BACKGROUND Clinical reports suggest that rather than directly driving cocaine use, stress may create a biological context within which other triggers for drug use become more potent. We hypothesize that stress-induced increases in corticosterone "set the stage" for relapse by promoting endocannabinoid-induced attenuation of inhibitory transmission in the prelimbic cortex (PL). METHODS We have established a rat model for these stage-setting effects of stress. In this model, neither a stressor (electric footshock) nor stress-level corticosterone treatment alone reinstates cocaine seeking following self-administration and extinction, but each treatment potentiates reinstatement in response to an otherwise subthreshold cocaine priming dose (2.5 mg/kg, intraperitoneal). The contributions of endocannabinoid signaling in the PL to the effects of stress-level corticosterone on PL neurotransmission and cocaine seeking were determined using intra-PL microinfusions. Endocannabinoid-dependent effects of corticosterone on inhibitory synaptic transmission in the rat PL were determined using whole-cell recordings in layer V pyramidal neurons. RESULTS Corticosterone application attenuated inhibitory synaptic transmission in the PL via cannabinoid receptor type 1 (CB1R)- and 2-arachidonoylglycerol-dependent inhibition of gamma-aminobutyric acid release without altering postsynaptic responses. The ability of systemic stress-level corticosterone treatment to potentiate cocaine-primed reinstatement was recapitulated by intra-PL injection of corticosterone, the CB1R agonist WIN 55,212-2, or the monoacylglycerol lipase inhibitor URB602. Corticosterone effects on reinstatement were attenuated by intra-PL injections of either the CB1R antagonist, AM251, or the diacylglycerol lipase inhibitor, DO34. CONCLUSIONS These findings suggest that stress-induced increases in corticosterone promote cocaine seeking by mobilizing 2-arachidonoylglycerol in the PL, resulting in CB1R-mediated attenuation of inhibitory transmission in this brain region.

中文翻译：

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压力通过前肢皮质中依赖糖皮质激素的内源性大麻素动员促进药物寻找

背景 临床报告表明，压力不是直接推动可卡因的使用，而是创造了一种生物学背景，在这种背景下，其他药物使用诱因变得更加有效。我们假设压力诱导的皮质酮增加通过促进内源性大麻素诱导的前边缘皮层 (PL) 抑制性传递的衰减“为复发奠定了基础”。方法 我们已经建立了压力的这些阶段设置效应的大鼠模型。在该模型中，单独的压力源（电足震）和压力水平的皮质酮治疗都不能恢复自我给药和灭绝后的可卡因寻求，但每种治疗都会增强对其他阈下可卡因启动剂量（2.5 mg/kg，腹膜内）的响应. PL 中的内源性大麻素信号传导对应激水平皮质酮对 PL 神经传递和可卡因寻求的影响的贡献是使用 PL 内微量输注确定的。使用 V 层锥体神经元中的全细胞记录确定皮质酮对大鼠 PL 中抑制性突触传递的内源性大麻素依赖性影响。结果 皮质酮应用通过大麻素受体 1 型 (CB1R) 和 2-花生四烯酸甘油依赖性抑制 γ-氨基丁酸释放减弱了 PL 中的抑制性突触传递，而不会改变突触后反应。通过 PL 内注射皮质酮，CB1R 激动剂 WIN 55,212-2，概括了全身应激水平皮质酮治疗增强可卡因引发恢复的能力，或单酰基甘油脂肪酶抑制剂 URB602。皮质酮对恢复的影响通过 PL 内注射 CB1R 拮抗剂 AM251 或二酰基甘油脂肪酶抑制剂 DO34 减弱。结论 这些发现表明，压力诱导的皮质酮增加通过动员 PL 中的 2-花生四烯酰甘油促进可卡因的寻找，导致 CB1R 介导的该大脑区域抑制性传输的减弱。