Avalos María P, Guzman Andrea S, Garcia-Keller Constanza, Mongi-Bragato Bethania, Esparza María A, Rigoni Daiana, Sanchez Marianela A, Calfa Gastón D, Bollati Flavia A, Cancela Liliana M
Departamento de Farmacología Otto Orsingher, Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
Front Physiol. 2022 Aug 26;13:896268. doi: 10.3389/fphys.2022.896268. eCollection 2022.
Though the facilitating influence of stress on drug abuse is well documented, the mechanisms underlying this interaction have yet to be fully elucidated. The present study explores the neurobiological mechanisms underpinning the sensitized response to the psychomotor-stimulating effects of cocaine following chronic restraint stress (CRS), emphasizing the differential contribution of both subcompartments of the nucleus accumbens (NA), the core (NAcore) and shell (NAshell), to this phenomenon. Adult male Wistar rats were restrained for 2 h/day for 7 days and, 2 weeks after the last stress exposure (day 21), all animals were randomly assigned to behavioral, biochemical or neurochemical tests. Our results demonstrated that the enduring CRS-induced increase in psychostimulant response to cocaine was paralleled by an increase of extracellular dopamine levels in the NAcore, but not the NAshell, greater than that observed in the non-stress group. Furthermore, we found that CRS induced an impairment of glutamate homeostasis in the NAcore, but not the NAshell. Its hallmarks were increased basal extracellular glutamate concentrations driven by a CRS-induced downregulation of GLT-1, blunted glutamate levels in response to cocaine and postsynaptic structural remodeling in pre-stressed animals. In addition, ceftriaxone, a known GLT-1 enhancer, prevented the CRS-induced GLT-1 downregulation, increased basal extracellular glutamate concentrations and changes in structural plasticity in the NAcore as well as behavioral cross-sensitization to cocaine, emphasizing the biological importance of GLT-1 in the comorbidity between chronic stress exposure and drug abuse. A future perspective concerning the paramount relevance of the stress-induced disruption of glutamate homeostasis as a vulnerability factor to the development of stress and substance use disorders during early life or adulthood of descendants is provided.
尽管压力对药物滥用的促进作用已有充分记录，但这种相互作用的潜在机制尚未完全阐明。本研究探讨了慢性束缚应激（CRS）后对可卡因精神运动刺激作用的敏化反应背后的神经生物学机制，强调伏隔核（NA）的两个亚区，即核心（NAcore）和壳（NAshell）对这一现象的不同贡献。成年雄性Wistar大鼠每天束缚2小时，持续7天，在最后一次应激暴露后2周（第21天），所有动物被随机分配到行为、生化或神经化学测试中。我们的结果表明，持久的CRS诱导的对可卡因精神刺激反应的增加与NAcore而非NAshell中细胞外多巴胺水平的增加平行，且增加幅度大于非应激组。此外，我们发现CRS诱导了NAcore而非NAshell中谷氨酸稳态的损害。其特征是CRS诱导的GLT-1下调导致基础细胞外谷氨酸浓度升高，对可卡因的反应中谷氨酸水平减弱，以及应激前动物的突触后结构重塑。此外，已知的GLT-1增强剂头孢曲松可防止CRS诱导的GLT-1下调，增加基础细胞外谷氨酸浓度以及NAcore中的结构可塑性变化以及对可卡因的行为交叉敏化，强调了GLT-1在慢性应激暴露和药物滥用共病中的生物学重要性。提供了一个关于应激诱导的谷氨酸稳态破坏作为后代早期或成年期应激和物质使用障碍发展的脆弱性因素的至关重要相关性的未来展望。
