和蘑菇状树突棘增加有关。相反，ERK2激活的下调减弱了强迫游泳试验中与情感相关的行为反应，并减弱了可卡因的奖赏效应，而不影响伏隔核树突棘形态。
伏隔核ERK2导致应激诱导的行为缺陷，包括焦虑和抑郁样表型，同时促进觅可卡因行为。这些发现表明，伏隔核中的ERK2信号传导在这些相关综合征的共病中起作用。
