Serotonin Receptor Subtypes: Regulation and Interaction

描述（由申请人提供）：5-HT 1A受体与精神疾病有关，如情感障碍和精神分裂症，以及酗酒、冲动和攻击性。在脑中，5-HT 1A受体以高密度存在于肾上腺素能细胞体区域中，在那里它作为体树突自身受体起作用，因此在调节肾上腺素能神经元放电中起关键作用。5-HT 1A受体也以高密度存在于皮质和边缘区，其位于突触后。5-HT 1A受体激动剂具有抗焦虑和抗抑郁样作用，并且在精神分裂症的治疗中引起极大兴趣。众所周知，在长期施用5-HT 1A受体激动剂或多种抗抑郁药物后，突触前和突触后5-HT 1A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。事实上，有大量的证据表明NE和5-HT在脑中的功能相互作用。例如，肾上腺素能神经元放电通过肾上腺素能细胞体上的兴奋性突触后α 1-肾上腺素能受体而增加，并且通过去甲肾上腺素能末梢上的α 2自身受体的激活而减少。我们的总体目标是研究肾上腺素能调节5-HT 1A受体功能的抗抑郁药或5-HT 1A受体激动剂。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。我们推测，NE输入到肾上腺素能细胞体的减少，作为长期抑制NE和5-HT再摄取、α 1-肾上腺素能受体阻断或α 2-肾上腺素能自身受体激活的结果，阻止了体树突5-HT 1A受体在受体-G蛋白相互作用水平的脱敏。我们将使用[35 S] GTP γ S放射自显影术在受体-G蛋白相互作用水平上检查5-HT 1A受体功能的调节。我们将评估体树突和突触后5-HT 1A受体敏感性的变化，使用行为措施，生理反应和神经化学测定。对5-HT 1A受体功能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

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