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 受体与精神疾病有关，例如情感障碍和精神分裂症，以及酗酒、冲动和攻击性。在大脑中，5-HT1A 受体以高密度存在于血清素能细胞体区域，其功能相当于体树突自身受体，因此在调节血清素能神经元放电中发挥着关键作用。 5-HT1A 受体在位于突触后的皮质和边缘区域也以高密度存在。 5-HT1A 受体激动剂具有抗焦虑和抗抑郁样作用，在精神分裂症的治疗中具有重要意义。众所周知，长期服用5-HT1A受体激动剂或多种抗抑郁药物后，突触前和突触后5-HT1A受体的敏感性会降低。去甲肾上腺素 (NE) 和血清素 (5-HT) 神经元之间的相互作用可能是治疗情感障碍药物的重要作用部位。事实上，有大量证据表明 NE 和 5-HT 在大脑中存在功能相互作用。例如，血清素能神经元放电通过血清素细胞体上的兴奋性突触后α1-肾上腺素受体而增加，并通过去甲肾上腺素能末端的α2自身受体的激活而减少。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。由于过去两年选择性 5-HT/NE 再摄取抑制剂在临床中的使用急剧增加，因此这些研究解决了一个重要而及时的问题。我们假设，由于长期抑制 NE 和 5-HT 再摄取、α1-肾上腺素能受体阻断或 α2-肾上腺素能自身受体激活，导致 NE 输入到血清素能细胞体的减少，从而防止体细胞树突 5- 脱敏。 HT1A 受体在受体-G 蛋白相互作用水平。我们将使用 [35S]GTPgammaS 放射自显影检查受体-G 蛋白相互作用水平上 5-HT1A 受体功能的调节。我们将使用行为测量、生理反应和神经化学测定来评估体树突和突触后 5-HT1A 受体敏感性的变化。 5-HT1A 受体功能调节的研究可能对我们理解该受体在治疗精神疾病的药物的治疗作用中的作用具有重要意义