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BIOCHEMISTRY OF DRINKING BEHAVIOR & ALCOHOLISM

饮酒行为的生物化学

基本信息

批准号：
3108817
负责人：
TING-KAI K LI
金额：
$ 53.51万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-07-01 至 1990-06-30
项目状态：
已结题

项目摘要

The long-term objectives of this research program are to determine the behavioral. physiological and biochemical associations of aberrant alcohol-seeking behavior and to elucidate underlying mechanisms. To this end, we have developed the alcohol-preferring P and alcohol-nonpreferring NP lines of rats through selective breeding and have shown that the P line satisfies all the perceived requirements of an animal mode) of alcoholism. The P and NP rats are now in the 27th generation of selection. We are also performing duplicate bidirectional selection or high-alcohol- drinking (HAD-1 and HAD-2) and low-alcohol-drinking (LAD-1 and LAD- 2) lines from the N/Nih heterogenous stock rats. These lines have now reached the S-7 generations. The objectives of this new selection experiment are to address the issue of generality of a number of discovered associations of high alcohol-seeking behavior and to establish the HAD line as another suitable animal model of alcoholism. We propose to continue the maintenance of the P and NP lines and to continue the selective breeding of the HAD and LAD lines. These animals will be used to test the general hypothesis that an enhanced responsiveness to the low-dose reinforcing effects of alcohol and the rapid development and persistence of tolerance to the high-dose aversive effects of ethanol promote high alcohol- seeking. behavior. To this end, the association of these traits in F2 offspring of P and NP crosses will be studied, and backcrosses to the parent P and NP lines will.be made. A major effort in the next 5 years will be the elucidation of the underlying neurobiological basis of the differences in these behavioral responses. Place preference and intracranial self- stimulation experiments will be performed to further examine the reinforcing properties of ethanol. The CNS sites responsive to the low-dose rewarding properties of ethanol and participating in tolerance development will be localized by selective lesioning, by single unit electrophysiological recording and by site-specific administration of ethanol. Neurotransmitter/neuroregulator systems to be studied include serotonin, dopamine. gamma-aminobutyric acid, vasopressin and opioid peptides. Differential responses of these systems to alcohol between P and NP rats and between tolerant and nontolerant animals will be assessed by measurements of in vivo release, neuronal activity and receptor function. A newly discovered association of alcohol preference, heterozygosity at four genetic marker loci, will be studied in relation to dominance or overdominance of the plus alleles for alcohol preference.

该研究计划的长期目标是确定行为的。生理和生化协会异常饮酒行为，并阐明潜在的机制等为此，我们开发了通过选择性地建立大鼠P系和不喜欢酒精的NP系育种，并已表明，P线满足所有的感知动物模式的要求）酒精中毒。 P和NP大鼠已经是第27代了我们也进行重复双向选择或高醇- 饮酒（HAD-1和HAD-2）和低度饮酒（LAD-1和LAD-2） 2)来自N/Nih异种大鼠的品系。这些线有到了S-7代。新的目标选择实验是为了解决一个普遍性的问题，发现的酗酒行为的关联数量并建立HAD系作为另一种合适的动物模型，酒精中毒我们建议继续维持P和 NP系，并继续HAD和LAD的选育线这些动物将被用来测试一般假设对低剂量强化效应的反应增强酒精的快速发展和持久的耐受性高剂量酒精的厌恶作用促进高酒精- 寻找行为为此，这些特征的关联将研究P和NP杂交的F2后代，回交到亲本P和NP系will.be。一个主要未来5年的努力将是阐明这些差异的潜在神经生物学基础行为反应位置偏好和颅内自我- 将进行刺激实验，以进一步检查增强乙醇的性能。对药物有反应的中枢神经系统部位乙醇的低剂量奖励特性，通过选择性损伤，单单位电生理记录和部位特异性乙醇的管理。神经递质/神经调节系统包括血清素多巴胺γ-氨基丁酸，加压素和阿片肽。不同的反应， P和NP大鼠之间以及耐受和将通过测量体内释放、神经元活动和受体功能。一个新发现酒精偏好，四个遗传标记位点，将研究与显性或者是酒精偏好的正等位基因的超显性。