DOPAMINERGIC SUBSTRATES OF STARTLE GATING ACROSS SPECIES

跨物种惊吓门控的多巴胺能底物

• 批准号: 6629166
• 负责人: NEAL R SWERDLOW
• 金额: $ 12.13万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6629166
• 关键词: amantadine; amphetamines; antipsychotic agents; behavioral /social science research tag; behavioral habituation /sensitization; bromocriptine; caffeine; clinical research; dopamine agonists; drug interactions; human subject; limbic system; male; neural inhibition; neurochemistry; neuropharmacology; pergolide; psychophysiology; sensory feedback; startle reaction; young adult human (21-34)

For 20 years, systematic studies in rodents have identified specific neural substrates regulating pre-pulse inhibition (PPI) of startle, including parts of the prefrontal cortex, hippocampus, amygdala, ventral striatum and pallidum, and pontine tegmentum. These limbic cortico- striato-pallido-pontine (CSPP) substrates regulating PPI are relevant to several neuropsychiatric disorders, and are implicated in the reinforcing properties of drugs of abuse. Now that the neural substrates of PPI have been delineated in rats, the next major challenge is to develop the capacity to probe and understand this PPI-regulatory circuitry in humans. If neural circuit information, derived from animal studies, could be translated across species, PPI could become an important, new tool for understanding this circuitry in normal and neuropsychiatric disordered populations. Specific drug effects on PPI in rats are highly predictable, and are understood at the level of neural circuitry. The present proposal will initiate a translocational approach to understanding limbic CSPP circuitry, by assessing the homology of pharmacologic manipulations of PPI across species. In tests of PPI, startle habituation, latent inhibition and measures of sensory gating, we will carefully assess the time course and dose response effects of the direct dopamine (DA) agonists bromocriptine, per-golide and ropinirole, the indirect DA agonists amphetamine and amantadine, and an active comparison drug (caffeine) in normal humans. Contemporaneous measurement of physiological and psychological variables will facilitate interpretation of changes in the critical dependent measures. Based on initial results, we will assess DA agonist effects on the dependent measures after pretreatment with typical and atypical anti-psychotics. Future studies will assess the serotonergic, glutamatergic and nicotinic regulation of PPI and related measures, and sex differences and menstrual cyclicity of drug effects on these measures, in normal humans. Data from the proposed studies will provide new information for interpreting the neurochemical basis of PPI deficits in schizophrenic patients, as well as the sensitivity of these deficits to antipsychotics. By developing an important new strategy for under- standing limbic CSPP circuitry in humans, the proposed studies will have direct relevance to a broad range of issues in neuropsychiatry, including the neurobiology of drug abuse. More generally, these studies will begin the important process of examining the neuro-chemistry of sensorimotor gating processes that fundamentally shape behavior and cognition in humans.

20年来，对啮齿动物的系统研究已经确定了调节惊吓前脉冲抑制（PPI）的特定神经底物，包括前额叶皮质的一部分，海马，杏仁核，腹侧纹状体和pallidum和pallidum和pontine teggentum。 这些边缘性皮质 - 纹状体 - 甲状腺纤维杆菌（CSPP）底物调节PPI与几种神经精神疾病有关，并且与滥用药物的增强特性有关。 现在，PPI的神经底物已在大鼠中描绘出来，下一个主要挑战是发展探测和了解人类PPI调节电路的能力。 如果可以从动物研究中衍生出的神经回路信息可以跨物种翻译，则PPI可能成为理解正常和神经精神错乱种群中这种电路的重要，新工具。 大鼠对PPI的特定药物影响是高度可预测的，并且在神经回路的水平上得到了理解。 本提案将通过评估跨物种PPI的药理学操纵的同源性来启动一种理解边缘CSPP电路的易位方法。 In tests of PPI, startle habituation, latent inhibition and measures of sensory gating, we will carefully assess the time course and dose response effects of the direct dopamine (DA) agonists bromocriptine, per-golide and ropinirole, the indirect DA agonists amphetamine and amantadine, and an active comparison drug (caffeine) in normal humans.同时测量生理和心理变量将有助于解释关键依赖措施的变化。基于初始结果，我们将用典型和非典型的抗精神药物预处理后对DA激动剂对依赖措施的影响。 未来的研究将评估PPI和相关措施的血清素能，谷氨酸能和烟碱调节，以及在正常人类中，药物对这些措施的影响的性别差异和月经循环。 拟议研究的数据将提供新的信息，以解释精神分裂症患者PPI缺陷的神经化学基础，以及这些缺陷对抗精神病药的敏感性。 通过制定一项重要的新策略，以了解人类的边缘CSPP电路，拟议的研究将直接与神经精神病学的广泛问题有关，包括药物滥用的神经生物学。 更笼统地，这些研究将开始重要的过程，以检查从根本上塑造人类行为和认知的感觉运动门控过程的神经化学。