DOPAMINERGIC MODULATION OF THE STARTLE REFLEX

描述：(改编自《调查者摘要》)该项目的目标 修订后的研究方案是研究参与 多巴胺能对声学惊厥反射的调制。此外，基于 最新数据，没有包含在最初的提案中，我们将评估如何 参与惊厥的多巴胺能调制的一些电路也可能 与恐惧强化的惊吓效果有关，惊吓幅度是 在先前配对的提示存在的情况下引发时增加 足部电击。惊吓反射目前被许多调查人员用来 研究注意、恐惧、焦虑与运动的药物调节 行为。许多动物研究都利用了描述得很好的 神经解剖学和神经化学在研究基底神经节内的作用 多巴胺在运动行为的产生中的作用，如运动活动或 刻板的行为。运动反射也受多巴胺的调节，因此 代表另一类重要的运动行为，由基本的 神经节。我们一直在使用声学惊吓反射来阐明一些 多巴胺能调节反射行为的神经机制。 选择性多巴胺D_1受体激动剂SKF的全身给药 82958或SKF 81297显著增强了惊吓反应。相比之下， D2激动剂奎比罗或D2/3激动剂的全身给药 7-OHDPAT显著抑制惊厥反应。局部输注 多巴胺D1受体拮抗剂SCH 23390完全进入黑质 阻断系统给予的SKF 82958产生的惊吓增强。在……里面 此外，阻断黑质网状部GABA传递 阻断对SKF 82958产生的惊吓的促进作用 而激活中脑网状结构中的GABA传递 队形也有同样的效果。这些相同的治疗方法也会阻止 恐惧强化的惊吓效果。这表明，大脑中的抑制作用 中脑黑质网状部及其去抑制作用 网状结构既介导D_1激动剂易化惊厥，又介导D_1激动剂易化 恐惧强化的惊吓。进一步的研究将调查GABA在 这些脑区在介导惊厥的多巴胺能调制以及 恐惧调制的惊吓。因为多巴胺D1受体似乎增加了 黑质网状部通过激活cAMP释放GABA， 其他研究将测试局部向大脑中注入cAMP类似物 区域会影响惊吓本身以及所给SKF 82958的能力 系统性地增加惊吓幅度。这些影响将与 恐惧强化的惊吓。这些研究将提供进一步的证据 关于基本惊吓反射的多巴胺能调制，这是 与注意力相关的。他们还将评估条件性恐惧是否会 一些相同的电路来促进反射行为，以及如何从 杏仁核与这个环路相交。

DESCRIPTION: (Adapted from the Investigator's Abstract) The goals of this revised research proposal are to study the neural systems involved in dopaminergic modulation of the acoustic startle reflex. In addition, based on very recent data, not contained in the original proposal, we will evaluate how some of the circuitry involved in dopaminergic modulation of startle also may be related to the fear-potentiated startle effect, where startle amplitude is increased when elicited in the presence of a cue previously paired with footshock. The startle reflex is currently being used by many investigators to study attention, fear, anxiety and pharmacological modulation of motor behavior. Numerous animal studies have capitalized on the well-described neuroanatomy and neurochemistry within the basal ganglia to study the role of dopamine in the generation of motor behaviors, such as locomotor activity or stereotyped behavior. Motor reflexes also are modulated by dopamine and thus represent another important class of motor behaviors regulated by the basal ganglia. We have been using the acoustic startle reflex to elucidate some of the neural mechanisms underlying dopaminergic modulation of reflexive behavior. Systemic administration of the selective dopamine D1 receptor agonists SKF 82958 or SKF 81297 markedly enhances the startle response. In contrast, systemic administration of the D2 agonist quinpirole or the D2/3 agonist 7-OHDPAT significantly depresses the startle response. Local infusion of the dopamine D1 receptor antagonist SCH 23390 into the substantia nigra completely blocks the enhancement of startle produced by SKF 82958 given systemically. In addition, blockade of GABA transmission in the substantia nigra pars reticulata blocks the facilitation of startle produced by SKF 82958 given systemically whereas activation of GABA transmission in the mesencephalic reticular formation has the same effect. These same treatments also block the fear-potentiated startle effect. This suggests that inhibition in the substantia nigra pars reticulata and disinhibition in the mesencephalic reticular formation mediate both D1 agonist facilitation of startle and fear-potentiated startle. Further studies will investigate the role of GABA in these brain areas in mediating dopaminergic modulation of startle as well as fear modulation of startle. Because dopamine D1 receptors appear to increase GABA release in the substantia nigra pars reticulata via activation of cAMP, other studies will test how local infusion of cAMP analogues into this brain area will affect startle itself as well as the ability of SKF 82958 given systemically to increase startle amplitude. These effects will be compared with fear-potentiated startle. These studies will provide further evidence concerning dopaminergic modulation of the basic startle reflex, which is relevant to attention. They also will evaluate whether conditioned fear uses some of the same circuitry to facilitate reflex behavior and how outputs from the amygdala intersect with this circuitry.