Physiological Implications of Serotonin Receptor Regulation

血清素受体调节的生理意义

• 批准号: 8080359
• 负责人: Laura M. Bohn
• 金额: $ 48.78万
• 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/8080359
• 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（由申请人提供）：作为大脑和整个身体中丰富的神经递质，5-羟色胺在确定许多生物学过程中起着重要作用。 5-羟色胺通过与神经元和其他细胞表面上的G蛋白偶联受体（GPCR）结合并激活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疾病有关，并且已经进行了数十年的许多努力，以调节该受体的活性以改善精神疗法。例如，设计非典型的抗精神病药氯氮平以阻断该受体的活性。其他药物治疗剂，例如选择性5-羟色胺摄取抑制剂（SSRIS）和相关抗抑郁药，可能通过改变脑血清素水平而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标，尤其是被归类为幻觉量的药物。丁甲酸二乙酰胺（LSD）通过直接激活该受体来介导其致幻作用。间接作用于2A受体的其他滥用药物是苯丙胺，尤其是MDMA或“狂喜”。我们提出了针对5-羟色胺2A受体调节的药物开发的新基础。我们发现5-羟色胺激活2A受体，下游信号传导是由称为“阻止蛋白”的细胞内调节蛋白介导的。血清素2a受体在体内的调节可能为内源性血清素水平以及对药理学剂的反应定下神经系统敏感性的基调。我们的研究探讨了破坏体内5-羟色胺2a受体的抑制素相互作用的生化，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能够维持所需基础血清素能张力的药物的发展，同时消除过度受体对内源性羟色胺的反应。药物设计中的此类策略可能被证明对治疗神经精神疾病在临床上有用，包括与滥用药物有关的疾病。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，破坏该调节的药物可能会提供一种方法，以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可能在治疗神经精神疾病（如精神分裂症以及与药物成瘾相关的神经精神疾病）上有用的药物的发展。