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。这方面的研究主要集中在成瘾性药物篡夺自然学习机制的方式，以及多巴胺（DA）系统中神经适应的作用，这可能有助于这些影响。最近对多巴胺在学习中的作用的重新概念化表明，它可能作为一种错误信号作用于锥体边缘目标区域，干扰正常多巴胺功能的物质可能会对该信号产生病理影响。其中一种干扰可能包括干扰一种被称为阻碍的学习效应，这种效应限制了与给定奖励相关的线索的数量。这种效应已经被提出依赖于反应完全预测奖励的阶段性DA神经元放电的损失；由于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，理论上也可以否定阻断作用。本研究的目的是检验这种可能性。在拟议的研究中，甲基安非他明（MA）、可卡因（COC）和吗啡（MO）对阻断的影响将使用条件位置偏好（CPP）和工具学习程序进行研究。由于这三种物质在DA释放上的作用方式不同，因此将对它们进行对比。在研究的第一部分，大鼠将在一个3室装置（1个中性室，2个配对室）中接受MA、COC、MO或载体（对照）的CPP训练。一旦环境-药物配对建立，每个配对室将引入一种独特的气味，然后继续训练。最后的测试将检验人们在新环境下对这种气味的偏好。该研究的工具部分将检验在指导先前训练过的行为（如戳鼻子）和新行为（如按杠杆）时，受阻和未受阻线索的动机特性。我假设，在实验的经典部分，老鼠不会对与食物搭配的气味表现出偏好（因为气味会被环境阻挡），但会对与药物搭配的气味表现出偏好。在工具部分，假设被阻断的线索只会指导受试者在一种或多种药物条件下的行为，而不是在食物条件下的行为。学习是用来指导行为的，而阻塞效应是大脑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，成瘾药物可能会进入几乎无限数量的关联，为慢性吸毒者创造一幅他们周围的地图，上面标有指向他们选择的成瘾物质的箭头，导致药物和相关线索对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.