BRAIN SUBSTRATES OF POSITIVE REINFORCEMENT

一种关于药物通过其脑机制的初步假设 滥用产生其强化效果的是，这些制剂作用于 内源性大脑奖赏底物，其“自然”功能是确保 生物基本刺激的激励价值，如食物和 水。因此，了解大脑机制是通过哪些自然的 增强剂的作用，应该与我们对药物如何 虐待行为起到了积极增强者的作用。在这方面，我们的 实验室已经参与了对行为功能的研究 中枢多巴胺能通路已有数年。更具体地说， 目前的建议旨在以我们最近的发现为基础， 多巴胺(DA)受体拮抗剂。对这种管理的管理 长期以来，人们一直知道药物会干扰操作者的表现 实验动物的行为。然而，兴趣和争议 关于准确的机制(S)继续存在，这些 毒品发挥它们的行为影响。我们已经取得了相当大的进步 同时建立边缘(奖赏)和锥体外系(运动)缺陷 在使用DA拮抗剂治疗的动物中，使用了一系列新的仔细- 我们实验室开发的受控行为测试程序。这个 我们强化化验的新奇之处在于，它们允许调查 在测试时间内药物引起的奖赏不足 调查不再进行。这显然增加了功率。 我们的数据集，因为药物的非特定表现后果 考试当天，管理人员不在场。在提议的实验中 我们计划以三种具体的方式使用我们的行为测试：1) 评估D_1和D_2多巴胺受体亚型的相对贡献 在DA拮抗剂激发时观察到的行为缺陷；2) 将对多巴胺拮抗剂作用的研究扩大到各种 阳性增强剂；以及3)确定负责的大脑部位 DA拮抗剂药物的行为作用。总而言之，建议的 实验应该提供关于a)精确的新的重要信息 这些药物发挥其行为影响的机制；以及 B)中枢多巴胺能神经元在奖赏和 激励过程。我们认为，这些信息将证明 对研究药物通过的神经底物有价值 滥用的人发挥了他们的强化作用。

A primary hypothesis about the brain mechanisms through which drugs of abuse producing their reinforcing effects, is that such agents act on endogenous brain reward substrates whose "natural" function is to ensure the incentive value of biologically essential stimuli such as food and water. Thus, understanding the brain mechanisms through which natural reinforcers act, should be relevant to our understanding of how drugs of abuse act in their role as positive reinforcers. In this regard, our laboratory has been involved in studies of the behavioral function of central dopaminergic pathways for several years. More specifically, the present proposal is intended to build upon our recent findings with dopamine (DA) receptor antagonist drugs. The administration of such drugs has long been known to interfere with the performance of operant behaviors in laboratory animals. However, interest and controversy continue to exist regarding the precise mechanism(s) through which these drugs exert their behavioral effects. We have made considerable progress establishing both limbic (reward) and extrapyramidal (motoric) deficits in DA antagonist-treated animals using a series of novel carefully- controlled behavioral test procedures developed in our laboratory. The novelty of our reinforcement assays is that they permit the investigation of drug-induced reward deficits at a test-time when the drug under investigation is no longer active. this obviously increases the power of our data set since non-specific performance consequences of drug administration are not present on test day. In the proposed experiments we plan to employ our behavioral tests in three specific ways: 1) to assess the relative contributions of D1 and D2 dopamine receptor subtypes to the behavioral deficits observed during DA antagonist challenge; 2) to extend the investigation of DA antagonist effects to a variety of positive reinforcers; and 3) to identify the brain sites responsible for the behavioral actions of DA antagonist drugs. Together, the proposed experiments should provide important new information on a) the precise mechanisms through which such drugs exert their behavioral effects; and b) the nature of the role of central dopaminergic neurons in reward and motivational processes. It is our view that such information will prove valuable to investigations of the neural substrates through which drugs of abuse exert their reinforcing actions.