Valdez M, Burke T F, Hensler J G
Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
Brain Res. 2002 Dec 6;957(1):174-82. doi: 10.1016/s0006-8993(02)03637-5.
Previous studies have shown that administration of the 5-HT(2) receptor agonist DOI to rats results in the heterologous desensitization of 5-HT(1A) receptor-mediated behavioral and neuroendocrine responses [Neuropsychopharmacology 19 (1998) 354; J. Neurosci. 21 (2001) 7919]. We hypothesized that the basis for these changes in 5-HT(1A) receptor function may involve changes in the capacity of the 5-HT(1A) receptor to activate G proteins. We examined the effect of chronic administration of DOI on the regulation of 5-HT(1A) receptor function at the level of receptor-G protein interaction using quantitative autoradiography of [(35)S]GTPgammaS binding stimulated by the 5-HT(1A) receptor agonist (+/-)8-OH-DPAT (1 microM). Repeated administration of DOI (1 mg/kg, s.c. once daily for 8 days) resulted in a marked down-regulation in 5-HT(2A) binding sites, as labeled by the antagonist radioligand [(3)H]ketanserin, throughout the cerebral cortex. Chronic DOI treatment also resulted in a significant and selective attenuation of 5-HT(1A) receptor-stimulated [(35)S]GTPgammaS binding in the anterior cingulate cortex (vehicle-treated: 74+/-7.7% above basal; DOI-treated: 43+/-4.6% above basal). Interestingly, 5-HT(1A) receptor-stimulated [(35)S]GTPgammaS binding was not altered in the dorsal or median raphe, or in the limbic structures and other cortical regions examined. The decrease in 5-HT(1A) receptor-stimulated [(35)S]GTPgammaS binding in anterior cingulate cortex was not due to a decrease in 5-HT(1A) receptor number, indicating that the capacity of the 5-HT(1A) receptor to activate G proteins is attenuated in this cortical area following repeated DOI treatment. The heterologous regulation of 5-HT(1A) receptor function by chronic 5-HT(2) receptor activation in the anterior cingulate cortex raises interesting questions as to how the regulatory interaction between these serotonin receptor subtypes influences cognition, memory and emotion.
先前的研究表明，给大鼠施用5-羟色胺（5-HT）2受体激动剂DOI会导致5-HT1A受体介导的行为和神经内分泌反应的异源脱敏[《神经精神药理学》19 (1998) 354；《神经科学杂志》21 (2001) 7919]。我们推测，5-HT1A受体功能这些变化的基础可能涉及5-HT1A受体激活G蛋白能力的改变。我们使用5-HT1A受体激动剂(+/-)8-OH-DPAT（1微摩尔）刺激的[(35)S]GTPγS结合的定量放射自显影技术，研究了慢性施用DOI对受体-G蛋白相互作用水平上5-HT1A受体功能调节的影响。重复施用DOI（1毫克/千克，皮下注射，每日一次，共8天）导致整个大脑皮层中5-HT2A结合位点显著下调，该位点由拮抗剂放射性配体[(3)H]酮色林标记。慢性DOI处理还导致前扣带回皮层中5-HT1A受体刺激的[(35)S]GTPγS结合显著且选择性地减弱（载体处理组：比基础水平高74±7.7%；DOI处理组：比基础水平高43±4.6%）。有趣的是，在背侧或中缝核，或在所检查的边缘结构和其他皮层区域，5-HT1A受体刺激的[(35)S]GTPγS结合没有改变。前扣带回皮层中5-HT1A受体刺激的[(35)S]GTPγS结合的减少不是由于5-HT1A受体数量的减少，这表明在重复DOI处理后，该皮层区域中5-HT1A受体激活G蛋白的能力减弱。前扣带回皮层中慢性5-HT2受体激活对5-HT1A受体功能的异源调节引发了关于这些5-羟色胺受体亚型之间的调节相互作用如何影响认知、记忆和情绪的有趣问题。
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