RECEPTOR RESERVE AT BRAIN NEUROTRANSMITTER RECEPTORS

这个项目的长期目标是了解如何 受体储备(RR；备用受体)和相对受体的差异 多巴胺D2和5-羟色胺5-羟色胺受体激动剂的作用 大脑中的位置与调节的功能效应的差异有关 被这些激动剂。以前的研究表明，在不同的时间 突触前和突触后D2受体解释为什么某些DA激动剂诱导 功能反应由突触前而不是突触后D2受体介导。 初步研究表明，这种方法可能会为 并对新型非苯二氮卓类抗焦虑药的作用机制进行了探讨。 丁螺环酮)是选择性的5-HT1A激动剂。三个主要假设将 被测试：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 脑D2突触前受体和垂体对DA激动剂的敏感性 D2受体调节催乳素(PRL)的分泌，是由于类似的， 两个部位的RR都很大；此外，雄性PRL反应的差异 雌性大鼠的差异是由于RR的差异；以及3)RR在 突触前和突触后5-HT1a受体的差异 对5-羟色胺-1A激动剂的敏感性。为了检验这些假设，我们将：1) 确定各种慢性药物治疗的效果(氟哌啶醇， 利血平，DA激动剂)，大鼠品系(F344和水牛)，发育年龄 (出生后2-60天)和百日咳毒素治疗对RR的影响 突触前和突触后D2受体。突触前D2(自身)受体 功能将使用GBL模型进行评估；突触后D2受体 功能评估将通过检测DA激动剂诱导的 纹状体ACh水平；2)确定不同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 抑制血清催乳素水平。慢性雌激素和雌激素的作用 利血平治疗也将被检查；3)确定RR的程度 多种选择性5-HT1A的突触前和突触后受体 激动剂(如8-羟基-DPAT、丁螺环酮、吉培酮、爱普沙酮)；生化类(5- 羟色胺合成抑制)、生理(低温)和协同作用 电生理学(细胞外单个单位记录)方法将 受雇的。DA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对治疗黑素瘤的影响 精神分裂症、帕金森氏病、迟发性运动障碍和抽动症 对5-HT1A激动剂的研究也有类似的意义。 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.