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血清素转运体敲除大鼠对可卡因短时间和长时间接触的反应：伏隔核壳层中谷氨酸信号的调制。

Responsivity of serotonin transporter knockout rats to short and long access to cocaine: Modulation of the glutamate signalling in the nucleus accumbens shell.

机构信息

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.

出版信息

Br J Pharmacol. 2022 Jul;179(14):3727-3739. doi: 10.1111/bph.15823. Epub 2022 Mar 8.

DOI:10.1111/bph.15823
PMID:35174489
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9310702/
Abstract

BACKGROUND AND PURPOSE

It has been well established that glutamate in the nucleus accumbens (NAc) plays a critical role in the motivation to take drugs of abuse. We have previously demonstrated that rats with ablation of the serotonin transporter (SERT rats) show increased cocaine intake reminiscent of compulsivity.

EXPERIMENTAL APPROACH

By comparing SERT to SERT rats, we investigated whether SERT deletion influences glutamate homeostasis under control conditions as well as after short access (ShA: 1 h per session) or long access (LgA: 6 h per session) to cocaine self-administration. Rats were killed at 24 h after the last self-administration session for ex vivo molecular analyses of the main determinants of the glutamate system, including transporters (vesicular and glial), receptors (main post-synaptic subunits of NMDA and AMPA receptors together with the metabotropic subunit mGLUR5), and scaffolding proteins (SAP102, SAP97, and GRIP) in the NAc shell (sNAc) KEY RESULTS: In cocaine-naive animals, SERT deletion was associated with changes indicative for a reduction in glutamate signalling. ShA and LgA exposure led to a further dysregulation of the glutamatergic synapse.

CONCLUSION

SERT deletion may render the glutamatergic synapses of the NAc shell more responsive to both ShA and LgA intake of cocaine.

摘要

背景与目的

众所周知，伏隔核（NAc）中的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（SERT）缺失的大鼠表现出可卡因摄入量增加，类似于强迫性。

实验方法

通过比较 SERT 和 SERT 大鼠，我们研究了 SERT 缺失是否会影响可卡因自我给药的对照条件下以及短时间（ShA：每次 1 小时）或长时间（LgA：每次 6 小时）暴露后谷氨酸稳态。在最后一次自我给药后 24 小时，处死大鼠进行分子分析，以研究谷氨酸系统的主要决定因素，包括转运体（囊泡和神经胶质）、受体（NMDA 和 AMPA 受体的主要突触后亚基以及代谢型谷氨酸受体 mGLUR5）和支架蛋白（SAP102、SAP97 和 GRIP）在壳核（sNAc）中的表达。

主要结果

在可卡因未处理的动物中，SERT 缺失与谷氨酸信号减少的变化相关。ShA 和 LgA 暴露导致谷氨酸能突触进一步失调。

结论

SERT 缺失可能使 NAc 壳层的谷氨酸能突触对 ShA 和 LgA 摄入可卡因更敏感。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/528f/9310702/a3216c3267e7/BPH-179-3727-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/528f/9310702/d9890b60e208/BPH-179-3727-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/528f/9310702/3cd0aa626a43/BPH-179-3727-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/528f/9310702/3067fbc6f502/BPH-179-3727-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/528f/9310702/05215e584b5c/BPH-179-3727-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/528f/9310702/e440cd620c79/BPH-179-3727-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/528f/9310702/a3216c3267e7/BPH-179-3727-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/528f/9310702/d9890b60e208/BPH-179-3727-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/528f/9310702/3cd0aa626a43/BPH-179-3727-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/528f/9310702/3067fbc6f502/BPH-179-3727-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/528f/9310702/05215e584b5c/BPH-179-3727-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/528f/9310702/e440cd620c79/BPH-179-3727-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/528f/9310702/a3216c3267e7/BPH-179-3727-g004.jpg

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