Béïque Jean-Claude, Imad Mays, Mladenovic Ljiljana, Gingrich Jay A, Andrade Rodrigo
Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9870-5. doi: 10.1073/pnas.0700436104. Epub 2007 May 29.
Classic hallucinogens such as lysergic acid diethylamide are thought to elicit their psychotropic actions via serotonin receptors of the 5-hydroxytryptamine 2A subtype (5-HT(2A)R). One likely site for these effects is the prefrontal cortex (PFC). Previous studies have shown that activation of 5-HT(2A)Rs in this region results in a robust increase in spontaneous glutamatergic synaptic activity, and these results have led to the widely held idea that hallucinogens elicit their effect by modulating synaptic transmission within the PFC. Here, we combine cellular and molecular biological approaches, including single-cell 5-HT(2A)Rs inactivation and 5-HT(2A)R rescue over a 5-HT(2A)R knockout genetic background, to distinguish between competing hypotheses accounting for these effects. The results from these experiments do not support the idea that 5-HT(2A)Rs elicit the release of an excitatory retrograde messenger nor that they activate thalamocortical afferents, the two dominant hypotheses. Rather, they suggest that 5-HT(2A)Rs facilitate intrinsic networks within the PFC. Consistent with this idea, we locate a discrete subpopulation of pyramidal cells that is strongly excited by 5-HT(2A)R activation.
诸如麦角酸二乙酰胺之类的经典致幻剂被认为是通过5-羟色胺2A亚型（5-HT(2A)R）的血清素受体引发其精神otropic作用。这些作用的一个可能部位是前额叶皮层（PFC）。先前的研究表明，该区域5-HT(2A)Rs的激活会导致自发性谷氨酸能突触活动显著增加，这些结果导致了一种广泛持有的观点，即致幻剂通过调节PFC内的突触传递来发挥其作用。在这里，我们结合细胞和分子生物学方法，包括在5-HT(2A)R基因敲除遗传背景下进行单细胞5-HT(2A)Rs失活和5-HT(2A)R拯救，以区分解释这些作用的相互竞争的假设。这些实验的结果不支持5-HT(2A)Rs引发兴奋性逆行信使释放的观点，也不支持它们激活丘脑皮质传入神经的观点，这是两个主要假设。相反，它们表明5-HT(2A)Rs促进了PFC内的内在网络。与此观点一致，我们定位了一个离散的锥体细胞亚群，该亚群被5-HT(2A)R激活强烈兴奋。
