Drugs of Abuse, Reward Comparison, and the Thalamus

滥用药物、奖励比较和丘脑

• 批准号: 7659269
• 负责人: Patricia Sue Grigson
• 金额: $ 34.26万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659269
• 关键词: Animal Model; Brain Diseases; Cell Nucleus; Chronic; Classification; Cocaine; Conditioned Stimulus; Cues; Data; Dopamine; Dose; Elements; Funding; Glean; Glucose; Goals; Hand; Heroin; Histology; Ibotenic Acid; Intake; Learning; Left; Lesion; Microdialysis; Modeling; Morphine; Nucleus Accumbens; Pathway interactions; Pharmaceutical Preparations; Preparation; Process; Property; Rattus; Recovery; Relapse; Request for Proposals; Rewards; Role; Saccharin; Self-Administered; Stimulus; Sucrose; Taste Perception; Testing; Thalamic structure; Time; Withdrawal; addiction; brain behavior; craving; drug of abuse; drug reward; neural circuit; prevent; research study

Rats avoid intake of a saccharin conditioned stimulus (CS) when paired with a drug of abuse (LeMagnen, 1969; for reviews, see Gamzu, Vincent, & Boff, 1985; Goudie, 1987; Hunt & Amit, 1987). For decades, the suppressive effects of drugs of abuse on CS intake have been attributed to presumed aversive drug properties (Lester, Nachman, & LeMagnen, 1970). Data gleaned over the past decade, however, have provided substantive support for the hypothesis that rats avoid intake of the taste cue because the tastant is devalued in anticipation of the availability of the highly rewarding properties of the abused substance (Grigson, 1997; for review, see Grigson et al., 2008; Grigson, in press). As such, the present model serves as a unique model for the systematic study of drug-induced devaluation of natural rewards. New data, however, suggest that there may be a second process contributing to devaluation of the taste cue and this process includes an element of aversion (Wheeler et al., 2008). We hypothesize, then, that there are two processes: Devaluation of the taste cue by the highly rewarding drug properties and devaluation of the taste cue as it becomes associated with craving and withdrawal in anticipation of the impending availability of drug. The goal here is to identify the underlying circuitry. Lesion data collected over the last funding period clearly demonstrate an essential role for the gustatory thalamocortical loop (Schroy et al., 2005; Geddes et al., 2008; Geddes et al., in preparation). Even so, there is some indication that the disruptive effect of lesions of this pathway may be overridden by the use of higher doses of the drugs. Specific Aim 1A, 1B, and 1C will test the hypothesis that disconnection of the gustatory thalamocortical loop will disrupt the suppressive effects of low and high concentrations/doses of sweets and drugs, but not those of the illness-inducing agent, LiCl. Recent microdialysis data show that dopamine in the NAc tracks morphine-induced devaluation of the saccharin cue when morphine is administered by the experimenter (Grigson & Hajnal, 2007). Specific Aim 2A will use central lesions and microdialysis to test the hypothesis that the NAc depends upon an intact gustatory thalamocortical loop to track devaluation induced by self-administered cocaine. The present set of studies can be completed in 2 years. The results will: (a) Verify that an intact gustatory thalamocoritical loop is essential for devaluation induced by ‘self-administered’ sweets and drug; (b) Demonstrate that the disruptive effect of this lesion is retained even when using higher concentrations/ doses of rewarding sweets and drugs (i.e., cocaine and heroin); and (c) Reveal that the nucleus accumbens depends upon an intact thalamocoritical loop to track cocaine’s devaluation of a sweet.

当与滥用药物配对时，大鼠避免摄入糖精条件的刺激（CS）（CS）（Lemagnen，1969；有关评论，请参见Gamzu，Vincent和Boff，＆Boff，1985; Goudie，1987; Hunt＆Amit，1987）。几十年来，滥用药物对CS摄入的抑制作用一直归因于表现出的厌恶性药物特性（Lester，Nachman和Lemagnen，1970年）。然而，在过去十年中收集的数据为大鼠避免摄入味道提示的假设提供了实质性的支持，因为预期味道会贬值，因为预期滥用物质的高度有益的特性（Grigson，1997;有关审查，请参阅Grigson等人，参见Grigson等，2008; Grigson; Grigson;印刷中）。因此，本模型是对药物诱导的自然奖励定义系统研究的独特模型。但是，新数据表明，可能有第二个过程有助于味觉提示的定义，并且该过程包括厌恶的元素（Wheeler等，2008）。因此，我们假设有两个过程：通过高度有益的药物特性和味觉提示的定义贬值，因为它与渴望和戒断有关，因为预期即将来临的药物可用性。这里的目标是确定基础电路。在最后一个资金期间收集的病变数据清楚地表明了味觉丘脑皮层环的重要作用（Schroy等，2005； Geddes等，2008； Geddes等人，Geddes等人）。即便如此，也有一些迹象表明，使用较高剂量的药物可能会覆盖该途径的破坏作用。具体的目标1A，1B和1C将检验以下假设：味觉丘脑皮质环的断开将破坏低浓度和高浓度/剂量的糖果和药物的抑制作用，但不会破坏疾病引起的剂的抑制作用。最近的微透析数据表明，NAC中的多巴胺跟踪吗啡诱导的糖精提示定义时，当实验者施用吗啡时（Grigson＆Hajnal，2007）。特定的目标2a将使用中央病变和微透析来检验NAC取决于完整的味觉丘脑皮层环以跟踪由自加加工的可卡因引起的定义的假设。目前的研究可以在2年内完成。结果将：（a）验证完整的味觉丘脑皮质环对“自我加工”的糖果和药物引起的定义至关重要； （b）证明即使使用更高浓度/剂量的有益糖果和药物（即可卡因和海洛因），这种病变的破坏性也会保留； （c）表明伏隔核取决于完整的丘脑皮层环，以跟踪可卡因对甜的定义。