Department of Neurochemistry and Neuropharmacology, IIBB-CSIC (IDIBAPS), Barcelona, Spain.
Int J Neuropsychopharmacol. 2010 Nov;13(10):1299-314. doi: 10.1017/S146114571000009X. Epub 2010 Feb 17.
Atypical antipsychotic drugs (APDs) increase dopamine (DA) release in prefrontal cortex (PFC), an effect probably mediated by the direct or indirect activation of the 5-HT(1A) receptor (5-HT(1A)R). Given the very low in-vitro affinity of most APDs for 5-HT(1A)Rs and the large co-expression of 5-HT(1A)Rs and 5-HT(2A) receptors (5-HT(2A)Rs) in the PFC, this effect might result from the imbalance of 5-HT(1A)R and 5-HT(2A)R activation after blockade of these receptors by APDs, for which they show high affinity. Here we tested this hypothesis by examining the dependence of the APD-induced DA release in medial PFC (mPFC) on each receptor by using in-vivo microdialysis in wild-type (WT) and 5-HT(1A)R and 5-HT(2A)R knockout (KO) mice. Local APDs (clozapine, olanzapine, risperidone) administered by reverse dialysis induced a dose-dependent increase in mPFC DA output equally in WT and 5-HT(2A)R KO mice whereas the DA increase was absent in 5-HT(1A)R KO mice. To examine the relative contribution of both receptors to the clozapine-induced DA release in rat mPFC, we silenced G-protein-coupled receptors (GPCRs) in vivo with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) while 5-HT(1A)Rs or 5-HT(2A)/2CRs in the mPFC were selectively protected with the respective antagonists WAY-100635 or ritanserin. The inactivation of GPCRs while preserving ∼70% of 5-HT(2A)/(2C)Rs prevented the clozapine-induced DA rise in mPFC. In contrast, clozapine increased DA in mPFC of EEDQ-treated rats whose 5-HT(1A)Rs were protected (∼50% of control rats). These results indicate that (1) 5-HT(1A)Rs are necessary for the APDs-induced elevation in cortical DA transmission, and (2) this effect does not require 5-HT(2A)R blockade by APDs.
非典型抗精神病药物 (APD) 增加前额叶皮层 (PFC) 中的多巴胺 (DA) 释放，这种效应可能是通过 5-羟色胺 (1A) 受体 (5-HT(1A)R) 的直接或间接激活介导的。鉴于大多数 APD 对 5-HT(1A)R 的体外亲和力非常低，以及 PFC 中 5-HT(1A)R 和 5-HT(2A) 受体 (5-HT(2A)R) 的大量共表达，这种效应可能是由于 APD 阻断这些受体后 5-HT(1A)R 和 5-HT(2A)R 的激活失衡所致，因为它们对这些受体具有高亲和力。在这里，我们通过在野生型 (WT) 和 5-HT(1A)R 和 5-HT(2A)R 敲除 (KO) 小鼠中使用体内微透析来检查每种受体对 APD 诱导的 PFC 中 DA 释放的依赖性，从而检验了这一假设。局部 APD(氯氮平、奥氮平、利培酮)通过逆行透析给药，在 WT 和 5-HT(2A)R KO 小鼠中均引起剂量依赖性的 PFC 中 DA 输出增加，而在 5-HT(1A)R KO 小鼠中则没有 DA 增加。为了研究这两种受体对氯氮平诱导的大鼠 PFC 中 DA 释放的相对贡献，我们使用 N-乙氧羰基-2-乙氧基-1,2-二氢喹啉 (EEDQ) 在体内沉默 G 蛋白偶联受体 (GPCRs)，同时选择性地用各自的拮抗剂 WAY-100635 或 ritanserin 保护 PFC 中的 5-HT(1A)R 或 5-HT(2A)/2CR。在保留约 70%的 5-HT(2A)/(2C)R 的情况下，EEDQ 处理的大鼠中 GPCRs 的失活阻止了 PFC 中氯氮平诱导的 DA 升高。相比之下，氯氮平增加了 EEDQ 处理的大鼠的 PFC 中的 DA，而这些大鼠的 5-HT(1A)R 得到了保护 (约为对照组大鼠的 50%)。这些结果表明，(1)5-HT(1A)R 是 APD 诱导的皮质 DA 传递升高所必需的，(2)这种效应不需要 APD 对 5-HT(2A)R 的阻断。
