PERTUSSIS TOXIN AND EFFECTS OF PSYCHOSTIMULANT DRUGS

描述：(申请人摘要) 中脑边缘多巴胺神经元的异常活动被认为与 对精神刺激性药物的心理依赖，如 安非他明和可卡因，以及精神分裂症的病因学。一种型号的 中脑边缘多巴胺神经元兴奋性的改变产生于 百日咳毒素经腹段给药的临床观察 老鼠。经过这种治疗后，动物在 自发性运动活动与运动诱发的行为激活 精神刺激剂。需要检验的假设是，增强的 异常引起的自发活动和药物反应 伏隔核对多巴胺的强烈反应。因此，任何刺激措施， 如暴露在新的环境中，会导致DA在体内释放 伏隔核在这个模型中会引起夸大的反应。vt.在.上 生化水平上，有人提出后行为的改变 百日咳毒素与中枢神经系统神经元反应增强有关 伏隔核对D1受体的激活作用可能是通过介导的 通过增强蛋白激酶A的活性。具体目标是：1) 确定环境新颖性在自发性增加中的作用 百日咳毒素产生的苯丙胺的运动性和敏感性 腹侧节段给药；2)确定重要性 VTA和VTA内的站点作为PTX的目标 安非他明和安非他明的自发活动及兴奋作用 阿朴吗啡；3)确定D1受体介导的事件是否 增强的，并且与功能关系的改变相关联 百日咳伏核中D_1和D_2受体之间的关系 毒素处理的大鼠；4)确定变化的特异性 百日咳患者伏核的神经递质活性 毒素处理的大鼠；5)确定神经变化是否与 百日咳毒素也出现在伏隔核下游部位； 以及6)以确定在以下情况之间是否存在关系 腹侧节段的功能性GI/GO蛋白，或者可能是 伏核与自发性运动增强和增强 百日咳毒素处理动物对药物的反应。

DESCRIPTION: (Applicant's Abstract) Abnormal activity of meso-limbic dopamine neurons has been implicated in the development of psychological dependence to psychostimulant drugs, such as amphetamine and cocaine, and in the etiology of schizophrenia. One model of altered excitability of meso-limbic dopamine neurons is produced following the administration of pertussis toxin into the ventral segmental area of rats. After this treatment, animals exhibit a marked enhancement in spontaneous locomotor activity and the behavioral activation produced by psychostimulant drugs. The hypothesis to be tested is that the enhanced spontaneous locomotor activity and responses to drugs result from abnormally large responses to dopamine in the nucleus accumbens. Thus, any stimulus, such as exposure to a novel environment, that causes DA release in the nuc1eus accumbens will elicit exaggerated response in this model. On a biochemical level, it is proposed that the changes in behavior after pertussis toxin are associated with enhanced responses of neurons in the nucleus accumbens to D1 receptor activation, an effect that may be mediated by an enhanced protein kinase A activity. The specific aims are 1) To determine the role of environmental novelty in the increased spontaneous locomotion and sensitivity to amphetamine produced by pertussis toxin administration into the ventral segmental area; 2) determine the importance of the VTA and sites within the VTA as targets for PTX in increasing spontaneous locomotor activity and the stimulant effects of amphetamine and apomorphine; 3) To determine whether D1 receptor mediated events are enhanced and are associated with a change in the functional relationship between D1 and D2 receptors in the nucleus accumbens of pertussis toxin-treated rats; 4) To determine the specificity of changes in neurotransmitter activity in the nucleus accumbens in pertussis toxin-treated rats; 5) To determine if neural changes associated with pertussis toxin also occur at sites downstream from the nucleus accumbens; and 6) To determine wether there is a relationship between the decrease in functional Gi/Go proteins in the ventral segmental area or possibly the nucleus accumbens and the increased spontaneous locomotion and enhanced responses to drugs in pertussis toxin-treated animals.