Social Stress and CRF-Dopamine Interactions in the VTA: Role in Long-Term Escalation of Cocaine Self-Administration
Social Stress and CRF-Dopamine Interactions in the VTA: Role in Long-Term Escalation of Cocaine Self-Administration
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DOI：
10.1523/jneurosci.3942-13.2014
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发表时间：
2014-05-07
影响因子：
5.3
通讯作者：
Miczek, Klaus A.
中科院分区：
文献类型：
--
作者：
Boyson, Christopher O.;Holly, Elizabeth N.;Miczek, Klaus A.
可卡因摄入量增加的起源中神经适应的性质仍然是一个相当感兴趣的话题。间歇性社交失败压力诱导运动和多巴胺能交叉致敏可卡因，以及可卡因自我管理升级。本研究旨在探讨社交失败应激时腹侧被盖区（VTA）促肾上腺皮质激素释放因子受体亚型1和2（CRFR 1，CRFR 2）的作用。本研究调查了在每次社交失败之前将CRFR 1或CRFR 2拮抗剂直接注射到腹侧被盖区是否会防止大鼠发生以后的（1）运动致敏、（2）多巴胺能致敏和（3）可卡因自我给药增加。在第1、4、7和10天社交失败应激（或处理）前20分钟，将CRFR 1拮抗剂CP 376395（50或500 ng/侧）、CRFR 2拮抗剂Astressin（2）-B（100或1000 ng/侧）或溶媒（aCSF）显微注射到VTA中。10天后，将大鼠注射可卡因（10 mg/kg，i. p.）并通过体内微透析评估通过行走活动测量的运动致敏性或通过丘脑核壳（NAcSh）中的细胞外多巴胺（DA）测量的多巴胺能致敏性。运动致敏试验后，静脉注射可卡因自我管理。CRFR 1（而非CRFR 2）的VTA内拮抗作用抑制了可卡因对运动交叉致敏的诱导，而在24小时狂欢期间，两者均阻止了多巴胺能交叉致敏并增加了可卡因自我给药。“这可能表明运动敏感性和可卡因服用之间的分离。这些数据还表明，CRF和腹侧被盖区DA神经元之间的相互作用投射到NAcSh是必不可少的多巴胺能交叉致敏可卡因的发展。
The nature of neuroadaptations in the genesis of escalated cocaine taking remains a topic of considerable interest. Intermittent social defeat stress induces both locomotor and dopaminergic cross-sensitization to cocaine, as well as escalated cocaine self-administration. The current study examines the role of corticotropin releasing factor receptor subtypes 1 and 2 (CRFR1, CRFR2) within the ventral tegmental area (VTA) during social defeat stress. This study investigated whether injecting either a CRFR1 or CRFR2 antagonist directly into the VTA before each social defeat would prevent the development of later (1) locomotor sensitization, (2) dopaminergic sensitization, and (3) escalated cocaine self-administration in rats. CRFR1 antagonist CP376395 (50 or 500 ng/side), CRFR2 antagonist Astressin(2)-B (100 or 1000 ng/side), or vehicle (aCSF) was microinjected into the VTA 20 min before social defeat stress (or handling) on days 1, 4, 7, and 10. Ten days later, rats were injected with cocaine (10 mg/kg, i.p.) and assessed for either locomotor sensitization, measured by walking activity, or dopaminergic sensitization, measured by extracellular dopamine (DA) in the nucleus accumbens shell (NAcSh) through in vivo microdialysis. Locomotor sensitization testing was followed by intravenous cocaine self-administration. Intra-VTA antagonism of CRFR1, but not CRFR2, inhibited the induction of locomotor cross-sensitization to cocaine, whereas both prevented dopaminergic cross-sensitization and escalated cocaine self-administration during a 24 h "binge." This may suggest dissociation between locomotor sensitization and cocaine taking. These data also suggest that interactions between CRF and VTA DA neurons projecting to the NAcSh are essential for the development of dopaminergic cross-sensitization to cocaine.