GENETIC AND BEHAVIORAL DISSECTION OF INHIBITORY CONTROL

描述（由申请人提供）：对明显自愿的运动行为缺乏抑制控制是注意缺陷多动障碍、药物成瘾、图雷特综合征和强迫症中发现的一种行为症状。这是高度争论是否受损的抑制控制是由于高或低多巴胺能活性。为了研究其神经生物学基础，我们通过降低多巴胺转运蛋白表达（DAT敲低）产生了“高多巴胺能”转基因小鼠。 我们的初步研究表明，DAT敲除小鼠模型方面的抑制控制受损，突触后多巴胺D2受体功能受损可能是这种行为缺陷的基础。 目的1拟议的研究是确定具体的生化变化受损的抑制控制DAT敲低小鼠。我们将首先确定DAT基因敲除小鼠抑制控制受损的行为机制：无论是延迟厌恶还是反应抑制，这两个过程都涉及抑制控制受损的核心行为缺陷。然后，我们将研究什么信号分子是负责受损的突触后D2受体功能的DAT敲除小鼠：受体，G蛋白，受体-G蛋白偶联或腺苷酸环化酶活性。我们将对每只动物进行行为测量和生化测量，并检查它们之间的关联程度。 目的2是测试的假设，受损的突触后D2受体功能受损的抑制控制使用的药物救援方法。我们的初步研究表明，慢性D2拮抗剂治疗能够逆转DAT敲除小鼠的行为缺陷。我们将分析用D2拮抗剂长期治疗后DAT敲低小鼠的D2信号传导和行为变化。我们将测试这样的治疗将逆转DAT敲除小鼠中的D2信号传导和行为缺陷的假设。 目的3是使用缺乏或具有减少的突触后D2受体的小鼠直接测试D2受体功能受损是抑制控制受损的基础的假设。

DESCRIPTION (provided by applicant): Lack of inhibitory control over apparently voluntary motor acts is a behavioral symptom found in attention deficit hyperactivity disorder, drug addiction, Tourette's Syndrome, and obsessive-compulsive disorder. It is highly debated whether impaired inhibitory control is due to hyper- or hypo-dopaminergic activity. To investigate its neurobiological basis, we have generated "hyperdopaminergic" transgenic mice by reducing the dopamine transporter expression (DAT knockdown). Our preliminary studies suggest that DAT knockdown mice model aspects of impaired inhibitory control and that impaired postsynaptic dopamine D2 receptor function may underlie such behavioral deficits. Aim 1 of the proposed studies is to determine the specific biochemical changes underlying impaired inhibitory control in DAT knockdown mice. We will first identify the behavioral mechanisms underlying impaired inhibitory control in DAT knockdown mice: whether it's delay aversion or response inhibition, two processes implicated as core behavioral deficits in impaired inhibitory control. We will then investigate what signaling molecule is responsible for the impaired postsynaptic D2 receptor function in DAT knockdown mice: receptor, G protein, receptor-G protein coupling or adenytyl cyclase activity. We will take both behavioral measures and biochemical measures from each animal and examine the degree of association between them. Aim 2 is to test the hypothesis that impaired postsynaptic D2 receptor function underlies impaired inhibitory control using a pharmacological rescue approach. Our preliminary studies suggest that chronic D2 antagonist treatment is able to reverse behavioral deficits in DAT knockdown mice. We will analyze D2 signaling and behavioral changes in DAT knockdown mice after chronic treatment with D2 antagonists. We will test the hypothesis that such treatment will reverse D2 signaling and behavioral deficits in DAT knockdown mice. Aim 3 is to test directly the hypothesis that impaired D2 receptor function underlies impaired inhibitory control using mice that lack or have reduced postsynaptic D2 receptors.