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。这项研究的大部分集中在成瘾药物篡夺自然学习机制的方式，以及神经适应在多巴胺(DA)系统中可能有助于这些影响的作用。最近对多巴胺在学习中作用的重新认识表明，它可能作为错误信号作用于中央边缘靶区，干扰正常多巴胺功能的物质可能在病理上影响这一信号。这些干扰之一可能包括干扰一种被称为阻断的学习效应，这种效应限制了与给定奖励相关的线索的数量。这种效应被认为依赖于对完全预测的奖励反应中DA相神经元放电的丧失；因为成瘾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。这项研究的目的就是考察这种可能性。在拟议的研究中，将使用条件性位置偏好(CPP)和工具性学习程序来检验甲基苯丙胺(MA)、可卡因(COC)和吗啡(MO)对阻断的影响。由于对DA释放的作用方式不同，这3种物质将进行对比。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)中接受与MA、COC、MO或载体(对照)的CPP训练。一旦建立了上下文-药物配对，每个配对室将引入一种独特的气味，培训将恢复。最终测试将在新的背景下检查对气味的偏好。这项研究的工具性部分将考察封闭和非封闭线索在指导先前训练的(例如，戳鼻子)和新的(例如，杠杆按压)行为时的动机特性。我假设，在研究的经典部分，老鼠不会表现出对与食物配对的气味的偏好(因为气味会被上下文所阻挡)，但会对与药物配对的气味表现出偏好。在工具部分，假设被阻断的线索只会指导一个或多个药物条件下的受试者的行为，而不是那些处于食物条件下的受试者的行为。学习被用来指导行为，而阻断效应是大脑限制“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，成瘾药物可能可以进入几乎无限数量的关联，为慢性吸毒者创建一张地图，用箭头标记他们周围的地图，指向他们选择的成瘾物质，导致对毒品行为和相关线索的不可逾越的控制。

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.