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

IF 4 Q2 NEUROSCIENCES
Lyonna F. Parise , Sergio D. Iñiguez , Brandon L. Warren , Eric M. Parise , Ryan K. Bachtell , David M. Dietz , Eric J. Nestler , Carlos A. Bolaños-Guzmán
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Abstract

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.
伏隔核ERK2信号通路促进应激敏感性和可卡因恢复。
背景:中脑边缘奖赏回路中的第二信使信号在压力的负面影响和促进药物滥用的潜在机制中起着关键作用。由于伏核(NAc)整合了奖励价,我们研究了ERK2(细胞外信号调节蛋白激酶-2)信号如何影响应激相关合并症的发展,包括负面影响和药物敏感性。方法:我们评估了慢性不可预测的应激如何影响雄性sd大鼠NAc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NAc ERK2的激活,并评估对应激刺激(升高加上迷宫、开阔场地、强迫游泳测试)和可卡因寻求行为(条件位置偏好、自我给药)的行为反应。我们还研究了erk2介导的NAc内中棘神经元脊柱形态的改变。结果:慢性不可预测的应激增加了NAc内erk2信号蛋白的磷酸化。病毒介导的NAc ERK2激活增强了对抑郁和焦虑相关刺激的易感性,并增加了可卡因寻求行为(条件位置偏好和恢复)。这些行为变化与NAc中棘神经元粗短棘和蘑菇棘的增加有关。相反,ERK2激活的下调减弱了强迫游泳试验中与情绪相关的行为反应,减弱了可卡因的奖励作用,但不影响NAc脊柱形态。结论:NAc ERK2有助于应激诱导的行为缺陷,包括焦虑和抑郁样表型,同时促进可卡因寻求行为。这些发现表明,NAc中的ERK2信号在这些相关综合征的合并症中起作用。
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来源期刊
Biological psychiatry global open science
Biological psychiatry global open science Psychiatry and Mental Health
CiteScore
4.00
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