Serotonin Receptor Subtypes: Regulation and Interaction

血清素受体亚型：调节和相互作用

• 批准号: 7058235
• 负责人: JULIE Gorton HENSLER
• 金额: $ 28.87万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7058235
• 关键词: CHO cells; adenylate cyclase; adrenergic receptor; antidepressants; autoradiography; cell surface receptors; electrophysiology; enzyme activity; gene induction /repression; hydrolysis; ketanserin; laboratory rat; neurochemistry; neurophysiology; neurotransmitter antagonist; receptor binding; receptor coupling; receptor expression; receptor sensitivity; serotonin inhibitor; serotonin receptor; transfection

DESCRIPTION (provided by applicant): 5-HT1A receptors have been implicated in psychiatric illnesses, such as affective disorders and schizophrenia, as well as alcoholism, impulsivity and aggression. In brain, the 5-HT1A receptor is present in high density in serotonergic cell body areas, where it functions as the somatodendritic autoreceptor and therefore plays a key role in regulating serotonergic neuronal firing. The 5-HT1A receptor is also present in high density in cortical and limbic areas where it is located postsynaptically. Agonists at the 5-HT1A receptor have both anxiolytic and antidepressant-like effects, and are of great interest in the treatment of schizophrenia. It is well known that the sensitivity of pre- and postsynaptic 5-HT1A receptors is decreased following chronic administration of 5-HT1A receptor agonists, or a variety of antidepressant drugs. The interaction between norepinephrine (NE) and serotonin (5-HT) neurons may serve as a significant site of action for drugs used to treat affective disorders. Indeed, there is abundant evidence of functional interactions between NE and 5-HT in brain. For example, serotonergic neuronal firing is increased via excitatory postsynaptic alpha1-adrenergic receptors on serotonergic cell bodies, and decreased by activation of alpha2 autoreceptors on noradrenergic terminals. Our overall goal is to examine adrenergic modulation of the regulation of 5-HT1A receptor function by antidepressants or 5-HT1A receptor agonists. Because the use of selective 5-HT/NE re-uptake inhibitors in the clinic has increased dramatically over the last two years, these studies address an important and timely issue. We hypothesize that a reduction in NE input to serotonergic cell bodies, as a result of chronic inhibition of both NE and 5-HT re-uptake, alpha1-adrenergic receptor blockade, or activation of alpha2-adrenergic autoreceptors, prevents desensitization of somatodendritic 5-HT1A receptors at the level of receptor-G protein interaction. We will examine the regulation of 5-HT1A receptor function at the level of receptor-G protein interaction using [35S]GTPgammaS autoradiography. We will assess changes in somatodendritic and postsynaptic 5-HT1A receptor sensitivity using behavioral measures, physiological responses and neurochemical assays. Studies of the regulation of 5-HT1A receptor function may have important implications for our understanding the role of this receptor in the therapeutic action of drugs used to treat mental illness

描述（由申请人提供）：5-HT1A受体与精神病有关，例如情感疾病和精神分裂症，以及酒精中毒，冲动和侵略性。在大脑中，5-HT1A受体存在于5-羟色胺能细胞体区域的高密度，在该区域起作用，在该区域起作用，在该区域起作用，在调节血清素能神经元触发中起关键作用。 5-HT1A受体也存在于高密度的高度密度，其位于突触后的皮质和边缘区域。 5-HT1A受体的激动剂既具有抗焦虑和抗抑郁药样的作用，并且对精神分裂症的治疗引起了极大的兴趣。众所周知，在长期施用5-HT1A受体激动剂或多种抗抑郁药后，突触前和突触后5-HT1A受体的敏感性降低。去甲肾上腺素（NE）和5-羟色胺（5-HT）神经元之间的相互作用可能是用于治疗情感障碍的药物的重要作用部位。实际上，有大量证据表明大脑中NE和5-HT之间的功能相互作用。例如，血清素能神经元通过血清素能细胞体上的兴奋性突触后α1-肾上腺素能受体增加，并通过在去甲肾上腺素能末端激活α2自感受器的激活减少。我们的总体目标是检查抗抑郁药或5-HT1A受体激动剂对5-HT1A受体功能调节的肾上腺素能调节。由于在过去两年中，在诊所中使用选择性5-HT/NE再摄取抑制剂已大大增加，因此这些研究涉及一个重要且及时的问题。我们假设，由于慢性抑制NE和5-HT再摄取，α1-肾上腺素能受体阻断或激活α2-肾上腺素能自身自身自身自动化体，导致NE输入对血清素能细胞体的减少，可预防体内蛋白质5-HT1A受体的脱敏，以阻止其脱敏。我们将使用[35S] GTPGAMMAS放射自显影检查在受体-G蛋白相互作用水平上对5-HT1A受体功能的调节。我们将使用行为措施，生理反应和神经化学测定法评估体内根质和突触后5-HT1A受体敏感性的变化。对5-HT1A受体功能的调节的研究可能对我们理解该受体在用于治疗精神疾病的药物的治疗作用中的作用具有重要意义