[Utility of organotypic raphe slice cultures to investigate the effects of psychotropic drugs on the function of serotoninergic neurons].

Takayuki Nakagawa, Kazuki Nagayasu, Shuji Kaneko
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Abstract

A number of behavioral, neurochemical and electrophysiological studies have emphasized the importance of the serotonergic neurons in the pathophysiology of psychiatric disorders and the therapeutic actions of psychotropics. However, no in vitro serotonergic culture systems have successfully analyzed the long-term effects of psychotropics or the neural interaction between serotonergic and excitatory/inhibitory neurons. Recently, we have established rat organotypic raphe slice cultures, which have functional serotonergic neurons with the ability to release 5-HT in response to stimulation and to reuptake 5-HT through serotonin transporter and retain neural and synaptic functions. Here, we show the following results in the raphe slice cultures: 1) acute and sustained treatments with 3,4-methylenedioxymethamphetamine induce the 5-HT efflux via serotonin transporter and AMPA receptor-mediated exocytotic 5-HT release, respectively; 2) sustained treatment with antidepressants enhances the exocytotic 5-HT release, which is dependent on AMPA receptor stimulation, but not on desensitization of 5-HT(1A/1B) autoreceptors; 3) the augmentation therapy of an atypical antipsychotic, olanzapine, with antidepressants is caused by the decrease in the raphe inhibitory GABAergic tone through 5-HT6 receptor antagonism. Our findings suggest that the raphe slice cultures are suitable for analyzing the neural and molecular mechanisms underlying the efficacy of psychotropics in vitro.

[利用器官型缝片培养研究精神药物对血清素能神经元功能的影响]。
许多行为学、神经化学和电生理学的研究都强调了血清素能神经元在精神疾病的病理生理学和精神药物的治疗作用中的重要性。然而,没有体外血清素能培养系统成功地分析了精神药物的长期影响或血清素能和兴奋/抑制性神经元之间的神经相互作用。最近,我们建立了大鼠器官型中叶切片培养,其具有功能的血清素能神经元,能够在刺激下释放5-羟色胺,并通过血清素转运体再摄取5-羟色胺,并保持神经和突触功能。研究结果表明:1)3,4-亚甲基二氧甲基苯丙胺的急性和持续治疗分别通过血清素转运体和AMPA受体介导的胞外释放诱导5-HT外排;2)持续服用抗抑郁药物可增强胞外5-HT的释放,这种释放依赖于AMPA受体的刺激,而不依赖于5-HT(1A/1B)自身受体的脱敏;3)非典型抗精神病药奥氮平与抗抑郁药的强化治疗是由于5-HT6受体拮抗作用导致中速抑制性gaba能张力降低所致。我们的研究结果表明,中缝片培养适合于分析精神药物体外疗效的神经和分子机制。
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