Impact of serotonin 2C receptor null mutation on physiology and behavior associated with nigrostriatal dopamine pathway function.
Impact of serotonin 2C receptor null mutation on physiology and behavior associated with nigrostriatal dopamine pathway function.
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DOI：
10.1523/jneurosci.3905-08.2009
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发表时间：
2009-06-24
期刊：
影响因子：
--
通讯作者：
Tecott LH
中科院分区：
文献类型：
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作者：
Abdallah L;Bonasera SJ;Hopf FW;O'Dell L;Giorgetti M;Jongsma M;Carra S;Pierucci M;Di Giovanni G;Esposito E;Parsons LH;Bonci A;Tecott LH
5 -羟色胺能神经传递对脑多巴胺能通路的影响与许多神经精神疾病具有实质性的相关性。5-羟色胺2C受体（5-HT2CR）激活对中边缘多巴胺能通路，特别是伏隔核末端区域的生理和行为的抑制作用被认为是一个特别突出的作用。该受体亚型对黑质纹状体多巴胺能通路介导的功能的影响尚不清楚。在这里，我们报告了消除5-HT2CRs表达的零突变会导致该途径的活性和功能输出发生显著变化。5-HT2CR突变小鼠表现出黑质致密部（SNc）多巴胺能神经元活性增加，背纹状体（DSt）细胞外多巴胺基线浓度升高，修饰行为改变，以及对d -安非他明和GBR 12909的刻板行为效应的敏感性增强。这些精神兴奋剂反应发生在药物诱导的细胞外多巴胺浓度没有表型差异的情况下，这表明对释放的多巴胺的行为反应存在表型改变。突变小鼠对D1受体激动剂SKF 81297的行为反应增强进一步证明了这一点。多巴胺刺激后，DSt D1或D2受体表达没有差异，中棘神经元放电模式或内在膜特性也没有差异。我们得出结论，5-HT2CRs调节黑质纹状体多巴胺能活性和功能，在SNc多巴胺能神经元和DSt下游的一个位点。
The impact of serotonergic neurotransmission on brain dopaminergic pathways has substantial relevance to many neuropsychiatric disorders. A particularly prominent role has been ascribed to the inhibitory effects of serotonin 2C receptor (5-HT2CR) activation on physiology and behavior mediated by the mesolimbic dopaminergic pathway, particularly in the terminal region of the nucleus accumbens. The influence of this receptor subtype on functions mediated by the nigrostriatal dopaminergic pathway is less clear. Here we report that a null mutation eliminating expression of 5-HT2CRs produces marked alterations in the activity and functional output of this pathway. 5-HT2CR mutant mice displayed increased activity of substantia nigra pars compacta (SNc) dopaminergic neurons, elevated baseline extracellular dopamine concentrations in the dorsal striatum (DSt), alterations in grooming behavior, and enhanced sensitivity to the stereotypic behavioral effects of D-amphetamine and GBR 12909. These psychostimulant responses occurred in the absence of phenotypic differences in drug-induced extracellular dopamine concentration, suggesting a phenotypic alteration in behavioral responses to released dopamine. This was further suggested by enhanced behavioral responses of mutant mice to the D1 receptor agonist SKF 81297. Differences in DSt D1 or D2 receptor expression were not found, nor were differences in medium spiny neuron firing patterns or intrinsic membrane properties following dopamine stimulation. We conclude that 5-HT2CRs regulate nigrostriatal dopaminergic activity and function both at SNc dopaminergic neurons and at a locus downstream of the DSt.