A-ADRENERGIC RECEPTOR BINDING AND FUNCTION IN THE BRAIN

我们建议检查的结合和功能特性， 大鼠脑内α-肾上腺素能受体亚型及其在脑内的定位 特定的细胞类型和神经束，受体密度的调节 和反应性的变化传入输入，以及相互作用， 各种精神药物与大脑中的这些受体。 Alpha 1-和 使用拮抗剂直接标记α 2-肾上腺素能受体 放射性配体125 I-BE 2254和3 H-萝乌辛。 测量功能 对受体刺激的反应将包括去甲肾上腺素诱导的 增加3 H-肌醇代谢和可乐定诱导的减少 α 1-和α 2-肾上腺素能神经递质脑切片中的环磷酸腺苷水平 受体分别。 3 H-5-羟色胺释放减少 还将在大鼠中检查α 2-肾上腺素能受体刺激 大脑皮层 拮抗剂效力之间的关联 竞争放射性配体结合位点并抑制受体介导的 反应将提供证据表明放射性配体正在标记 合适的受体位点。 激动剂的效力比较， 与受体结合并激活功能反应将估计 受体占有率和组织反应之间的关系。 的 将通过减少受体来检查备用受体的存在。 浓度与酚苄明和检查反应性的条件下 感受器密度下降。 受体亚型定位于 特定的细胞群和神经束将通过 化学损伤后和大量分离的受体密度检查 细胞群 受体密度和反应性的调节， 去甲肾上腺素能输入和慢性激动剂或拮抗剂的改变 治疗，将提供证据的机制控制适应性 这些受体的反应。 慢性感染后观察到的效果 精神活性药物治疗将提供证据， 与这些受体有显著的相互作用。 这些实验将 增加我们的知识的性质，本地化和监管 大鼠脑内α-肾上腺素能受体亚型。 这将有助于 了解去甲肾上腺素在大脑中的作用， 评估一些药物对中枢神经系统的影响， 与α-肾上腺素能受体相互作用， 使用.

We propose to examine the binding and functional properties of Alpha-adrenergic receptor subtypes in rat brain, their localization to specific cell types and nerve tracts, the regulation of receptor density and responsiveness by changes in afferent input, and the interaction of various psychoactive drugs with these receptors in the brain. Alpha1- and Alpha2-adrenergic receptors will be directly labelled using the antagonist radioligands 125I-BE2254 and 3H-rauwolscine. Measurement of functional responses to receptor stimulation will include norepinephrine-induced increases in 3H-inositol metabolism and clonidine-induced decreases in cyclic AMP levels in brain slices by Alpha1- and Alpha2-adrenergic receptors respectively. Decreases in 3H-5-hydroxytryptamine release by Alpha2-adrenergic receptor stimulation will also be examined in rat cerebral cortex. Correlation between the potencies of antagonists in competing for radioligand binding sites and inhibiting receptor-mediated responses will provide evidence that the radioligands are labelling the appropriate receptor sites. Comparison of the potencies of agonists in binding to the receptors and activating functional responses will estimate the relationship between receptor occupancy and tissue response. The existence of spare receptors will be examined by decreasing receptor density with phenoxybenzamine and examining responsiveness under conditions of decreased receptor density. Localization of receptor subtypes to specific cell populations and nerve tracts will be accomplished by examination of receptor density after chemical lesions and in bulk isolated cell populations. The regulation of receptor density and responsiveness by alterations in the noradrenergic input, and chronic agonist or antagonist treatment, will provide evidence on mechanisms controlling the adaptive responsiveness of these receptors. Effects observed after chronic treatment with psychoactive drugs will provide evidence as to which drugs have significant interactions with these receptors. These experiments will increase our knowledge of the properties, localization and regulation of Alpha-adrenergic receptor subtypes in rat brain. This will be useful in understanding the actions of norepinephrine in the brain, as well as in evaluating the central nervous system effects of a number of drugs that interact with Alpha-adrenergic receptors and that are in current medical usage.