FUNCTIONAL PROPERTIES OF BRAIN SOMATOSTATIN RECEPTORS

神经肽生长抑素(SRIF)发挥多种生理作用 在中枢神经系统。在新纹状体中，它引起多巴胺释放并刺激 活动活动。在细胞内SRIF抑制腺苷环化酶 活性，并调节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病中，并与 这些紊乱的行为异常。这样做的目的是 应用是阐明SRIF诱导的细胞机制 它的核心作用。我们发现SRIF刺激两种不同的 受体亚型以诱导其生理作用。这些受体 可以使用新开发的SRIF选择性地激活亚型 激动剂MK678和CGP23996。这项提议的目标是测试 假设两种SRIF受体介导不同的作用 SRIF。这将使用多学科方法来实现 脑新纹状体SRIF受体特性的研究 既表达受体亚型又表达SRIF受体诱导的 多种生物反应。解剖学技术将被用于 确定SRIF受体亚型是否定位于不同的 新纹状体中的细胞群。特别是，我们将确定 其中一种受体亚型是否局限于专门的 纹状体的亚区，纹状体外基质。SRIF受体 将在体内被独立激活，以测试它们是否在 不同的SRIF诱导的行为。对于这些研究，MK678或CGP23996 会被微量注射到伏隔核内，并对 运动活动或奖励系统，由受限制的地方评估 偏好范式，将被衡量。调查SRIF是否 受体亚型偶联到不同的细胞效应系统以介导 SRIF的不同生理行为，我们将检测MK的能力 678和CGp 23996对新生纹状体细胞电压依赖性K~+和Ca~(++)的调节 使用全细胞膜片钳技术培养细胞。在这些相同的地方 细胞，我们将确定SRIF激动剂是否对 腺苷环化酶活力。除了针对以下方面的研究 新纹状体SRIF受体，我们还将检测SRIF的特性 其他脑区的受体。边缘区域的SRIF受体 已被提出用来调节SRIF的认知效应。我们将测试 受体亚型中的一种是否选择性地介导了 SRIF对认知功能的影响。对于这些研究，我们将确定是否 SRIF激动剂可以逆转由 脑部SRIF耗竭。要做到这一点，亚型选择性激动剂 将在脑室内给与预先处理的动物 半胱胺，耗尽中枢SRIF，以及它们对两个不同的 空间学习任务将被确定。如果我们提议的研究表明 SRIF受体亚型介导不同的生理活动 如果是SRIF，则可以使用MK678和CGP670或其类似物 诱导SRIF的选择性中枢作用。这可能会在 改良SRIF治疗神经精神障碍 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.