RECEPTOR RESERVE AT BRAIN NEUROTRANSMITTER RECEPTORS

该项目的长期目标是了解如何 受体储备（RR;备用受体）和相对 多巴胺（DA）D2和5-羟色胺5-HT 1A受体激动剂的疗效 大脑中的位点与介导的功能效应的差异有关 这些激动剂。 先前的研究表明， 突触前和突触后D2受体解释了为什么某些DA激动剂引起 由突触前而非突触后D2受体介导的功能反应。 初步研究表明，这种方法可以提供洞察力， 新的非苯并二氮卓类抗焦虑药的作用机制（例如， 丁螺环酮），它们是选择性5-HT 1A激动剂。 三个主要假设将 受试者：1）伴随药物诱导的受体敏感性变化 上调和下调与RR的变化有关; 2）类似的 对脑D2突触前受体的DA激动剂的敏感性，和垂体 D2受体调节催乳素（PRL）分泌，是由于类似的， 大RR在这两个网站;此外，差异PRL反应的男性 和雌性大鼠是由于RR的差异;和3）在 突触前与突触后5-HT 1A受体解释了它们的差异 对5-HT-1A激动剂敏感。 为了验证这些假设，我们将：1） 确定各种慢性药物治疗（氟哌啶醇， 利血平，DA受体激动剂），大鼠品系（F344和布法罗），发育年龄 (2-60天出生后）和百日咳毒素治疗的RR的程度， 突触前和突触后D2受体。 突触前D2（自身）受体 将使用GBL模型评估功能;突触后D2受体 功能将通过检查DA激动剂诱导的 纹状体ACh水平; 2）确定各种DA激动剂的RR程度 通过测量雄性和雌性大鼠的脑垂体D2受体， 抑制血清PRL水平。 慢性雌激素和 利血平治疗也将进行检查; 3）确定RR的程度， 各种选择性5-HT 1A的突触前和突触后5-HT 1A受体 激动剂（例如8-OH-DPAT、丁螺环酮、吉哌隆、伊沙匹隆）;生化（5- HT合成抑制）、生理（体温过低）和协同 电生理（细胞外单单位记录）方法将被 就业。 DA受体激动剂的研究具有重要的临床意义。 这些药物的设计和使用在治疗 精神分裂症、帕金森氏病、迟发性运动障碍和图雷特氏症 综合征; 5-HT 1A激动剂的研究对 焦虑症的治疗

The long-term objective of this project is to gain an understanding of how differences in receptor reserve (RR; spare receptors) and in the relative efficacies of agonists for dopamine (DA) D2 and serotonin 5-HT1A receptor sites in the brain relate to differences in the functional effects mediated by these agonists. Previous studies demonstrated that differences in RR at pre- and postsynaptic D2 receptors explain why certain DA agonists elicit functional responses mediated by pre- but not postsynaptic D2 receptors. Preliminary studies indicate that this approach may provide insights into the mechanism of action of new nonbenzodiazepine anxiolytics (e.g. buspirone) which are selective 5-HT1A agonists. Three main hypotheses will be tested: 1) Receptor sensitivity changes which accompany drug-induced up- and downregulation are related to changes in RR; 2) The similar sensitivity to DA agonists of brain D2 presynaptic receptors, and pituitary D2 receptors regulating prolactin (PRL) secretion, is due to a similar, large RR at both sites; furthermore, the differential PRL response of male and female rats is due to differences in RR; and 3) A differential RR at pre- vs. postsynaptic 5-HT1A receptors accounts for their differential sensitivity to 5-HT-1A agonists. To test these hypotheses we will: 1) determine the effects of various chronic drug treatments (haloperidol, reserpine, DA agonists), rat strain (F344 and Buffalo), developmental age (2-60 days postnatal) and pertussis toxin treatment on the extent of RR at pre- and postsynaptic D2 receptors. presynaptic D2 (auto) receptor function will be assessed using the GBL model; postsynaptic D2 receptor function will be assessed by examining DA agonist-induced elevation of striatal ACh levels; 2) determine the extent of RR for various DA agonists at the pituitary D2 receptor in male and female rats by measuring their suppression of serum PRL levels. The effects of chronic estrogen and reserpine treatment will also be examined; 3) determine the extent of RR at pre- and postsynaptic 5-HT1A receptors for various selective 5-HT1A agonists (e.g. 8-OH-DPAT, buspirone, gepirone, ipsapirone); biochemical (5- HT synthesis inhibition), physiological (hypothermia) and collaborative electrophysiological (extracellular single unit recording) methods will be employed. The studies with DA agonists have important clinical implications for the design and use of these agents in the treatment of schizophrenia, Parkinson's disease, tardive dyskinesia and Tourette's syndrome; the studies with 5-HT1A agonists have similar implications for the therapy of anxiety disorders.