引用

在人类和啮齿动物中，压力引发可卡因寻求的能力是可变的，由先前吸毒的数量和模式决定。本研究研究了促肾上腺皮质激素释放因子(CRF-)调节的多巴胺能投射从腹侧被盖区(VTA)到前边缘皮层在休克诱导的可卡因寻求和自我给药条件下的招募的作用，建立了复发脆弱性。有每日长接触史的雄性大鼠(LgA;14 × 6小时/天)，但不包括短时间访问(ShA;14 x 2小时/天)自我给药表现出强烈的休克诱导可卡因寻求。这与休克诱导的边缘前皮层Fos反应增强和霍乱毒素b回溯标记的VTA神经元投射到边缘前皮层的激活有关。使用基于双病毒交叉hM4Di DREADD(设计药物独家激活的设计受体)的方法对该途径进行化学抑制，防止了休克诱导的可卡因寻求。通过双侧vta内注射CRF受体1 (CRFR1)拮抗剂antalarmin，可以防止休克诱导的恢复和前边缘皮层Fos反应。此外，通过向一侧VTA注射anttalarmin和向对侧半球前边缘皮层注射D1受体拮抗剂SCH23390, crf调节的多巴胺能投射到前边缘皮层的药物学断开，可以防止休克诱导的可卡因寻求。最后，LgA，而不是ShA，可卡因自我给药导致VTA CRFR1 mRNA水平增加，使用原位杂交测量。 Altogether, these findings suggest that excessive cocaine use may establish susceptibility to stress-induced relapse by recruiting CRF regulation of a stressor-responsive mesocortical dopaminergic pathway.SIGNIFICANCE STATEMENTUnderstanding the neural pathways and mechanisms through which stress triggers relapse to cocaine use is critical for the development of more effective treatment approaches. Prior work has demonstrated a critical role for the neuropeptide corticotropin releasing factor (CRF) in stress-induced cocaine seeking. Here we provide evidence that stress-induced reinstatement in a rat model of relapse is mediated by a CRF-regulated dopaminergic projection from the ventral tegmental area (VTA) that activates dopamine D1 receptors in the prelimbic cortex. Moreover, we report that this pathway may be recruited as a result of daily cocaine self-administration under conditions of extended drug access/heightened drug intake, likely as a result of increased CRFR1 expression in the VTA, thereby promoting susceptibility to stress-induced cocaine seeking. Copyright 2018 the authors.