Serotonin Receptor Subtypes: Regulation and Interaction

描述（由申请人提供）：5-HT1A受体与精神疾病有关，如情感性障碍和精神分裂症，以及酗酒，冲动和攻击。在大脑中，5-HT1A受体高密度存在于5-羟色胺能细胞体区域，作为体树突自身受体，在调节5-羟色胺能神经元放电中起关键作用。5-HT1A受体也高密度存在于皮层和边缘区，它位于突触后。5-HT1A受体激动剂具有抗焦虑和抗抑郁的作用，在精神分裂症的治疗中有很大的兴趣。众所周知，长期服用5-HT1A受体激动剂或各种抗抑郁药物后，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用于治疗情感障碍的药物的重要作用位点。事实上，有大量证据表明NE和5-羟色胺在脑内的功能相互作用。例如，5 -羟色胺能神经元的放电通过5 -羟色胺能细胞体上的兴奋性突触后α 1-肾上腺素能受体而增加，并通过去甲肾上腺素能终端上的α 2自受体的激活而减少。我们的总体目标是研究抗抑郁药或5-HT1A受体激动剂对5-HT1A受体功能调节的肾上腺素能调节。由于选择性5-HT/NE再摄取抑制剂在临床上的使用在过去两年中急剧增加，这些研究解决了一个重要而及时的问题。我们假设，由于NE和5-羟色胺再摄取的慢性抑制、α 1-肾上腺素能受体的阻断或α 2-肾上腺素能自身受体的激活，NE输入到血清素能细胞体的减少，在受体- g蛋白相互作用水平上阻止了体树突5-HT1A受体的脱敏。我们将使用[35S]GTPgammaS放射自显影技术在受体- g蛋白相互作用水平上研究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分析来评估体树突和突触后5-HT1A受体敏感性的变化。5-HT1A受体功能调控的研究可能对我们理解该受体在治疗精神疾病的药物治疗作用中的作用具有重要意义

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