ANTIDEPRESSANTS AND MONOAMINE RECEPTORS AND RESPONSES

目的是探索抗抑郁药物和其他药物的效果。 精神活性化合物对β-肾上腺素能和神经递质的调节 5-羟色胺能反应性，特别强调受体 机械装置。重点是β-肾上腺素能的作用。 激动剂，当反复给大鼠服用时，对中枢β-反应 为评估这些药物提供临床前的理论基础，如 抗抑郁药。大鼠也将被注射β-激动剂。 系统地或通过脑室内输注使用阿尔采特 迷你泵。通过测量来评估β-肾上腺素能反应性 异丙肾上腺素升高腺苷3‘浓度的能力， 大脑皮层和小脑切片中5‘-单磷酸(CAMP)的制备 来自对照或药物处理的大鼠。高度选择性的β-受体拮抗剂将 被用来将皮层中环磷酸腺苷的升高与β1联系起来 受体和小脑中的β2受体。分子 激动剂诱导的反应性改变的机制将 通过测量激动剂对亚型密度的影响来研究 大脑不同部位的β受体(使用两种体外配体 结合技术和定量放射自显影)以及 β受体亚型与鸟嘌呤核苷酸的相互作用 结合调节蛋白(N蛋白)。这样的研究将提供 激动剂诱导的中枢神经系统调节的重要信息 β-肾上腺素能受体及其与体内N蛋白的联系。 类似的方法将被用来检查抗抑郁剂是否会导致 中枢β反应性的变化受并发 甲状腺激素的管理。这样的数据可能会提供一种解释 观察到服用三碘甲腺原氨酸治疗抑郁症 女性患者加速丙咪嗪诱导的抑郁症康复。 对5-羟色胺受体的研究将集中在5-羟色胺1 受体，强调抗抑郁治疗的效果 和5-羟色胺激动剂对该受体亚型及其高表达的影响 关联状态。受体的改变可以解释这些影响 药物，当重复给大鼠时，对中枢5-羟色胺的反应。 目前，5-HT1B受体还没有选择性的放射性配体。 子类型。然而，哌啶基衍生物RU 24969对 因此，建议对这一亚型进行掺入氚的实验。 注入分子中，然后评估它是否可以用作 5-HT1B受体的放射性配基选择性。药物对人的影响 5-HT1受体的高亲和力状态可以通过 无GTP条件下的饱和实验及数据分析 借助计算机进行非线性回归分析。

The goals are to explore the effect of antidepressants and other psychoactive compounds on the regulation of beta-adrenergic and serotoninergic responsiveness, with particular emphasis on receptor mechanisms. Emphasis will be given to the effects of beta-adrenergic agonists, when given repeatedly to rats, on central beta-responsiveness so as to provide a pre-clinical rationale for the evaluation of such drugs as antidepressants. Beta-agonists will be administered to the rats either systemically or by intracerebroventricular infusion, using Alzet minipumps. Beta-adrenergic responsiveness will be assessed by measuring the ability isoproterenol to raise the concentration of adenosine 3', 5'-monophosphate (cyclic AMP) in slices of cortex and cerebellum prepared from control or drug-treated rats. Highly selective beta-antagonists will be used so as to link the rise in cyclic AMP in the cortex to beta1 receptors and in the cerebellum to beta2 receptors. The molecular mechanisms responsible for agonist-induced changes in responsiveness will be studied by measuring agonist effects on the density of subtypes of the beta-receptor in different parts of the brain (using both in vitro ligand binding techniques and quantitative autoradiography) as well as the interaction of the beta receptor subtypes with the guanine nucleotide binding regulatory protein (N protein). Such studies will provide important information on agonist-induced regultion of central beta-adrenergic receptors and their linkage with the N protein in vivo. Similar methodology will be used to examine whether antidepressant-induced changes in central beta-responsiveness are influenced by the concurrent administration of thyroid hormone. Such data might provide an explanation for the observation that administration of triiodothyronine to depressed female patients hastens imipramine-induced recovery from depression. Studies with receptors for serotonin (5-HT) will focus on the 5-HT1 receptor with emphasis placed on the effect of antidepressant treatments and serotonin agonists on the subtypes of this receptor and its high affinity state. Receptor alterations could explain the effects of these drugs, when given repeatedly to rats, on central serotonin responsiveness. At present, there is no selective radioligand for the 5-HT1B receptor subtype. However, the piperidinyl derivative, RU 24969, is selective for this subtype, consequently, experiments are proposed to incorporate tritium into the molecule and then to assess whether it could be used as a radioligand selective for 5-HT1B receptors. Drug-induced effects on the high affinity state of the 5-HT1 receptor can be assessed by doing saturation experiments in the absence of GTP and analyzing the data using non-linear regression analysis with the aid of a computer.