STARTLE GATING AND LOCOMOTION IN D2-FAMILY KNOCKOUT MICE

描述：(改编自《调查者摘要》)多巴胺神经元 从中脑到皮质和边缘结构的投射调节注意力 和信息处理职能，并有助于组织 运动行为。慢性阻塞性肺疾病患者相关行为损害 精神分裂症和其他精神障碍，表明 大脑皮质边缘多巴胺信号与人的病理生理学关系 疾病。D1样和D2样多巴胺受体参与了 这些多巴胺能回路的正常活动。功能上的区别 在D2样亚家族的3个克隆成员中(D2、D3和D4)仍然存在 难以捉摸，部分原因是药理配体的特异性有限。 缺乏D2、D3或D4受体的基因敲除小鼠品系 以遗传模型的形式生成，以了解系统的功能 水平，这些多个独立的基因。最初的特征表明 单个受体基因敲除菌株有许多独特的行为 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。这位将军 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制中的功能作用， 运动活动，以及行为的顺序组织。具体的 解决这一假设的目的是：(1)产生同源的C57BL/6毒株 具有单个D2、D3或D4多巴胺受体基因敲除和ALL的突变小鼠 双受体和三受体突变的排列；(2)表征 各品系纯合子和杂合子小鼠的表型 运动活动的数量和模式，对新物体的反应， 以及惊吓反应、习惯化和脉冲前抑制；(3)表征 苯丙胺和部分直接多巴胺激动剂对其的影响 措施；(4)说明苯丙胺和选定的直接毒品的影响 多巴胺激动剂对大鼠运动和探索行为模式的影响 突变菌株；以及(5)表征苯丙胺和 精选的直接多巴胺激动剂对惊厥反应、习惯性和 每种突变品系小鼠的预脉冲抑制。这些表型和 同源菌株D2亚型基因敲除的药理学比较 共同的遗传背景将提供关于 D2样受体在细胞周期调控中的特殊功能 与精神病患者有特别关联的无条件行为 精神障碍和精神刺激性虐待。这些信息将具有重要的意义 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.