Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, X5000HUA, Córdoba, Argentina.
Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), X5000HUA, Córdoba, Argentina.
Sci Rep. 2021 Jun 21;11(1):12964. doi: 10.1038/s41598-021-92389-4.
Preclinical models of stress-induced relapse to drug use have shown that the dysregulation of glutamatergic transmission within the nucleus accumbens (NA) contributes notably to the reinstatement of cocaine-seeking behavior in rodents. In this sense, there has been increasing interest in the cannabinoid type-1 receptor (CB1R), due to its crucial role in modulating glutamatergic neurotransmission within brain areas involved in drug-related behaviors. This study explored the involvement of CB1R within the NA subregions in the restraint stress-induced reinstatement of cocaine-conditioned place preference (CPP), as well as in the regulation of glutamatergic transmission, by using a pharmacological approach and the in vivo microdialysis sampling technique in freely moving rats. CB1R blockade by the antagonist/inverse agonist AM251 (5 nmol/0.5 μl/side) or CB1R activation by the agonist ACEA (0.01 fmol/0.5 μl/side), prevented or potentiated restraint stress-induced reinstatement of cocaine-CPP, respectively, after local administration into NAcore, but not NAshell. In addition, microdialysis experiments demonstrated that restraint stress elicited a significant increase in extracellular glutamate in NAcore under reinstatement conditions, with the local administration of AM251 or ACEA inhibiting or potentiating this, respectively. Interestingly, this rise specifically corresponded to the cocaine-associated CPP compartment. We also showed that this context-dependent change in glutamate paralleled the expression of cocaine-CPP, and disappeared after the extinction of this response. Taken together, these findings demonstrated the key role played by CB1R in mediating reinstatement of cocaine-CPP after restraint stress, through modulation of the context-specific glutamate release within NAcore. Additionally, CB1R regulation of basal extracellular glutamate was demonstrated and proposed as the underlying mechanism.
应激诱导药物复吸的临床前模型表明，伏隔核（NA）内谷氨酸能传递的失调对啮齿动物可卡因觅药行为的复吸有重要贡献。在这方面，由于大麻素 1 型受体（CB1R）在调节与药物相关行为相关脑区的谷氨酸能神经传递中起着至关重要的作用，因此人们对其越来越感兴趣。本研究通过药理学方法和在体微透析采样技术，在自由活动的大鼠中，探讨了 CB1R 在 NA 亚区中的作用，以及在应激诱导的可卡因条件性位置偏爱（CPP）复吸中的作用，以及在调节谷氨酸能传递中的作用。拮抗剂/反向激动剂 AM251（5 nmol/0.5 μl/侧）或激动剂 ACEA（0.01 fmol/0.5 μl/侧）对 CB1R 的阻断或激活，分别在 NAcore 局部给药后，阻止或增强了束缚应激诱导的可卡因-CPP 的复吸。此外，微透析实验表明，在复吸条件下，束缚应激会引起 NAcore 细胞外谷氨酸的显著增加，而 AM251 或 ACEA 的局部给药分别抑制或增强了这种增加。有趣的是，这种上升与可卡因相关的 CPP 室特异性对应。我们还表明，这种谷氨酸的上下文依赖性变化与可卡因-CPP 的表达平行，并在该反应的消退后消失。综上所述，这些发现表明，CB1R 通过调节 NAcore 内特定于上下文的谷氨酸释放，在束缚应激后可卡因-CPP 的复吸中发挥关键作用。此外，还证明了 CB1R 对基础细胞外谷氨酸的调节，并提出了其作为潜在机制的假设。
