DOPAMINERGIC SENSITIZATION AND DRUG SELF ADMINISTRATION

本申请中提出的实验是一个持续的实验的一部分。 申请人的研究工作旨在确定 在中脑边缘多巴胺（DA）神经元中药物诱导的敏化， 理解其行为表达的性质和意义。 精神兴奋剂和鸦片类药物，两者都是自我- 人和实验室动物给药，增加DA释放 这些神经元并产生运动激活。反复接触这些 药物可以增强或敏化这两种反应， 再次接触药物会产生更大的行为激活， 比最初看到的更大的DA释放。 相当多的证据表明中脑边缘DA能神经元在介导 兴奋剂和鸦片类药物的奖赏特性。变化 因此，这些神经元的功能可能在启动 和维持服药。最近一些报告 似乎表明，暴露于药物治疗方案， 敏感化也有助于获得药物自我给药 行为因此，我建议调查这种便利是否 与中脑边缘DA神经元的敏化有关。如果是的话， 易化应伴随着致敏的中脑边缘DA能神经元 在获得过程中对药物的反应性， 同样的操作，影响在这些敏感性的诱导 神经元通过研究获得自我管理的低剂量 我想回答三个问题 A.是促进自我管理行为的习得 伴随着致敏水平的DA溢出，如通过体内 微透析，在中脑边缘DA神经元的终末区域， 收购？ B。先前暴露于致敏注射安非他明到 中脑边缘DA能神经元胞体区促进获得 自我管理行为？ C.进行阻断致敏诱导的操作， 安非他明，如预先注射D-1 DA受体 拮抗剂，SCH-23390，也阻止了自我- 药物暴露导致的给药行为？ 敏感的发展援助职能与对发展援助的责任之间联系的可能性 药物滥用可以为药物的神经生物学提供重要的见解 依赖

The experiments proposed in this application are part of a continuing research effort by the applicant aimed at determining the neural basis of drug-induced sensitization in mesolimbic dopamine (DA) neurons and at understanding the nature and significance of its behavioral expression. Psychomotor stimulant and opiate drugs, both of which are self- administered by man and laboratory animals, increase the DA released by these neurons and produce locomotor activation. Repeated exposure to these drugs enhances or sensitizes both of these responses so that subsequent reexposure to the drug produces both greater behavioral activation and greater DA release than seen initially. Considerable evidence implicates mesolimbic DA neurons in the mediation of the rewarding properties of stimulant and opiate drugs. Changes in the functioning of these neurons may therefore be important in the initiation and maintenance of drug taking. Recently. a number of reports have appeared suggesting that exposure to drug regimens that produce behavioral sensitization also facilitates the acquisition of drug self-administration behavior. I propose, therefore, to investigate whether this facilitation is linked to sensitization in mesolimbic DA neurons. If it is, then facilitation should be accompanied by sensitized mesolimbic DA neuron responsivity to drug during acquisition and similarly influenced by the same manipulations that influence the induction of sensitization in these neurons. By studying the acquisition of self-administration of low doses of amphetamine in the rat, I will seek to answer three questions: A. Is facilitation of the acquisition of self-administration behavior accompanied by sensitized levels of DA overflow, as measured by in vivo microdialysis, in the terminal regions of mesolimbic DA neurons during acquisition? B. Does prior exposure to sensitizing injections of amphetamine into the cell body region of mesolimbic DA neurons facilitate the acquisition of self-administration behavior? C. Do manipulations that block the induction of sensitization to amphetamine, such as preceding injections with the D-1 DA receptor antagonist, SCH-23390, also block the facilitation of acquisition of self- administration behavior produced by prior exposure to the drug? The possibility of a link between sensitized DA function and liability to drug abuse could provide important insights into the neurobiology of drug dependence.