CNS SITES MEDIATING ALCOHOL DRINKING BEHAVIOR

该提案代表了八个交互式R01之一，这些R01 研究遗传因素对糖尿病患者的生物学决定因素的影响 不正常的酒精寻觅行为。实验的总体目标是 这项建议(IRG 7)是为了研究乙醇(Etoh)之间的关系 饮酒行为和遗传决定的差异 神经系统(CNS)神经生物学底物被认为调节 乙醇的药理作用。为了实现这一目标，这些实验 将需要有选择地培育用于饮用不同乙醇的大鼠品系 行为。在所有实验中使用两组选定的线 是嗜酒(P)大鼠和非嗜酒(NP)大鼠吗？ - (HAD)和低酒精组(LAD)。这些实验将集中在 中枢神经系统的神经递质受体和受体亚型 网站，这被认为是调解行动的Etoh。这是假设的 与NP和LAD大鼠相比，选择高EtoH的大鼠 摄入量(P和HAD)将在以下中枢神经系统部位表现出先天差异 调节乙醇的药理作用。中枢神经系统药理研究进展 Etoh的行为被推定为至少包括两种一般精神活性物质 效果；强化和厌恶。进一步的假设是老鼠 与生俱来的高乙醇摄入量将显示出增强的强化作用 乙醇的效果(愉悦和/或缓解焦虑的效果)和更高的阈值 因摄入乙醇而产生的不良后果。一组实验 将研究饮用乙醇的强化效果的变化 用中枢神经系统部位特异性微透析无水乙醇和微量注射 受体制剂。乙醇的特定部位的作用被提出以产生 反映乙醇药理作用的行为后果 在现场。微量注射受体试剂将提供一种测试 增强药理作用的神经递质途径 乙醇的影响。在另一组实验中， 脑电刺激强化(BSR)及无水乙醇对大鼠脑损伤的影响 将对选定品系的大鼠的BSR进行比较。预计Etoh将 P和HAD对BSR阈值的影响大于NP和LAD 老鼠。被发现改变乙醇饮酒的地点将随后被 操作剂中微量注射受体拮抗剂的研究 强化范式。被发现可以改变酒精饮用量的网站将 也可以通过中枢神经系统部位特定的乙醇微透析进行研究 调节厌恶(条件性厌恶味觉)和焦虑(加上迷宫)。 此IRPG中的共享资源(共享资源IV：行为测试) 将提供此IRPG和集团内的其他IRPG(IRPG 1、2、3、5和8) 通过对Etoh和其他解决方案的偏好进行行为评估， 厌恶、焦虑、强化和宽容的Est。

This proposal represents one of eight interactive R01s which are investigating hereditary influences on the biological determinants of abnormal ethanol-seeking behavior. The overall goal of the experiments in this proposal (IRG 7) is to study athe relationship between ethanol (EtOH) drinking behavior and genetically- determined differences in central nervous system (CNS) neurobiological substrates postulated to regulate the pharmacological effects of EtOH. To accomplish this goal, the experiments will require lines of rats selectively bred for divergent EtOH drinking behavior. Two sets of selected lines to be used throughout all experiments are the alcohol-preferring (P) and the -nonpreferring (NP) rats, and the hi - (HAD) and low-alcohol drinking (LAD) rats. The experiments will focus on CNS sites, and on neurotransmitter receptors and receptor subtypes at those sites, which are thought to mediate the actions EtOH. It is hypothesized that, when compared with the NP and lAD rats, rats selected for high EtOH intake (P and HAD) will exhibit innate differences at CNS sites that mediate the pharmacological consequences of EtOH. The CNS pharmacological actions of EtOH are presumed to include at least two general psychoactive effects; reinforcement and aversion. It is further hypothesized that rats innately predisposed to high EtOH intake will exhibit enhanced reinforcing effects of EtOH (euphoric and/or anxiolytic effects) and a higher threshold for the aversive consequences of EtOH ingestion. One set of experiments will examine the alterations of the reinforcing effects of EtoH drinking with CNS site-specific microdialysis of EtOH and microinjections of receptor agents. The site-specific actions of EtOH are proposed to yield behavioral consequences which reflect the pharmacological actions of EtOH at the site. Microinjections of receptor agents will provide a test of the neurotransmitter pathways involved in the reinforcing pharmacological effects of EtOH. In another set of experiments, the threshold for electrical brain stimulation reinforcement (BSR) and the effects of EtOH on BSR will be compared in rats from the selected lines. EtOH is expected to have a greater effect on BSR threshold in P and HAD than in NP and lAD rats. Sites that are found to alter EtOH drinking will subsequently be investigated with microinjections of receptor antagonists in an operant reinforcement paradigm. Sites that are found to alter EtOH drinking will also be investigated with site-specific EtOH microdialysis for CNS sites mediating aversion (conditioned taste aversion) and anxiety (plus maze). A shared resource in this IRPG (Shared Resource IV: Behavioral Testing) will provide this IRPG and others within the group (IRPGs 1,2, 3, 5 and 8) with behavioral assessment for preference for EtOH and other solutions, t ests of aversion, anxiety, reinforcement and tolerance.