Physiological Implications of Serotonin Receptor Regulation

血清素受体调节的生理意义

• 批准号: 7654585
• 负责人: Laura M. Bohn
• 金额: $ 48.83万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7654585
• 关键词: 5-Hydroxytryptophan; Adverse effects; Affect; Agonist; Animals; Antidepressive Agents; Antipsychotic Agents; Arrestins; Behavioral; Binding; Biochemical; Biological; Biological Process; Brain; Cells; Chemicals; Clinical; Clozapine; Disease; Drug Addiction; Drug Delivery Systems; Drug Design; Environment; Event; Functional disorder; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Genotype; Hallucinogens; Head; Immunohistochemistry; Intervention; Intestines; Knock-out; Lead; Life; Ligands; Lysergic Acid Diethylamide; Mediating; Mitogen-Activated Protein Kinases; Molecular; Motor Activity; Mus; Mutation; Nature; Neurologic; Neurons; Neurotransmitters; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pharmacotherapy; Physiological; Physiology; Play; Psychiatric therapeutic procedure; Psychotic Disorders; Recruitment Activity; Regulation; Rodent Model; Role; Schizophrenia; Serotonin; Serotonin Agents; Serotonin Agonists; Serotonin Receptor 5-HT2A; Serotonin Receptors 5-HT2; Serotonin Uptake Inhibitors; Signal Pathway; Signal Transduction; Signaling Protein; Substance Withdrawal Syndrome; Surface; System; Testing; Therapeutic; amphetamine receptor; atypical antipsychotic; base; cellular imaging; depression; design; drug development; drug discrimination; drug of abuse; ecstasy; frontal lobe; gastrointestinal function; genetic regulatory protein; improved; in vivo; inhibitor/antagonist; mutant; neuropsychiatry; novel; novel strategies; psychostimulant; public health relevance; receptor; receptor function; receptor internalization; receptor sensitivity; research study; response; serotonin receptor; serotonin transporter; trafficking; viral gene delivery

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.

描述（由申请人提供）：作为大脑和全身丰富的神经递质，血清素在决定许多生物过程中发挥着重要作用。血清素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。一种特定的 GPCR（血清素 2A 受体）的活性与多种神经精神疾病相关，几十年来，人们做出了许多努力来调节该受体的活性，以改善精神科治疗。例如，非典型抗精神病药物氯氮平就是为了阻断该受体的活性而设计的。其他药物疗法，例如选择性血清素摄取抑制剂（SSRI）和相关抗抑郁药，可能通过改变大脑血清素水平来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重要目标，特别是那些被归类为致幻剂的药物；麦角酸二乙酰胺 (LSD) 通过直接激活该受体来介导其致幻作用。其他间接作用于 2A 受体的滥用药物是安非他明，特别是 MDMA 或“摇头丸”。我们正在为针对血清素 2A 受体调节的药物开发提出新的基础。我们发现血清素激活 2A 受体，下游信号传导是由一种称为 ?arrestin 的细胞内调节蛋白介导的。体内血清素 2A 受体的调节可能决定神经系统对内源性血清素水平的敏感性以及对药物的反应性。我们的研究探讨了破坏体内 5-羟色胺 2A 受体 - 抑制蛋白相互作用所产生的生化、生理和行为后果。我们预测，破坏血清素 2A 受体与抑制蛋白相互作用的药物可能会提供一种方法来改变受体对大脑中血清素水平的敏感性。这些发现可能会激发药物的开发，这些药物可以维持所需的基础血清素张力，同时消除受体对内源性血清素的过度反应。药物设计中的此类策略可能被证明在临床上可用于治疗神经精神疾病，包括与滥用药物相关的疾病。公共健康相关性：我们的研究探讨了破坏血清素受体调节所产生的生化、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血清素水平的敏感性。这些发现可能会激发临床上可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的药物的开发。