Are drug-associated cues susceptible to the blocking effect?

描述（由申请人提供）：娱乐性使用非法药物成为强迫性的机制一直是大量研究的主题。大部分研究都集中在成瘾药物篡夺自然学习机制的方式，以及可能导致这些影响的多巴胺（DA）系统中神经适应的作用。最近对多巴胺在学习中的作用的重新概念化表明，它可能作为一个错误信号到cdrticolimbic目标区域，干扰正常多巴胺功能的物质可能会病理性地影响这个信号。其中一种干扰可能包括干扰被称为阻塞的学习效应，这限制了与给定奖励相关的线索数量。这种效应被认为是依赖于在完全预测的奖励反应中相性DA神经元放电的损失;因为成瘾性药物由于其药理作用而产生DA释放，即使在完全预测之后，它们也被理论上否定了阻断效应。本研究的目的就是探讨这种可能性。本研究采用条件性位置偏爱实验和工具性学习程序，考察了甲基苯丙胺（MA）、可卡因（COC）和吗啡（MO）对阻滞效应的影响。由于对DA释放的作用方式不同，将对这3种物质进行对比。在研究的第一部分，大鼠将在3室装置（1个中性室，2个配对室）中接受MA、COC、MO或溶剂（对照）的CPP训练。一旦环境-药物配对建立，每个配对室将引入独特的气味，训练将恢复。最后的测试将在一个新的背景下检查气味的偏好。该研究的工具部分将检查阻塞与未阻塞线索在指导先前训练（即，鼻子戳）和新颖（即，杠杆按压）行为。我假设，在研究的经典部分，大鼠对与食物配对的气味没有偏好（因为气味将被环境阻断），但会对与药物配对的气味表现出偏好。在工具部分，假设被阻断的线索将仅指导一种或多种药物条件下的受试者的行为，而不是食物条件下的受试者。学习是用来指导行为的，而阻塞效应是大脑用来限制“单一奖励”力量的工具之一。这项研究将评估一种机制，通过这种机制，成瘾性药物可能会进入近乎无限数量的关联，为慢性药物使用者创建一张标有箭头的周围地图，箭头指向他们选择的成瘾物质，导致对药物和相关线索行为的不可逾越的控制。

DESCRIPTION (provided by applicant): The mechanisms by which the recreational use of illicit drugs becomes compulsive have been the subject of a great deal of research. Much of this research has focused on ways in which addictive drugs usurp natural learning mechanisms, as well as the role for neuroadaptations in the dopamine (DA) system that may contribute to these effects. Recent reconceptualizations of the role of dopamine in learning have suggested that it may function as an error signal to cdrticolimbic target regions and that substances that interfere with normal dopamine functioning may pathologically-affect this signal. One of these disruptions may include interfering with a learning effect known as blocking, which limits the number of cues that can be associated with a given reward. This effect has been proposed to depend on the loss of phasic DA neuron discharge in response fully predicted rewards; because addictive drugs produce DA release due to their pharmacological effects, even after becoming fully predicted, they are theorized to negate the blocking effect. The aim of this study is to examine this possibility. In the proposed study, the effect of methamphetamine (MA), cocaine (COC) and morphine (MO) on blocking will be examined using a conditioned place preference (CPP) and an instrumental learning procedure. These 3 substances will be contrasted due to the difference in the modes of action on DA release. In the first part of the study, rats will undergo CPP training with either MA, COC, MO, or vehicle (control) in a 3 chamber apparatus (1 neutral, 2 pairing chambers). Once the context-drug pairing is established, each of the pairing chambers will have a unique odor introduced and training will resume. Final testing will examine preference for the odor in a novel context. The instrumental portion of the study will examine the motivational properties of blocked versus unblocked cues in directing previously trained (i.e., nose poke) and novel (i.e., lever press) behaviors. I hypothesize that in the classical portion of the study rats will show no preference for the odor paired with food (as the odor will have been blocked by the context) but will show preference for odors paired with drug. In the instrumental portion, it is hypothesized that blocked cues will only direct behavior for subjects in one or more of the drug conditions but not for those in the food condition. Learning is used to guide behavior, and the blocking effect is one of the brain's tools for limiting the power of'a single reward. This study will assess a mechanism by which addictive drugs may be available to enter into a near infinite number of associations, creating for the chronic drug user a map of their surrounding marked with arrows leading towards their addictive substance of choice, leading to an insurmountable control over behavior by drugs and related cues.