DOPAMINERGIC MODULATION OF THE STARTLE REFLEX

描述：（改编自研究者摘要） 修订后的研究计划是研究神经系统参与 声音惊吓反射的多巴胺能调节。另外基于 最近的数据，不包含在原来的建议，我们将评估如何 涉及惊吓的多巴胺能调节的一些回路也可能 与恐惧增强惊吓效应有关，惊吓幅度是 当在先前配对的线索存在时， 脚震惊吓反射目前被许多研究人员用来 研究注意力、恐惧、焦虑和运动的药物调节 行为许多动物研究都利用了 基底神经节内的神经解剖学和神经化学，以研究 多巴胺在产生运动行为，如自发活动或 刻板的行为运动反射也受到多巴胺的调节， 代表了另一类重要的运动行为， 神经节我们一直在使用听觉惊吓反射来阐明一些 反射行为的多巴胺能调制的神经机制。 选择性多巴胺D1受体激动剂SKF的全身给药 82958或SKF 81297显著增强惊吓反应。与此相反， D2激动剂喹吡罗或D2/3激动剂的全身给药 7-OHDPAT显著抑制惊吓反应。局部输注 多巴胺D1受体拮抗剂SCH 23390完全进入黑质 阻断了SKF 82958产生的惊吓增强作用。在 此外，阻断GABA在黑质网状部的传递 阻断SKF 82958系统性产生的惊吓促进作用 而激活中脑网状核中的GABA传递， 形成具有相同的效果。这些相同的治疗也会阻断 恐惧增强惊吓效应这表明，抑制在 黑质网状部和中脑的去抑制 网状结构介导D1激动剂对惊吓的促进作用， 恐惧增强的惊吓进一步的研究将调查GABA在 这些脑区在介导惊吓的多巴胺能调节以及 惊恐的恐惧调节因为多巴胺D1受体似乎增加了 GABA在黑质网状部通过激活cAMP释放， 其他研究将测试cAMP类似物如何局部输注到大脑中 区域将影响惊吓本身以及SKF 82958的能力， 系统地增加惊吓幅度。这些影响将与 恐惧增强的惊吓这些研究将提供进一步的证据 关于基础惊吓反射的多巴胺能调节， 与注意力有关。他们还将评估条件性恐惧是否利用 一些相同的电路，以促进反射行为，以及如何输出， 杏仁核与这个回路相交。

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.