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与脑内多巴胺的释放有关。 对精神兴奋剂药物产生心理依赖，如 安非他明和可卡因，以及精神分裂症的病因学。 的一个模型 中脑边缘多巴胺神经元的兴奋性改变产生于 将百日咳毒素注射到 大鼠 在这种治疗后，动物在以下方面表现出显著的增强： 自发运动活动和行为激活产生的 精神兴奋剂 有待检验的假设是， 自发运动活动和对药物的反应由异常 对多巴胺的强烈反应 因此，任何刺激， 例如暴露于新的环境中，这会导致 在该模型中，核分裂将引起夸大的反应。 上 生化水平，提出后的行为变化 百日咳毒素与增强的神经元反应有关， D1受体激活，这种效应可能是由 通过增强蛋白激酶A活性。 具体目标是：（1） 确定环境新奇在增加自发性中的作用 百日咳毒素引起的运动和对苯丙胺的敏感性 给药至腹侧节段区域; 2）确定 的VTA和VTA内的网站作为PTX的目标， 自发活动和安非他明的刺激作用， 阿扑吗啡; 3）为了确定D1受体介导的事件是否 增强并与功能关系的变化相关 百日咳菌斑核D1和D2受体之间的关系 毒素处理的大鼠; 4）为了确定 百日咳患者延髓核神经递质活性 毒素处理的大鼠; 5）为了确定是否与 百日咳毒素也出现在延髓核的下游部位; 和6）为了确定是否有一个减少之间的关系， 功能性Gi/Go蛋白在腹侧节段区或可能的 增加自发运动和增强 百日咳毒素治疗动物对药物的反应。

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.