Psychotogenic Drug Action on Chemically Defined Neurons

致精神病药物对化学确定的神经元的作用

• 批准号: 6650180
• 负责人: GEORGE AGHAJANIAN
• 金额: $ 20.72万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1975
• 资助国家: 美国
• 起止时间: 1975-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6650180
• 关键词: G protein; brain electrical activity; brain mapping; calcium channel; hallucinogens; laboratory rat; potassium channel; prefrontal lobe /cortex; psychopharmacology; psychotomimetic drug; serotonin; serotonin receptor; video microscopy; voltage /patch clamp

DESCRIPTION(From applicant's abstract): The overall aim of this proposal is to explore mechanisms by which serotonin (5-HT) and hallucinogenic drugs (acting via 5-HT2A receptors) enhance glutamatergic EPSPs/EPSCs (excitatory postsynaptic potentials/currents) in apical dendrites of layer V pyramidal cells of prefrontal cortex. Specific aims are (1) to map and characterize in rat brain slices, hot spots along the apical dendrite at which 5-HT2A receptor activation elicits an increase in EPSCs (e.g., using infrared/differential interference contrast videornicroscopy, whole cell patch-clamp recording, focal puff application of 5-HT, and close-in electrical stimulation) and (2) To explore preversus postsynaptic mechanisms underlying the 5-HT2A receptor mediated enhancement of EPSCs in layer V pyramidal cells (e.g., the role postsynaptic G protein activation and pre- and postsynaptic Ca2+ and K+ channel mechanisms). Previously, we have shown that activation of 5-HT2A receptors by 5-HT or hallucinogens increase the frequency of spontaneous EPSCs and a late component of electrically-evoked EPSCs. Our preliminary results indicate that these effects are likely to be mediated through activation of the two major 5-HT2A receptor signal transduction pathways: suppression of K+ currents and a release of intracellular Ca2+ via the PLC/PI/IP3 pathway. Based on our preliminary findings, it is suggested that the effects of psychedelic hallucinogens (in common with that reported for psychotomimetic NMDA antagonist drugs) are mediated by a hyperglutamatergic mechanism downstream from the initial receptor. If hypergiutamatergic states play a role in naturally occurring psychoses (e.g., schizophrenia), as they do in the psychotomimetic drug models, then treatments that normalize glutamate release (e.g., inhibitory presynaptic metabotropic autoreceptor agonists) may be therapeutic or prophylactic in these conditions.

描述（来自申请人的摘要）： 该建议的总体目的是探索5-羟色胺的机制 （5-HT）和致幻药（通过5-HT2A受体作用）增强 谷氨酸能EPSP/EPSP（兴奋性突触后电位/电流） 前额叶皮层的V层锥体细胞的顶端树突。具体目标 是（1）映射和特征在大鼠脑切片中，沿顶端的热点 5-HT2A受体激活引起EPSC的树突 （例如，使用红外/差分干扰对比造影剂， 全细胞斑块钳记录，5-HT的局灶性粉扑应用和近距离 电刺激）和（2）探索前反转后机制 5-HT2A受体介导的EPSC在V层V层的增强的基础 锥体细胞（例如，突触后G蛋白激活以及前和前和前的作用 突触后CA2+和K+通道机制）。以前，我们已经表明 通过5-HT或致幻剂激活5-HT2A受体会增加频率 自发EPSC和电诱发的EPSC的晚期。我们的 初步结果表明这些效果可能被介导 通过激活两个主要的5-HT2A受体信号转导 途径：抑制K+电流和细胞内Ca2+通过 PLC/PI/IP3途径。根据我们的初步发现，建议 迷幻致幻剂的影响（与报道的共同 心理NMDA拮抗剂）由高谷氨酸能介导 初始受体下游的机理。如果高二氨酸态状态 像他们一样在自然发生的精神病（例如精神分裂症）中发挥作用 在心理药物模型中，然后将谷氨酸正常的治疗 释放（例如，抑制性突触前代谢型自身受体激动剂）可能 在这些条件下要治疗或预防性。