Department of Integrative Physiology and Neuroscience, Washington State University College of Veterinary Medicine, Pullman, WA, USA.
Washington State University Alcohol and Drug Abuse Research Program, Pullman, WA, USA.
Neuropsychopharmacology. 2021 Aug;46(9):1554-1564. doi: 10.1038/s41386-020-00919-x. Epub 2021 Jan 15.
Re-exposure to a cocaine-associated context triggers craving and relapse through the retrieval of salient context-drug memories. Upon retrieval, context-drug memories become labile and temporarily sensitive to modification before they are reconsolidated into long-term memory stores. The effects of systemic cannabinoid type 1 receptor (CB1R) antagonism indicate that CB1R signaling is necessary for cocaine-memory reconsolidation and associated glutamatergic plasticity in the basolateral amygdala (BLA); however, the contribution of BLA CB1R signaling to cocaine-memory reconsolidation is unknown. Here, we assessed whether intra-BLA CB1R manipulations immediately after cocaine-memory retrieval alter cocaine-memory strength indexed by subsequent drug context-induced cocaine-seeking behavior in an instrumental rodent model of drug relapse. Administration of the CB1R antagonist, AM251 (0.3 µg/hemisphere) into the BLA increased subsequent drug context-induced cocaine-seeking behavior in a memory retrieval-dependent and anatomically selective manner. Conversely, the CB1R agonist, WIN55,212-2 (0.5 or 5 µg/hemisphere) failed to alter this behavior. In follow-up experiments, cocaine-memory retrieval elicited robust hypothalamic-pituitary-adrenal axis activation, as indicated by a rise in serum corticosterone concentrations. Intra-BLA AM251 administration during memory reconsolidation selectively increased this cocaine-memory retrieval-induced corticosterone response. Intra-BLA corticosterone administration (3 or 10 ng/hemisphere) during memory reconsolidation did not augment subsequent cocaine-seeking behavior, suggesting that CB1R-dependent effects of corticosterone on memory strength, if any, are mediated outside of the BLA. Together, these findings suggest that CB1R signaling in the BLA gates cocaine-memory strength, possibly by diminishing the impact of cue-induced arousal on the integrity of the reconsolidating memory trace or on the efficacy of the memory reconsolidation process.
重新暴露于与可卡因相关的环境中会通过提取突出的情境-药物记忆来引发渴望和复发。在提取之后，情境-药物记忆变得不稳定，并在重新巩固到长期记忆存储之前暂时对修饰敏感。系统大麻素 1 型受体 (CB1R) 拮抗剂的作用表明，CB1R 信号对于可卡因记忆的再巩固以及外侧杏仁核 (BLA) 中的谷氨酸能可塑性是必要的;然而，BLA CB1R 信号对可卡因记忆再巩固的贡献尚不清楚。在这里，我们评估了可卡因记忆检索后立即对 BLA 中的 CB1R 进行操作是否会改变可卡因记忆的强度，这种强度通过随后的药物情境诱导的可卡因寻求行为来索引，这是一种药物复发的仪器啮齿动物模型。将 CB1R 拮抗剂 AM251（0.3 µg/半球）注入 BLA 会以记忆检索依赖和解剖选择性的方式增加随后的药物情境诱导的可卡因寻求行为。相反，CB1R 激动剂 WIN55,212-2（0.5 或 5 µg/半球）未能改变这种行为。在后续实验中，可卡因记忆检索引起了强烈的下丘脑-垂体-肾上腺轴激活，表现为血清皮质酮浓度升高。在记忆再巩固期间，BLA 内 AM251 的给药选择性地增加了这种可卡因记忆检索诱导的皮质酮反应。在记忆再巩固期间，BLA 内皮质酮给药（3 或 10 ng/半球）不会增强随后的可卡因寻求行为，这表明皮质酮对记忆强度的 CB1R 依赖性影响（如果有的话）是在 BLA 之外介导的。总之，这些发现表明，BLA 中的 CB1R 信号调节可卡因记忆的强度，可能通过减弱线索诱导的唤醒对再巩固记忆痕迹完整性或记忆再巩固过程的效力的影响。
