Laboratorio de Neuroquímica y Neurofarmacología, Centro de Neurobiología y Plasticidad Cerebral, Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.
Laboratory of Cellular and Molecular Biology of Addiction, Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.
Pharmacol Res. 2015 Nov;101:116-23. doi: 10.1016/j.phrs.2015.08.015. Epub 2015 Aug 28.
A higher vulnerability to drug abuse has been observed in human studies of individuals exposed to chronic or persistent stress, as well as in animal models of drug abuse. Here, we explored the effect of repeated immobilization stress on cocaine-induced increase in dopamine extracellular levels in VTA and its regulation by corticotropin-releasing factor (CRF) and GABA systems. Cocaine (10mg/Kg i.p.) induced an increase of VTA DA extracellular levels in control rats. However, this effect was not observed in repeated stress rats. Considering the evidence relating stress with CRF, we decided to perfuse CRF and CP-154526 (selective antagonist of CRF1 receptor) in the VTA of control and repeated stress rats, respectively. We observed that perfusion of 20μM CRF inhibited the increase of VTA DA extracellular levels induced by cocaine in control rats. Interestingly, we observed that in the presence of 10μM CP-154526, cocaine induced a significant increase of VTA DA extracellular levels in repeated stress rats. Regarding the role of VTA GABA neurotransmission, cocaine administration induced a significant increase in VTA GABA extracellular levels only in repeated stress rats. Consistently, cocaine was able to increase VTA DA extracellular levels in repeated stress rats when 100μM bicuculline, an antagonist of GABAA receptor, was perfused intra VTA. Thus, both CRF and GABA systems are involved in the lack of response to cocaine in the VTA of repeated stress rats. It is tempting to suggest that the loss of response in VTA dopaminergic neurons to cocaine, after repeated stress, is due to an interaction between CRF and GABA systems.
在慢性或持续性应激的人类研究以及药物滥用的动物模型中，已经观察到个体对药物滥用的易感性更高。在这里，我们探讨了反复束缚应激对 VTA 中可卡因诱导的多巴胺细胞外水平升高的影响及其对促肾上腺皮质释放因子 (CRF) 和 GABA 系统的调节作用。可卡因 (10mg/Kg ip) 诱导对照大鼠 VTA 中 DA 细胞外水平升高。然而，这种作用在反复应激大鼠中并未观察到。考虑到应激与 CRF 相关的证据，我们决定分别在对照和反复应激大鼠的 VTA 中灌注 CRF 和 CP-154526（CRF1 受体的选择性拮抗剂）。我们观察到，20μM CRF 的灌注抑制了对照大鼠中可卡因诱导的 VTA DA 细胞外水平升高。有趣的是，我们观察到在存在 10μM CP-154526 的情况下，可卡因在反复应激大鼠中引起 VTA DA 细胞外水平的显著升高。关于 VTA GABA 神经传递的作用，可卡因给药仅在反复应激大鼠中引起 VTA GABA 细胞外水平的显著升高。一致地，当在 VTA 内灌注 100μM 荷包牡丹碱（GABAA 受体拮抗剂）时，可卡因能够增加反复应激大鼠的 VTA DA 细胞外水平。因此，CRF 和 GABA 系统都参与了反复应激大鼠 VTA 中对可卡因反应的缺失。这让人联想到，在反复应激后，VTA 多巴胺能神经元对可卡因的反应丧失是由于 CRF 和 GABA 系统之间的相互作用所致。
