Social defeat stress-induced sensitization and escalated cocaine self-administration: the role of ERK signaling in the rat ventral tegmental area.
Social defeat stress-induced sensitization and escalated cocaine self-administration: the role of ERK signaling in the rat ventral tegmental area.
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DOI：
10.1007/s00213-014-3796-7
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发表时间：
2015-05
影响因子：
3.4
通讯作者：
Miczek, Klaus A.
中科院分区：
文献类型：
--
作者：
Yap, Jasmine J.;Chartoff, Elena H.;Holly, Elizabeth N.;Potter, David N.;Carlezon, William A., Jr.;Miczek, Klaus A.
间歇性社交失败压力可以诱导神经适应，促进强迫性吸毒。在mesocorticolimbic电路，重复可卡因管理激活细胞外信号调节激酶（ERK）。本实验研究ERK磷酸化的变化是否是必要的行为和神经适应，发生作为间歇性失败的压力的结果。在10天的时间里，大鼠经历了四次短暂的间歇性失败。在最后一次失败后10天，用可卡因（10 mg/kg，i. p.）或生理盐水，并在中皮质边缘区检测ERK活性。为了确定ERK在失败应激诱导的行为敏化中的作用，我们在4次失败之前将MAPK/ERK激酶抑制剂U 0126（1 μg/侧）或载体（20%DMSO）双侧微量注射到腹侧被盖区（VTA）。在最后一次失败后10天，评估运动活动对可卡因（10 mg/kg，i. p.）的行为交叉致敏的表达。此后，大鼠自我管理的可卡因固定和渐进的比例强化计划，包括24小时连续访问“狂欢”（0.3毫克/公斤/输注）。我们发现，反复失败的压力增加ERK磷酸化的腹侧被盖区。在每次社交失败之前抑制VTA ERK减弱了应激诱导的致敏作用的发展，并防止了连续访问狂欢期间应激诱导的可卡因自我给药增强。这些结果表明，由于短暂的失败，增强VTA中ERK的激活在诱导致敏和可卡因服用升级中至关重要。
Intermittent social defeat stress can induce neuroadaptations that promote compulsive drug taking. Within the mesocorticolimbic circuit, repeated cocaine administration activates extracellular signal-regulated kinase (ERK). The present experiments examine whether changes in ERK phosphorylation are necessary for the behavioral and neural adaptations that occur as a consequence of intermittent defeat stress. Rats were exposed to four brief intermittent defeats over the course of 10 days. Ten days after the last defeat, rats were challenged with cocaine (10 mg/kg, i.p.) or saline, and ERK activity was examined in mesocorticolimbic regions. To determine the role of ERK in defeat stress-induced behavioral sensitization, we bilaterally microinjected the MAPK/ERK kinase inhibitor U0126 (1 μg/side) or vehicle (20% DMSO) into the ventral tegmental area (VTA) prior to each of 4 defeats. Ten days following the last defeat, locomotor activity was assessed for the expression of behavioral cross-sensitization to cocaine (10 mg/kg, i.p.). Thereafter, rats self-administered cocaine under fixed and progressive ratio schedules of reinforcement, including a 24-h continuous access “binge” (0.3 mg/kg/infusion). We found that repeated defeat stress increased ERK phosphorylation in the VTA. Inhibition of VTA ERK prior to each social defeat attenuated the development of stress-induced sensitization and prevented stress-induced enhancement of cocaine self-administration during a continuous access binge. These results suggest that enhanced activation of ERK in the VTA due to brief defeats is critical in the induction of sensitization and escalated cocaine taking.
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影响因子：
1.7
作者：
Bruchas MR;Xu M;Chavkin C
通讯作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.92.17.7686
发表时间：
1995-08-15
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
7.6
作者：
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Miczek, KA
DOI：
10.1073/pnas.172091899
发表时间：
2002-08-20
影响因子：
11.1
作者：
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通讯作者：
Nestler, EJ