Dopamine release induced by atypical antipsychotics in prefrontal cortex requires 5-HT(1A) receptors but not 5-HT(2A) receptors.
Dopamine release induced by atypical antipsychotics in prefrontal cortex requires 5-HT(1A) receptors but not 5-HT(2A) receptors.
复制标题
DOI：
10.1017/s146114571000009x
复制
发表时间：
2010-11
期刊：
影响因子：
--
通讯作者：
Artigas F
中科院分区：
文献类型：
--
作者：
Bortolozzi A;Masana M;Díaz-Mataix L;Cortés R;Scorza MC;Gingrich JA;Toth M;Artigas F
非典型抗精神病药物（APD）增加前额叶皮层（PFC）多巴胺（DA）的释放，这种作用可能是通过直接或间接激活5-HT 1A受体（5-HT 1AR）介导的。考虑到大多数APD对5-HT 1AR的体外亲和力非常低，并且PFC中5-HT 1AR和5-HT 2A受体（5-HT 2AR）大量共表达，这种效应可能是由于APD阻断这些受体后5-HT 1AR和5-HT 2AR活化失衡所致，APD对这些受体表现出高亲和力。在这里，我们测试了这一假设的依赖性APD诱导的DA释放在内侧PFC（mPFC）的每一个受体，通过使用在野生型（WT）和5-HT 1AR和5-HT 2AR敲除（KO）小鼠体内微透析。通过反向透析给予的局部APD（氯氮平、奥氮平、利培酮）在WT和5-HT 2AR KO小鼠中同样诱导了mPFC DA输出的剂量依赖性增加，而在5-HT 1AR KO小鼠中不存在DA增加。为了研究这两种受体对大鼠mPFC中氯氮平诱导的DA释放的相对贡献，我们在体内用N-乙氧羰基-2-乙氧基-1，2-二氢喹啉（EEDQ）沉默G蛋白偶联受体（GPCR），而mPFC中的5-HT 1AR或5-HT 2A/2CR则用各自的拮抗剂WAY-100635或利坦色林选择性保护。GPCR的失活，同时保留约70%的5-HT 2A/2CRs防止氯氮平诱导的DA升高mPFC。与此相反，氯氮平增加了EEDQ治疗的大鼠mPFC中的DA，其5-HT 1AR受到保护（对照组大鼠的约50%）。这些结果表明：（1）5-HT 1AR是APD诱导的皮层DA传递升高所必需的，（2）这种作用不需要APD阻断5-HT 2AR。
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-HT1A receptor (5-HT1AR). Given the very low in-vitro affinity of most APDs for 5-HT1ARs and the large co-expression of 5-HT1ARs and 5-HT2A receptors (5-HT2ARs) in the PFC, this effect might result from the imbalance of 5-HT1AR and 5-HT2AR 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-HT1AR and 5-HT2AR 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-HT2AR KO mice whereas the DA increase was absent in 5-HT1AR 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-HT1ARs or 5-HT2A/2CRs in the mPFC were selectively protected with the respective antagonists WAY-100635 or ritanserin. The inactivation of GPCRs while preserving ∼70% of 5-HT2A/2CRs prevented the clozapine-induced DA rise in mPFC. In contrast, clozapine increased DA in mPFC of EEDQ-treated rats whose 5-HT1ARs were protected (∼50% of control rats). These results indicate that (1) 5-HT1ARs are necessary for the APDs-induced elevation in cortical DA transmission, and (2) this effect does not require 5-HT2AR blockade by APDs.