Klawonn Anna M, Nilsson Anna, Rådberg Carl F, Lindström Sarah H, Ericson Mia, Granseth Björn, Engblom David, Fritz Michael
Cell Biology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
Front Pharmacol. 2017 Oct 10;8:714. doi: 10.3389/fphar.2017.00714. eCollection 2017.
Drug addiction is a chronic, debilitating disease that affects millions of people around the world causing a substantial societal burden. Despite decades of research efforts, treatment possibilities remain limited and relapse represents the most treatment-resistant element. Neurosteroid sigma-1 receptors have been meticulously studied in psychostimulant reinforced Pavlovian learning, while the sigma-2 receptor subtype has remained unexplored. Recent development of selective sigma-2 receptor ligands have now made it possible to investigate if the sigma-2 receptor system is a potential target to treat drug addiction. We examined the effect of the sigma-2 receptor agonist Siramesine (Lu 28-179) on cocaine-associated locomotion, Pavlovian learning, and reward neurocircuitry using electrophysiology recordings and microdialysis. We found that Siramesine significantly attenuated conditioned place preference acquisition and expression, as well as it completely blocked cocaine-primed reinstatement. Siramesine, in a similar manner as the selective sigma-1 receptor antagonist BD 1063, decreased acute locomotor responses to cocaine. Immunohistochemistry suggests co-expression of progesterone receptor membrane component 1/sigma-2 receptors and vesicular glutamate transporter 1 in presynaptic boutons of the nucleus accumbens (NAc). Whole-cell voltage clamp recordings of neurons in the NAc indicated that Siramesine decreases the presynaptic release probability of glutamate. Further, we demonstrated, via microdialysis, that Siramesine significantly decreased cocaine-evoked dopamine release in the striatum of freely moving mice. Collectively, these findings demonstrate that sigma-2 receptors regulate neurocircuitry responsible for positive reinforcement and thereby play a role in cocaine-reinforced Pavlovian behaviors.
药物成瘾是一种慢性、使人衰弱的疾病，影响着全球数百万人，造成了巨大的社会负担。尽管经过了数十年的研究努力，但治疗方法仍然有限，复发是最难治疗的因素。神经甾体σ-1受体在精神兴奋剂强化的巴甫洛夫学习中已得到细致研究，而σ-2受体亚型仍未被探索。选择性σ-2受体配体的最新进展使得研究σ-2受体系统是否是治疗药物成瘾的潜在靶点成为可能。我们使用电生理记录和微透析技术，研究了σ-2受体激动剂西拉米辛（Lu 28-179）对可卡因相关运动、巴甫洛夫学习和奖赏神经回路的影响。我们发现西拉米辛显著减弱了条件性位置偏爱获得和表达，并且完全阻断了可卡因引发的复吸。西拉米辛与选择性σ-1受体拮抗剂BD 1063的作用方式相似，降低了对可卡因的急性运动反应。免疫组织化学表明，在伏隔核（NAc）的突触前终扣中，孕激素受体膜成分1/σ-2受体与囊泡谷氨酸转运体1共表达。对NAc神经元的全细胞电压钳记录表明，西拉米辛降低了谷氨酸的突触前释放概率。此外，我们通过微透析证明，西拉米辛显著降低了自由活动小鼠纹状体中可卡因诱发的多巴胺释放。总的来说，这些发现表明σ-2受体调节负责正性强化的神经回路，从而在可卡因强化的巴甫洛夫行为中发挥作用。
