FUNCTIONAL PROPERTIES OF BRAIN SOMATOSTATIN RECEPTORS

神经肽生长抑素（SRIF）具有多种生理作用 在CNS。 在新纹状体，它引起多巴胺的释放， 自发活动 在细胞中SRIF抑制腺苷酸环化酶 活动和调节K+和Ca++电导来调节放电 大脑神经元的活动。 中枢SRIF神经传递的改变 发生在精神分裂症和阿尔茨海默氏病中， 这些疾病的行为异常 这个目标 应用是阐明SRIF诱导的细胞机制， 其核心效应。 我们发现SRIF刺激两种不同的 受体亚型诱导其生理作用。 这些受体 新开发的SRIF可选择性激活亚型 激动剂MK 678和CGP 23996。 本提案的目的是测试 这两种SRIF受体介导不同的作用的假设， SRIF。 这将通过多学科方法来实现， 研究新纹状体（一个大脑区域）中SRIF受体的特性 表达两种受体亚型且其中SRIF受体诱导 多种生物反应。 解剖技术将用于 确定SRIF受体亚型是否定位于不同的 新纹状体的细胞群。 特别是，我们将确定 是否有一种受体亚型定位于一个专门的 纹状体的亚区，即纹状体外基质。 SRIF受体 将在体内被独立激活，以测试它们是否介导 不同的SRIF诱导的行为。 对于这些研究，MK 678或CGP 23996 将被显微注射到丘脑核中， 自发活动或奖励系统，由条件场所评估 偏好范式，将被测量。 为了调查SRIF是否 受体亚型与不同的细胞效应子系统偶联以介导 SRIF的不同生理作用，我们将检查MK的能力， 678和CGP 23996调节新纹状体细胞内电压依赖性K+和Ca++ 使用全细胞膜片钳技术在培养的细胞中进行。 在这些相同 细胞，我们将确定SRIF激动剂是否差异影响 腺苷酸环化酶活性。 除了针对以下方面的研究之外， 新纹状体SRIF受体，我们还将研究SRIF的性质， 其他脑区的受体。 边缘区的SRIF受体具有 已被提议介导SRIF的认知效应。 我们将测试 受体亚型之一是否选择性地介导 SRIF对认知功能的影响。 在这些研究中，我们将确定 SRIF激动剂可以逆转由以下原因引起的学习缺陷： 脑SRIF的耗竭。 为了实现这一点，亚型选择性激动剂 将通过脑室内给药至用以下药物预处理的动物 半胱胺，消耗中央SRIF，以及它们对两种不同的 将确定空间学习任务。 如果我们的研究表明 SRIF受体亚型介导不同的生理作用， SRIF，则可以使用MK 678和CGP 23996或其类似物 诱导SRIF的选择性中枢作用。 这可能是有用的， 用改变的SRIF治疗神经精神疾病 神经传递

The neuropeptide somatostatin (SRIF) exerts diverse physiological actions in the CNS. In the neostriatum, it evokes dopamine release and stimulates locomotor activity. At the cellular SRIF inhibits adenylate cyclase activity and modulates K+ and Ca++ conductances to regulate the firing activity of brain neurons. Alterations in central SRIF neurotransmission occur in Schizophrenia and Alzheimer's disease and has been associated with the behavioral abnormalities of these disorders. The goal of this application is to elucidate the cellular mechanisms by which SRIF induces its central effects. We have found that SRIF stimulates two different receptor subtypes to induce its physiological actions. These receptor subtypes can be selectively activated with the newly developed SRIF agonists MK 678 and CGP 23996. The objective of this proposal is to test the hypothesis that the two SRIF receptors mediate different actions of SRIF. This will be accomplished using a multidisciplinary approach to study the properties of SRIF receptors in the neostriatum, a brain region that expresses both receptor subtypes and in which SRIF receptor induces multiple biological responses. Anatomical techniques will be used to determine whether the SRIF receptor subtypes are localized to different cell populations in the neostriatum. In particular, we will determine whether one of the receptor subtypes is localized to a specialized subregion of the striatum, the extrastriosomal matrix. The SRIF receptors will be independently activated in vivo to test whether they mediate distinct SRIF-induced behaviors. For these studies, MK 678 or CGP 23996 will be microinjected into the nucleus accumbens and their effects on locomotor activity or reward systems, as assessed by the conditioned place preference paradigm, will be measured. To investigate whether SRIF receptor subtypes couple to different cellular effector systems to mediate distinct physiological actions of SRIF, we will examine the ability of MK 678 and CGP 23996 to modulate voltage dependent K+ and Ca++ in neostriatal cells in culture using whole cell patch clamp techniques. In these same cells, we will determine whether the SRIF agonists differentially affect adenylate cyclase activity. In addition to the studies directed at neostriatal SRIF receptors, we will also examine the properties of SRIF receptors in other brain regions. SRIF receptors in limbic regions have been proposed to mediate the cognitive effects of SRIF. We will test whether one of the receptor subtypes selectively mediates the effects of SRIF on cognitive functions. For these studies, we will determine whether SRIF agonists can reverse the learning deficits resulting from the depletion of brain SRIF. To accomplish this, subtype selective agonists will be administered intracerebroventricularly to animals pretreated with cysteamine, to deplete central SRIF, and their effects on two different spacial learning tasks will be determined. If our proposed studies show that subtypes of SRIF receptors mediate distinct physiological actions of SRIF, then it may be possible to use MK 678 and CGP 23996 or their analogs to induce selective central actions of SRIF. This could be useful in the treatment of neuropsychiatric disorders with altered SRIF neurotransmission.