García-Pérez Daniel, Ferenczi Szilamer, Kovács Krisztina J, Laorden M Luisa, Milanés M Victoria, Núñez Cristina
Department of Pharmacology, University of Murcia, Murcia, Spain.
Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
Psychoneuroendocrinology. 2016 Dec;74:350-362. doi: 10.1016/j.psyneuen.2016.09.020. Epub 2016 Sep 28.
Drug-withdrawal aversive memories generate a motivational state leading to compulsive drug taking, with plasticity changes in the basolateral amygdala (BLA) being essential in aversive motivational learning. The conditioned-place aversion (CPA) paradigm allows for measuring the negative affective component of drug withdrawal. First, CPA triggers association between negative affective consequences of withdrawal with context (memory consolidation). Afterwards, when the animals are re-exposed to the paired environment, they avoid it due to the association between the context and aversive memories (memory retrieval). We examined the influence of glucocorticoids (GCs) for a morphine-withdrawal CPA paradigm, along with plasticity changes in the BLA, in sham-operated and adrenalectomized (ADX) animals. We demonstrated that sham+morphine animals robustly displayed CPA, whereas ADX-dependent animals lacked the affective-like signs of opiate withdrawal but displayed increased somatic signs of withdrawal. Glucocorticoid receptor (GR) actions promote memory consolidation but highly depend on increases in GC levels. Interestingly, we observed that GCs were only increased in sham-dependent rodents during aversive-withdrawal memory consolidation, and that GR expression correlated with phosphorylated cAMP response element binding (pCREB) protein, early growth response 1 (Egr-1) and activity-regulated cytoskeletal-associated (Arc) mRNA induction in this experimental group. In contrast, ADX-animals displayed reduced (pCREB). GCs are also known to impair memory retrieval. Accordingly, we showed that GCs levels remained at basal levels in all experimental groups following memory retrieval, and consequently GRs no longer acted as transcriptional regulators. Importantly, memory retrieval elicited increased pCREB levels in sham+morphine animals (not in ADX+morphine group), which were directly correlated with enhanced Arc mRNA/protein expression mainly in glutamatergic neurons. In conclusion, context-withdrawal associations are accompanied plasticity changes in the BLA, which are, in part, regulated by GR signaling. Moreover, dysregulation of CREB signaling, in part through Arc expression, may enhance reconsolidation, resulting in the maintenance of excessive aversive states. These findings might have important implications for drug-seeking behavior.
药物戒断厌恶记忆会产生一种导致强迫性药物摄取的动机状态，基底外侧杏仁核（BLA）的可塑性变化在厌恶动机学习中至关重要。条件性位置厌恶（CPA）范式可用于测量药物戒断的负面情感成分。首先，CPA引发戒断的负面情感后果与环境之间的关联（记忆巩固）。之后，当动物再次暴露于配对环境时，由于环境与厌恶记忆之间的关联，它们会避开该环境（记忆检索）。我们研究了糖皮质激素（GCs）对吗啡戒断CPA范式的影响，以及在假手术和肾上腺切除（ADX）动物中BLA的可塑性变化。我们证明，假手术+吗啡动物强烈表现出CPA，而依赖ADX的动物缺乏阿片类药物戒断的情感样体征，但表现出戒断的躯体体征增加。糖皮质激素受体（GR）的作用促进记忆巩固，但高度依赖于GC水平的升高。有趣的是，我们观察到，仅在假手术依赖的啮齿动物的厌恶戒断记忆巩固过程中GCs水平升高，并且在该实验组中GR表达与磷酸化的cAMP反应元件结合蛋白（pCREB）、早期生长反应1（Egr-1）和活性调节细胞骨架相关蛋白（Arc）mRNA诱导相关。相比之下，ADX动物的pCREB水平降低。已知GCs也会损害记忆检索。因此，我们表明，在记忆检索后所有实验组中的GCs水平都保持在基础水平，因此GRs不再作为转录调节因子起作用。重要的是，记忆检索在假手术+吗啡动物中引起pCREB水平升高（在ADX+吗啡组中未升高），这与主要在谷氨酸能神经元中增强的Arc mRNA/蛋白表达直接相关。总之，环境-戒断关联伴随着BLA的可塑性变化，这部分受GR信号调节。此外，CREB信号失调，部分通过Arc表达，可能增强重新巩固，导致过度厌恶状态的维持。这些发现可能对觅药行为具有重要意义。
