Hypersensitivity to amphetamine's psychomotor and reinforcing effects in serotonin transporter knockout rats: Glutamate in the nucleus accumbens
Hypersensitivity to amphetamine's psychomotor and reinforcing effects in serotonin transporter knockout rats: Glutamate in the nucleus accumbens
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DOI：
10.1111/bph.15211
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发表时间：
2020-08-30
影响因子：
7.3
通讯作者：
Homberg, Judith R.
中科院分区：
文献类型：
--
作者：
Caffino, Lucia;Verheij, Michel M. M.;Homberg, Judith R.
背景和目的安非他明（Amphetamine，AMPH）使用障碍是一个严重的健康问题，但令人惊讶的是，对这种精神兴奋剂的中度和强迫使用的脆弱性及其潜在机制知之甚少。先前的研究表明，遗传性5-羟色胺转运蛋白（SERT）下调增加了对可卡因的运动反应，以及对这种精神兴奋剂的中度（在每天1小时的自我给药期间测量）和强迫性（在每天6小时的自我给药期间测量）摄入。在这里，我们试图研究这些发现是否推广到AMPH和潜在的机制，在脑桥核。实验方法在5-羟色胺转运蛋白敲除（SERT-/-）和野生型对照（SERT +/+）大鼠中，我们评估了在短时间进入（ShA：每天1小时）和长时间进入（LgA：每天6小时）条件下对急性AMPH和i.v. AMPH自我给药的运动反应。在AMPH自身给药后24小时，我们分析了谷氨酸系统组分在丘脑核壳和核芯中的表达。关键结果我们发现，SERT（-/-）动物表现出增加AMPH诱导的运动反应和增加AMPH自我管理下LGA，但不是ShA条件。此外，我们观察到囊泡和神经胶质谷氨酸转运体，NMDA和AMPA受体亚基，以及它们各自的突触后支架蛋白作为SERT基因型和AMPH暴露（基线，ShA和LgA）的函数的变化，特别是在核壳。结论和影响我们表明，SERT基因缺失增加了AMPH的精神和增强作用，后者是潜在介导的，至少部分，由稳态的变化，在神经元突触的核壳和/或核心。
Background and Purpose Amphetamine (AMPH) use disorder is a serious health concern, but, surprisingly, little is known about the vulnerability to the moderate and compulsive use of this psychostimulant and its underlying mechanisms. Previous research showed that inherited serotonin transporter (SERT) down-regulation increases the motor response to cocaine, as well as moderate (as measured during daily 1-h self-administration sessions) and compulsive (as measured during daily 6-h self-administration sessions) intake of this psychostimulant. Here, we sought to investigate whether these findings generalize to AMPH and the underlying mechanisms in the nucleus accumbens. Experimental Approach In serotonin transporter knockout (SERT-/-) and wild-type control (SERT+/+) rats, we assessed the locomotor response to acute AMPH and i.v. AMPH self-administration under short access (ShA: 1-h daily sessions) and long access (LgA: 6-h daily sessions) conditions. Twenty-four hours after AMPH self-administration, we analysed the expression of glutamate system components in the nucleus accumbens shell and core. Key Results We found that SERT(-/-)animals displayed an increased AMPH-induced locomotor response and increased AMPH self-administration under LgA but not ShA conditions. Further, we observed changes in the vesicular and glial glutamate transporters, NMDA and AMPA receptor subunits, and their respective postsynaptic scaffolding proteins as function of SERT genotype and AMPH exposure (baseline, ShA, and LgA), specifically in the nucleus accumbens shell. Conclusion and Implications We demonstrate that SERT gene deletion increases the psychomotor and reinforcing effects of AMPH and that the latter is potentially mediated, at least in part, by homeostatic changes in the glutamatergic synapse of the nucleus accumbens shell and/or core.