Augmented cocaine seeking in response to stress or CRF delivered into the ventral tegmental area following long-access self-administration is mediated by CRF receptor type 1 but not CRF receptor type 2.
Augmented cocaine seeking in response to stress or CRF delivered into the ventral tegmental area following long-access self-administration is mediated by CRF receptor type 1 but not CRF receptor type 2.
复制标题
DOI：
10.1523/jneurosci.1393-11.2011
复制
发表时间：
2011-08-03
期刊：
影响因子：
--
通讯作者：
Mantsch JR
中科院分区：
文献类型：
--
作者：
Blacktop JM;Seubert C;Baker DA;Ferda N;Lee G;Graf EN;Mantsch JR
压力事件是可卡因成瘾者复吸的决定因素。过量使用可卡因可能会通过改变大脑促肾上腺皮质激素释放因子（CRF）对寻求药物的神经回路的调节而增加对压力源诱发的复发的易感性。我们之前报道过，压力源（足部电击）对可卡因的恢复是 CRF 依赖性的，并且与每天提供较短时间可卡因摄入的大鼠（ShA 大鼠；每天 2 小时）相比，在长期摄入（LgA；每天 6 小时）条件下自我施用可卡因 14 天的大鼠会增强。此外，我们已经证明，LgA 大鼠对 icv CRF 给药的恢复反应增强。这项研究探讨了腹侧被盖区 (VTA) 对 CRF 反应性的改变在 CRF 和压力引起的可卡因寻求依赖性增加中的作用。双侧 VTA 内给予 CRF（250 或 500 ng/侧）可在 LgA 大鼠中产生恢复，但在 ShA 大鼠中则不然。在 LgA 大鼠中，通过向 VTA 中施用 CRF-R1 受体拮抗剂 antalarmin（500 ng/侧）或 CP-376395（500 ng/侧）而不是 CRF-R2 受体拮抗剂 astressin-2B（500 ng 或 1 μg/侧）或 ASV-30（500 ng/侧）来阻断 VTA 内 CRF 诱导的恢复。同样，VTA 内的 antalarmin（而非 astressin-2B）可以阻断 LgA 大鼠中足部电击诱导的恢复。相比之下，VTA 内 antalarmin 和 CP-376395 都不会改变食物强化的杠杆压力。 VTA 内注射 CRF-R1 受体选择性激动剂 Cortagine（100 ng/侧）而非 CRF-R2 受体选择性激动剂大鼠尿皮质素 II（250 ng/侧）可产生恢复。这些发现表明，过量使用可卡因会增加对压力源诱发的复发的易感性，部分原因是增强了 VTA 中成瘾相关神经回路的 CRF-R1 受体依赖性调节。
Stressful events are determinants of relapse in recovering cocaine addicts. Excessive cocaine use may increase susceptibility to stressor-induced relapse through alterations in brain corticotropin-releasing factor (CRF) regulation of neurocircuitry involved in drug seeking. We previously reported that the reinstatement of cocaine seeking by a stressor (footshock) is CRF-dependent and is augmented in rats that self-administered cocaine under long-access (LgA; 6 hrs daily) conditions for 14 days when compared to rats provided shorter daily cocaine access (ShA rats; 2 hrs daily). Further, we have demonstrated that reinstatement in response to icv CRF administration is heightened in LgA rats. This study examined the role of altered ventral tegmental area (VTA) responsiveness to CRF in intake-dependent increases in CRF- and stress-induced cocaine seeking. Bilateral intra-VTA administration of CRF (250 or 500 ng/side) produced reinstatement in LgA but not ShA rats. In LgA rats, intra-VTA CRF-induced reinstatement was blocked by administration of the CRF-R1 receptor antagonists antalarmin (500 ng/side) or CP-376395 (500 ng/side) but not the CRF-R2 receptor antagonists astressin-2B (500 ng or 1 μg/side) or ASV-30 (500 ng/side) into the VTA. Likewise, intra-VTA antalarmin, but not astressin-2B, blocked footshock-induced reinstatement in LgA rats. By contrast, neither intra-VTA antalarmin nor CP-376395 altered food-reinforced lever pressing. Intra-VTA injection of the CRF-R1 receptor-selective agonist, cortagine (100 ng/side) but not the CRF-R2 receptor-selective agonist rat urocortin II (250 ng/side) produced reinstatement. These findings reveal that excessive cocaine use increases susceptibility to stressor-induced relapse in part by augmenting CRF-R1 receptor dependent regulation of addiction-related neurocircuitry in the VTA.