Group of Cellular and Molecular Pharmacology, Department of Pharmacology, University of Murcia, Campus de Ciencias de la Salud, 30120 Murcia, Spain; Murcia Research Institute of Health Sciences (IMIB-Arrixaca), Avda. Buenavista, 30120 Murcia, Spain.
Group of Cellular and Molecular Pharmacology, Department of Pharmacology, University of Murcia, Campus de Ciencias de la Salud, 30120 Murcia, Spain; Megalab Genética, Madrid, Spain.
Prog Neuropsychopharmacol Biol Psychiatry. 2018 Jun 8;84(Pt A):102-114. doi: 10.1016/j.pnpbp.2018.01.018. Epub 2018 Jan 31.
Drug withdrawal-associated aversive memories trigger relapse to drug-seeking behavior. Corticotrophin-releasing factor (CRF) is an important mediator of the reinforcing properties of drugs of abuse. However, the involvement of CRF1 receptor (CRF1R) in aversive memory induced by opiate withdrawal has yet to be elucidated. We used the conditioned-place aversion (CPA) paradigm to evaluate the role of CRF1R on opiate withdrawal memory acquisition, along with plasticity-related processes that occur after CPA within the basolateral amygdala (BLA) and dentate gyrus (DG). Male mice were rendered dependent on morphine and injected acutely with naloxone before paired to confinement in a naloxone-associated compartment. The CPA scores as well as the number of TH-positive neurons (in the NTS-A2 noradrenergic cell group), and the expression of the transcription factors Arc and pCREB (in the BLA and DG) were measured with and without CRF1R blockade. Mice subjected to conditioned naloxone-induced morphine withdrawal robustly expressed CPA. Pre-treatment with the selective CRF1R antagonist CP-154,526 before naloxone conditioning session impaired morphine withdrawal-induced aversive memory acquisition. CP-154,526 also antagonized the enhanced number of TH-positive neurons in the NTS-A2 that was seen after CPA. Increased Arc expression and Arc-pCREB co-localization were seen in the BLA after CPA, which was not modified by CP-154,526. In the DG, CPA was accompanied by a decrease of Arc expression and no changes in Arc-pCREB co-localization, whereas pre-treatment with CP-154,526 induced an increase in both parameters. These results indicate that CRF-CRF1R pathway could be a critical factor governing opiate withdrawal memory storage and retrieval and might suggest a role for TH-NA pathway in the effects of withdrawal on memory. Our results might indicate that the blockade of CRF1R could represent a promising pharmacological treatment strategy approach for the attenuation of the relapse to drug-seeking/taking behavior triggered by opiate withdrawal-associated aversive memories.
药物戒断相关的厌恶记忆会引发觅药行为的复发。促肾上腺皮质释放因子（CRF）是滥用药物强化作用的重要介质。然而，CRF1 受体（CRF1R）在阿片类药物戒断引起的厌恶记忆中的作用尚未阐明。我们使用条件性位置厌恶（CPA）范式来评估 CRF1R 在阿片类药物戒断记忆获得中的作用，以及 CPA 后在基底外侧杏仁核（BLA）和齿状回（DG）中发生的可塑性相关过程。雄性小鼠依赖于吗啡，并在与纳洛酮相关的隔间中被限制后，立即注射纳洛酮。使用和不使用 CRF1R 阻断剂测量 CPA 评分以及 TH 阳性神经元（在 NTS-A2 去甲肾上腺素能细胞群中）的数量和转录因子 Arc 和 pCREB（在 BLA 和 DG 中的表达）。接受条件性纳洛酮诱导的吗啡戒断的小鼠强烈表达 CPA。在纳洛酮条件训练之前，用选择性 CRF1R 拮抗剂 CP-154,526 预处理会损害吗啡戒断引起的厌恶记忆获得。CP-154,526 还拮抗了 CPA 后 NTS-A2 中 TH 阳性神经元数量的增加。CPA 后 BLA 中观察到 Arc 表达增加和 Arc-pCREB 共定位，CP-154,526 没有改变这一点。在 DG 中，CPA 伴随着 Arc 表达的减少，Arc-pCREB 共定位没有变化，而 CP-154,526 预处理诱导了这两个参数的增加。这些结果表明，CRF-CRF1R 途径可能是控制阿片类药物戒断记忆存储和检索的关键因素，并且可能表明 TH-NA 途径在戒断对记忆的影响中起作用。我们的结果可能表明，CRF1R 阻断可能代表一种有前途的药物治疗策略，可用于减轻与阿片类药物戒断相关的厌恶记忆引发的觅药/觅药行为的复发。
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