Department of Pharmacology, University of Murcia, Murcia, Spain.
Farmacología Celular y Molecular, Murcia Institute of Biomedical Research (IMIB), Murcia, Spain.
Addict Biol. 2020 Mar;25(2):e12728. doi: 10.1111/adb.12728. Epub 2019 Feb 19.
Aversive memories related to drug withdrawal can generate a motivational state leading to compulsive drug taking. However, the mechanisms underlying the generation of these withdrawal memories remain unclear. Limbic structures, such as the basolateral amygdala (BLA) and the dentate gyrus (DG) of the hippocampus, play a crucial role in the negative affective component of morphine withdrawal. Given the prominent role of glucocorticoids (GCs), noradrenaline (NA), and dopamine (DA) in memory-related processes, in the present study, we employed the conditioned place aversion (CPA) paradigm to uncover the role of GCs on NA and DA neurotransmission within the BLA and NA neurotransmission within the DG during opiate-withdrawal conditioning (memory formation consolidation), and after reexposure to the conditioned environment (memory retrieval). We observed that adrenalectomy impaired naloxone-induced CPA. Memory retrieval was associated with an increase in dihydroxyphenylacetic acid (DOPAC) levels in the BLA in morphine-addicted animals in a GC-independent manner. Importantly, NA turnover was related with the expression of withdrawal physical signs during the conditioning phase and with locomotor activity during the test phase. On the other hand, reduced DA concentration in the BLA was correlated with the CPA score. Our results indicate that while noradrenergic system is more associated with the somatic consequences of withdrawal, dopaminergic neurotransmission modulates the affective state. Nevertheless, it seems necessary that both systems work together with GCs to enable aversive-memory formation and recall.
与药物戒断相关的厌恶记忆会产生一种动机状态，导致强迫性药物使用。然而，这些戒断记忆产生的机制仍不清楚。边缘结构，如外侧杏仁核（BLA）和海马齿状回（DG），在吗啡戒断的负面情感成分中起着至关重要的作用。鉴于糖皮质激素（GCs）、去甲肾上腺素（NA）和多巴胺（DA）在记忆相关过程中的突出作用，在本研究中，我们采用条件位置厌恶（CPA）范式，以揭示 GC 在阿片戒断条件作用期间（记忆形成巩固）和重新暴露于条件环境后（记忆检索）内 BLA 中的 NA 和 DA 神经传递以及 DG 中的 NA 神经传递中的作用。我们观察到肾上腺切除术损害了纳洛酮诱导的 CPA。记忆检索与吗啡成瘾动物在 GC 独立的情况下 BLA 中二羟苯乙酸（DOPAC）水平的增加有关。重要的是，NA 周转率与条件作用阶段的戒断体征表达和测试阶段的运动活性有关。另一方面，BLA 中 DA 浓度的降低与 CPA 评分相关。我们的结果表明，虽然去甲肾上腺素能系统与戒断的躯体后果更相关，但多巴胺能神经传递调节情绪状态。然而，似乎需要这两个系统与 GCs 一起工作，以实现厌恶记忆的形成和回忆。
