Physiological Implications of Serotonin Receptor Regulation

血清素受体调节的生理意义

• 批准号: 8265696
• 负责人: Laura M. Bohn
• 金额: $ 46.93万
• 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/8265696
• 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; Drug Psychoses; Environment; Event; Functional disorder; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Genotype; Hallucinogens; Head; Health; Immunohistochemistry; Intervention; Intestines; Knockout Mice; Lead; Life; Ligands; Lysergic Acid Diethylamide; Mediating; Mental Depression; 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; 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; 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; 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(申请人提供)：作为大脑和全身的一种丰富的神经递质，5-羟色胺在决定许多生物过程中扮演着重要的角色。5-羟色胺通过与神经元和其他细胞表面的G蛋白偶联受体(GPCR)结合并激活来介导其作用。一种特殊的gpr，5-羟色胺2A受体的活性与几种神经精神疾病有关，几十年来人们做出了许多努力来调节这种受体的活性，以改善精神治疗。例如，非典型抗精神病药物氯氮平的设计就是为了阻断这种受体的活性。额外的药物疗法，如选择性5-羟色胺摄取抑制剂(SSRI)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重要靶点，特别是那些被归类为致幻剂的药物；麦角酸二乙胺(LSD)通过直接激活该受体来调节其致幻作用。其他间接作用于2A受体的滥用药物是苯丙胺，特别是摇头丸或“摇头丸”。我们提出了一种针对调节5-羟色胺2A受体的药物开发的新基础。我们已经发现，5-羟色胺激活了2A受体，下游信号是由一种名为？arrestin的细胞内调节蛋白介导的。在体内调节5-羟色胺2A受体可以为神经学对内源性5-羟色胺水平的敏感性以及对药物的反应性设定基调。我们的研究探索了体内扰乱5-羟色胺2A受体-？arrestin相互作用的生化、生理和行为后果。我们预测，破坏5-羟色胺2A受体-？arrestin相互作用的药物可能提供一种方法，改变该受体对大脑中存在的5-羟色胺水平的敏感性。这些发现可能会激励药物的开发，这些药物可以保持所需的基础5-羟色胺张力，同时消除对内源性5-羟色胺的过度受体反应。药物设计中的这种策略可能被证明在临床上对治疗神经精神障碍有用，包括那些与滥用药物有关的疾病。与公共健康相关：我们的研究探索了扰乱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手段，改变受体对大脑中存在的5-羟色胺水平的敏感性。这些发现可能会启发药物的开发，这些药物可能在临床上对治疗精神分裂症等神经精神疾病以及与药物成瘾有关的疾病有用。