STARTLE GATING AND LOCOMOTION IN D2-FAMILY KNOCKOUT MICE

描述：（改编自研究者摘要）多巴胺神经元， 从中脑投射到皮层和边缘结构调节注意力 和信息处理职能，并有助于组织 运动行为患者的相关行为受损 精神分裂症和其他精神疾病，这表明 中皮质边缘多巴胺信号传导在人类中具有病理生理学相关性 疾病D1样和D2样多巴胺受体与 多巴胺能回路的正常活动功能区别 在D2样亚家族的3个克隆成员（D2、D3和D4）中， 难以捉摸，部分原因是药理学配体的特异性有限。 缺乏D2、D3或D4受体的基因敲除小鼠品系， 作为遗传模型生成，以了解系统的功能， 这些独立的基因。初步特征显示 单个受体敲除菌株具有许多独特的行为， 表型，包括运动行为和惊吓反应的变化 精神分裂症患者感觉运动门控缺陷的测量。总 有待检验的假设是，D2样受体亚型具有选择性 在信息处理的多巴胺能调节中的功能作用， 自发活动和行为的顺序组织。具体 目的是解决这一假设是：（1）产生同源C57 BL/6菌株的 D2、D3或D4多巴胺受体敲除的突变小鼠，以及所有 双重和三重受体突变的排列;（2）表征 表型的每种品系的纯合和杂合小鼠使用的措施， 运动活动的数量和模式，对新物体的反应， 和惊吓反应性、习惯化和前脉冲抑制;（3）表征 安非他明和选择的直接多巴胺激动剂对相同的 （4）确定安非他明和选定的直接 多巴胺激动剂对运动模式和探索行为的影响， 突变菌株;和（5）表征安非他明的作用， 选择的直接多巴胺激动剂对惊吓反应性、习惯性和 前脉冲抑制在每一个突变品系的小鼠。这些表型和 D2-亚型敲除在同源株中的药理学比较， 共同的遗传背景将提供关于 D2样受体在调节 无条件行为与精神病患者 精神障碍和精神兴奋剂滥用。这些信息将具有重要意义 对进一步发展治疗方法的影响 精神分裂症和药物滥用的治疗。

DESCRIPTION: (Adapted from the Investigator's Abstract) Dopamine neurons that project from the midbrain to cortical and limbic structures modulate attention and information processing functions and contribute to the organization of locomotor behavior. Related behaviors are impaired in patients with schizophrenia and other psychiatric disorders, suggesting that alterations in mesocorticolimbic dopamine signaling have pathophysiological relevance in human diseases. D1-like and D2-like dopamine receptors have been implicated in the normal activity of these dopaminergic circuits. The functional distinctions among the 3 cloned members of the D2-like subfamily (D2, D3, and D4) remain elusive, in part because of the limited specificity of pharmacological ligands. Strains of gene knockout mice that lack either the D2, D3, or D4 receptors have been generated as genetic models to understand the functions, at a systems level, of these multiple independent genes. Initial characterizations reveal that the individual receptor knockout strains have many unique behavioral phenotypes, including changes in locomotor behavior and startle response measures of sensorimotor gating deficits seen in schizophrenia. The general hypothesis to be tested is that the D2-like receptor subtypes have selective functional roles in the dopaminergic modulation of information processing, locomotor activity, and the sequential organization of behavior. The specific aims to address this hypothesis are: (1) generate congenic C57BL/6 strains of mutant mice with individual D2, D3, or D4 dopamine receptor knockouts and all permutations of double and triple receptor mutations; (2) characterize the phenotype of each strain of homozygous and heterozygous mice using measures of the amount and patterns of locomotor activity, the response to a novel object, and startle reactivity, habituation, and prepulse inhibition; (3) characterize the effects of amphetamine and selected direct dopamine agonists on the same measures; (4) characterize the effects of amphetamine and selected direct dopamine agonists on patterns of locomotor and exploratory behavior in each of the mutant strains; and (5) characterize the effects of amphetamine and selected direct dopamine agonists on startle reactivity, habituation, and prepulse inhibition in each of the mutant strains of mice. These phenotypic and pharmacological comparisons of D2-subtype knockouts in congenic strains having a common genetic background will provide fundamental information regarding the specific functional roles of D2-like receptors in the regulation of unconditioned behaviors that have particular relevance to both psychotic disorders and psychostimulant abuse. This information will have important implications for the further development of therapeutic approaches to the treatment of both schizophrenia and drug abuse.