Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.
Department of Cognitive Neuroscience, Division of Molecular Neurogenetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Br J Pharmacol. 2022 Sep;179(17):4254-4264. doi: 10.1111/bph.15496. Epub 2021 May 20.
It is well established that the nucleus accumbens and glutamate play a critical role in the motivation to take drugs of abuse. We have previously demonstrated that rats with ablation of the serotonin (5-HT) transporter (SERT rats) show increased cocaine intake reminiscent of compulsivity.
By comparing SERT to SERT rats, we set out to explore whether SERT deletion influences glutamate neurotransmission under control conditions as well as after short access (1 h/session) or long access (6 h/session) to cocaine self-administration.
Rats were killed at 24 h after the final self-administration session for ex vivo molecular analyses of the glutamate system (vesicular and glial transporters, post-synaptic subunits of NMDA and AMPA receptors and their related scaffolding proteins). Such analyses were undertaken in the nucleus accumbens core. In cocaine-naïve animals, SERT deletion evoked widespread abnormalities in markers of glutamatergic neurotransmission that, overall, indicate a reduction of glutamate signalling. These results suggest that 5-HT is pivotal for the maintenance of accumbal glutamate homeostasis. We also found that SERT deletion altered glutamate homeostasis mainly after long access, but not short access, to cocaine.
Our findings reveal that SERT deletion may sensitize the glutamatergic synapses of the nucleus accumbens core to the long access but not short access, intake of cocaine.
This article is part of a themed issue on New discoveries and perspectives in mental and pain disorders. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.17/issuetoc.
众所周知，伏隔核和谷氨酸在滥用药物的动机中起着关键作用。我们之前的研究表明，5-羟色胺转运体（5-HTT）敲除的大鼠表现出可卡因摄入量增加，类似于强迫性。
通过比较 SERT 和 SERT 大鼠，我们旨在探讨 SERT 缺失是否会影响可卡因自我给药控制条件下以及短时间（1 小时/次）或长时间（6 小时/次）接触后的谷氨酸能神经传递。
在最后一次自我给药后 24 小时，处死大鼠进行伏隔核核心区的谷氨酸系统（囊泡和胶质转运体、NMDA 和 AMPA 受体的突触后亚基及其相关支架蛋白）的离体分子分析。在可卡因-naïve 动物中，SERT 缺失引起了广泛的谷氨酸能神经传递标志物异常，总体上表明谷氨酸信号减少。这些结果表明 5-HT 对伏隔核谷氨酸稳态的维持至关重要。我们还发现 SERT 缺失主要在长时间接触而不是短时间接触可卡因后改变了谷氨酸稳态。
我们的研究结果表明，SERT 缺失可能会使伏隔核核心区的谷氨酸能突触对长时间而不是短时间接触可卡因的摄入敏感。
本文是关于精神和疼痛障碍新发现和新视角的专题文章的一部分。要查看该部分中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.17/issuetoc.
