Mechanisms of Opiate and Stimulant Drug Reinforcement

描述（由申请人提供）：本项目的主要长期目标是了解导致阿片类药物和兴奋剂滥用的自我管理的神经机制。行为药理学方法将用于解决三个具体目标，每个目标都建立在和/或扩展本项目前14年开展的工作基础上。这包括：1)将引发药物寻求行为的潜在动机过程与自我给药所激活的强化过程分离开来；2)继续并扩大对药物滥用行为“复发”机制的调查，正如反应-恢复的操作性跑道测试所模拟的那样；3)继续研究自我给药可卡因的性质和神经生物学的推测的焦虑/厌恶特性。在这项工作中采用的主要自我给药方法是一种独特的静脉药物强化操作跑道试验。动物们被训练成每天穿过一条笔直的手臂跑道，以获得由静脉注射药物强化（即可卡因、海洛因、速度球、诺非芬、可卡因）组成的奖励。在这种情况下，未受过训练的动物穿越跑道回到之前接受药物强化物的地方的速度，为s获得强化物的动机提供了一个有效且高度可靠的指标。此外，由于这些动物每天只进行一次试验，由此产生的操作数据缺乏药物强化剂本身产生的非特异性效应。由于动机状态（包括那些激活药物寻找行为的状态）在一定程度上是由内部激活或唤醒的存在来定义的，因此该项目已经开始使用小型植入的无线电遥测设备，这些设备在行为测试期间提供有关动物内部状态的生理数据（心率、呼吸、心电图、核心温度……）。这些行为和生理测量的结合将允许开始旨在调查中枢和交感神经系统在产生动机行为中的复杂关系的研究。实验计划在跑道上IV和IC自我给药强化药物，在药物预测环境刺激出现时产生“激活”药物寻求行为的潜在机制。

DESCRIPTION (provided by applicant): The primary long-term goal of this project is to understand the neural mechanisms that contribute to the self-administration of opiate and stimulant drugs of abuse. Behavioral pharmacological methodologies will be applied to address three specific aims each of which builds upon and/or extends work conducted during the first fourteen years of this project. These are: 1) To dissociate the underlying motivational processes that serve to initiate drug-seeking behavior, from the reinforcing processes that are activated as a consequence of drug self-administration; 2) To continue and extend investigations of the mechanisms involved in the "relapse" of drug-abuse behavior as modeled in an operant runway test of response-reinstatement; and 3) To continue investigation of the nature and neurobiology of the putative anxiogenic/aversive properties of self-administered cocaine. The primary self-administration methodology employed in this work is a unique operant runway test of IV drug reinforcement. Animals are trained to traverse a straight arm runway once each day for a reward consisting of IV drug reinforcement (i.e., cocaine, heroin, speedball, nomefensine, cocaethylene) delivered upon the Ss' entry into the goal box. In this context, the speed with which the undrugged animal traverses the runway to return to a place where it had previously received the drug reinforcer, provides a valid and highly reliable index of the Ss' motivation to obtain the reinforcer. In addition, because the animals are tested on a single trial per day, the resulting operant data are devoid of nonspecific effects produced by the drug reinforcers themselves. Since motivated states (including those activate drug-seeking behavior) are defined, in part, by the presence of internal activation or arousal, the project has begun the use of small implanted radio-telemetric devices that provide physiological data (heart rate, respiration, ECG, core temperature...) about the internal state of the animal during behavioral testing. The combination of these behavioral and physiological measures will permit the initiation of studies intended to investigate the complex relationship between central and sympathetic nervous systems in the production of motivated behavior. Experiments are planned on the IV and IC self-administration of reinforcing drugs in the runway, on the underlying mechanisms that produce the "activation" of drug-seeking behavior upon presentation of drug-predictive environmental stimuli.