Physiological Implications of Serotonin Receptor Regulation

描述（由申请人提供）：作为大脑和整个身体中丰富的神经递质，5-羟色胺在决定许多生物过程中起着重要作用。5-羟色胺通过结合并激活神经元和其他细胞表面的G蛋白偶联受体（GPCR）来介导其作用。特定GPCR（5-羟色胺2A受体）的活性与几种神经精神障碍相关，并且已经进行了跨越几十年的许多努力来调节该受体的活性以改善精神病治疗。例如，非典型抗精神病药物氯氮平被设计成阻断这种受体的活性。其他药物治疗，如选择性5-羟色胺摄取抑制剂（SSRIs）和相关的抗抑郁药，可能通过改变大脑5-羟色胺水平间接影响该受体的活性。5-羟色胺2A受体也是滥用药物的一个突出目标，特别是那些被归类为致幻剂的药物;麦角酰二乙胺（LSD）通过直接激活该受体介导其致幻作用。间接作用于2A受体的其他滥用药物是安非他明，特别是MDMA或“摇头丸”。我们正在为针对5-羟色胺2A受体调节的药物开发提供新的基础。我们已经发现，血清素激活2A受体和下游信号是由细胞内调节蛋白称为？抑制素。5-羟色胺2A受体在体内的调节可以为神经系统对内源性5-羟色胺水平的敏感性以及对药理学试剂的响应性设定基调。我们的研究探讨了破坏血清素2A受体的生化，生理和行为后果？体内抑制蛋白相互作用。我们预测破坏血清素2A受体的药物-？抑制蛋白相互作用可能提供一种改变受体对脑中存在的5-羟色胺水平的敏感性的方法。这些发现可能会激发药物的发展，可以保持所需的基础多巴胺能紧张，同时消除过度的受体对内源性5-羟色胺的反应。药物设计中的这种策略可能被证明在临床上用于治疗神经精神疾病，包括与药物滥用相关的疾病。公共卫生相关性：我们的研究探讨了破坏5-羟色胺受体调节的生化，生理和行为后果。我们预测，破坏这种调节的药物可能会提供一种方法来改变受体对大脑中5-羟色胺水平的敏感性。这些发现可能会激发药物的开发，这些药物可能在临床上用于治疗精神分裂症等神经精神疾病以及与药物成瘾相关的疾病。

DESCRIPTION (provided by applicant): As an abundant neurotransmitter in the brain and throughout the body, serotonin plays a significant role in determining many biological processes. Serotonin mediates its actions by binding to and activating G protein-coupled receptors (GPCR) on the surface of neurons and other cells. The activity of a particular GPCR, the serotonin 2A receptor, is associated with several neuropsychiatric disorders and many efforts spanning several decades have been made to modulate the activity of this receptor to improve psychiatric treatments. For example, the atypical antipsychotic drug clozapine was designed to block the activity of this receptor. Additional pharmaceutical therapeutics, such as selective serotonin uptake inhibitors (SSRIs) and related antidepressants, may indirectly affect activity at this receptor by altering brain serotonin levels. The serotonin 2A receptor is also a prominent target for drugs of abuse, particularly those classified as hallucinogens; lysergic acid diethylamide (LSD) mediates its hallucinogenic effects by directly activating this receptor. Other drugs of abuse that indirectly act at the 2A receptor are amphetamines, particularly MDMA or "ecstacy". We are proposing a new basis for drug development targeting the regulation of the serotonin 2A receptor. We have found that serotonin activates the 2A receptor and downstream signaling is mediated by an intracellular regulatory protein called ?arrestin. Regulation of the serotonin 2A receptor in vivo may set the tone for neurological sensitivity to endogenous levels of serotonin as well as the responsiveness to pharmacological agents. Our studies explore the biochemical, physiological and behavioral consequences of disrupting the serotonin 2A receptor-?arrestin interactions in vivo. We predict that drugs that disrupt the serotonin 2A receptor-?arrestin interaction might provide a means to alter the sensitivity of the receptor to the levels of serotonin present in the brain. These findings may inspire the development of drugs that could maintain a desired basal serotonergic tone while eliminating excessive receptor responsiveness to endogenous serotonin. Such strategies in drug design may prove to be clinically useful for treating neuropsychiatric disorders including those associated with drugs of abuse. PUBLIC HEALTH RELEVANCE: Our studies explore the biochemical, physiological and behavioral consequences of disrupting serotonin receptor regulation. We predict that drugs that disrupt this regulation might provide a means to alter the sensitivity of the receptor to the levels of serotonin present in the brain. These findings may inspire the development of drugs that could be clinically useful for treating neuropsychiatric disorders such as schizophrenia as well as those associated with drug addiction.