Department of Behavioral Neurogenomics, Institute of Cytology and Genetics, Siberian Division of the Russian Academy of Science, Lavrentyeva Avenue 10, Novosibirsk 630090, Russia.
Neuroscience. 2010 Aug 11;169(1):229-35. doi: 10.1016/j.neuroscience.2010.04.044. Epub 2010 Apr 25.
Dysfunction in brain serotonin (5-HT) system has been implicated in the psychopathology of anxiety, depression, drug addiction, and schizophrenia. The 5-HT(1A) receptors play a central role in the control of 5-HTergic neurotransmission. There are some scarce data showing cross-regulation between 5-HT receptors. Here, we investigated whether interaction exists between 5-HT(1A) receptor and genes encoding key members in brain 5-HT system. Chronic treatment with selective agonist of 5-HT(1A) receptor 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (1.0 mg/kg i.p., 14 days) produced considerable decrease in hypothermic response to acute administration of 8-OH-DPAT in CBA/Lac mice indicating desensitization of 5-HT(1A) receptors. The decrease in 5-HT(1A) gene expression as well as decrease in the expression of gene encoding key enzyme in 5-HT synthesis, tryptophan hydroxylase-2 (TPH-2) in the midbrain, and the expression of the gene encoding 5-HT(2A) receptor in the frontal cortex was shown. There were no significant changes in 5-HT transporter mRNA level in the midbrain. Despite considerable decrease in the expression of the genes encoding tryptophan hydroxylase-2, 5-HT(1A) and 5-HT(2A) receptors, chronic 8-OH-DPAT treatment failed to produce significant changes in 5-HT(1A)-linked behavior (intermale aggression, open-field behavior, light-dark box, and pinch-induced catalepsy), suggesting compensatory and adaptive effect of genes suppression. The obtained data on the effect of 8-OH-DPAT-induced desensitization of 5-HT(1A) receptors on 5-HT(1A), 5-HT(2A) and TPH-2 gene expression demonstrated the role of 5-HT(1A) receptor as indirect regulator of gene expression. The results provide the first evidence of receptor-key genes interaction in brain 5-HT system and may have profound implications in understanding the functioning of the brain neurotransmitter systems.
脑内 5-羟色胺（5-HT）系统功能障碍与焦虑症、抑郁症、药物成瘾和精神分裂症的发病机制有关。5-HT1A 受体在控制 5-HT 能神经传递中起核心作用。有一些稀缺的数据表明 5-HT 受体之间存在交叉调节。在这里，我们研究了 5-HT1A 受体与脑内 5-HT 系统关键成员编码基因之间是否存在相互作用。选择性 5-HT1A 受体激动剂 8-羟基-2-（二丙基氨基）四氢萘（8-OH-DPAT）（1.0mg/kg，腹腔注射，14 天）的慢性治疗导致 CBA/Lac 小鼠对急性 8-OH-DPAT 给药的体温降低反应明显减少，表明 5-HT1A 受体脱敏。5-HT1A 基因表达减少，以及脑中部 5-HT 合成关键酶色氨酸羟化酶-2（TPH-2）和额叶皮层 5-HT2A 受体基因表达减少。脑中部 5-HT 转运体 mRNA 水平无显著变化。尽管编码色氨酸羟化酶-2、5-HT1A 和 5-HT2A 受体的基因表达明显减少，但慢性 8-OH-DPAT 治疗未能导致 5-HT1A 相关行为（雄性间攻击、旷场行为、明暗箱和夹伤性强直）发生显著变化，提示基因抑制的代偿和适应性效应。8-OH-DPAT 诱导的 5-HT1A 受体脱敏对 5-HT1A、5-HT2A 和 TPH-2 基因表达的影响数据表明 5-HT1A 受体作为基因表达的间接调节剂的作用。这些结果提供了脑 5-HT 系统中 5-HT1A 受体-关键基因相互作用的第一个证据，并可能对理解大脑神经递质系统的功能具有深远意义。
