ANTIDEPRESSANTS AND MONOAMINE RECEPTORS AND RESPONSES

目的是探索抗抑郁药和其他药物的作用， 调节β-肾上腺素能和 胆碱能反应，特别强调受体 机制等 重点将放在β-肾上腺素能的影响， 激动剂，当反复给予大鼠，对中枢β-反应， 为评价此类药物提供临床前依据， 抗抑郁药 将对大鼠给予β-受体激动剂， 全身或通过脑室内输注，使用Alzet 微型泵 将通过测量β-肾上腺素能反应性来评估 异丙肾上腺素提高腺苷3 '浓度的能力， 制备的皮质和小脑切片中的5 '-单磷酸（环AMP） 来自对照组或药物治疗组大鼠。 高选择性β-拮抗剂将 用于将皮质中环AMP的升高与β 1 受体和小脑中的β 2受体。 分子 负责激动剂诱导的反应性变化的机制将 通过测量激动剂对细胞的亚型密度的影响来研究。 β-受体在大脑的不同部分（使用体外配体 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）。 这些研究将提供 激动剂诱导中枢神经调节重要信息 β-肾上腺素能受体及其与体内N蛋白的连接。 类似的方法将用于检查抗抑郁药诱导的 中枢β-反应性的变化受同时发生的 给予甲状腺激素。 这些数据或许可以解释 三碘甲状腺原氨酸治疗抑郁症 女性患者加速丙咪嗪诱导抑郁症的恢复。 5-羟色胺（5-HT）受体的研究将集中在5-HT 1 受体，强调抗抑郁治疗的效果 和5-羟色胺激动剂对这种受体的亚型及其高 亲和态 受体的改变可以解释这些效应。 药物，当反复给予大鼠，对中枢5-羟色胺反应。 目前，还没有5-HT 1B受体的选择性放射性配体 亚型 然而，哌啶基衍生物RU 24969对 这种亚型，因此，实验提出，以纳入氚 然后评估它是否可以被用作 对5-HT 1B受体具有选择性的放射性配体。 药物诱导的对 5-HT 1受体的高亲和力状态可以通过以下方式评估： 在不存在GTP的情况下进行饱和实验，并使用 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.