Diametric changes in phasic dopamine to contingent and non-contingent drug cues in the regulation of drug taking and drug seeking

在吸毒和寻求药物调节中，阶段性多巴胺对偶然和非偶然药物线索的直径变化

• 批准号: 9230365
• 负责人: Paul E. M. Phillips
• 金额: $ 33.99万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9230365
• 关键词: Abstinence; Address; Advocate; Animals; Basic Science; Behavior; Behavioral; Characteristics; Chronic; Cocaine; Cognitive; Consumption; Control Locus; Corpus striatum structure; Cues; Data; Data Set; Disease; Dopamine; Drug Addiction; Drug Controls; Drug Regulations; Drug abuse; Drug usage; Drug user; Employee Strikes; Exhibits; Extinction (Psychology); Harm Reduction; Hour; Human; Individual Differences; Intake; Intervention; Levodopa; Measures; Modeling; Monitor; Nucleus Accumbens; Pattern; Periodicity; Peripheral; Pharmaceutical Preparations; Phase; Probability; Rattus; Recording of previous events; Recreational Drugs; Regimen; Relapse; Scanning; Self Administration; Signal Transduction; Stimulus; Substance abuse problem; Testing; Time; Withdrawal; Work; addiction; behavioral response; cocaine use; craving; decarboxylase inhibitor; drug craving; drug relapse; drug withdrawal; indexing; neurochemistry; public health relevance; recreational drug use; response; spatiotemporal; theories; trait; transmission process

 DESCRIPTION (provided by applicant): Altered dopamine transmission is implicated in most contemporary theories of drug abuse, but the manner and even the direction of these changes are quite controversial. The most salient behavioral characteristics of the switch from recreational drug use to drug abuse are an increased focus on drug seeking and increased drug consumption. We recently demonstrated that increased drug consumption following chronic use is driven by a decrement in a specific dopamine signal: phasic dopamine release evoked by the response- contingent presentation of drug cues. However, our preliminary data indicate that phasic dopamine release to non-contingent presentation of drug cues (i.e., a potent stimulus for drug seeking and relapse to drug use during abstinence) change in the opposite direction and actually increase with chronic drug use. Collectively, this notion of diametric changes in phasic dopamine release to contingent and non-contingent drug cues, respectively, can resolve apparently contradictory theories of drug addiction. In the proposed work we will test this hypothesis by measuring dopamine release with fast-scan cyclic voltammetry and observing behavior to drug-related cues using different regimens of cocaine self-administration and following periods of drug withdrawal. We will also test whether or not the effect of L-DOPA on restoring dopamine release to contingent presentation of drug cues to reduce drug consumption is mitigated by increasing dopamine release to non-contingent cues and potentially increasing the likelihood of relapse. If not, and L-DOPA selectively increases depleted dopamine release (to contingent cues) without significantly elevating non- depleted dopamine (to contingent cues), we would advocate L-DOPA as a harm-reduction pharmacotherapeutic for reducing drug consumption to provide a window for behavioral and cognitive interventions.

 描述（由申请人提供）：大多数当代药物滥用理论都涉及多巴胺传递的改变，但这些变化的方式甚至方向都颇具争议。从消遣性药物使用到药物滥用的转变最显着的行为特征是。我们最近证明，长期使用后药物消耗的增加是由特定多巴胺信号的减少引起的：由药物的反应相关呈现引起的阶段性多巴胺释放。然而，我们的初步数据表明，药物线索的非偶然呈现（即，在戒断期间寻求药物和吸毒复发的有效刺激）的阶段性多巴胺释放呈相反方向变化，并且实际上随着长期吸毒而增加。总的来说，阶段性多巴胺释放分别针对偶然和非偶然药物线索的直径变化的概念可以解决明显矛盾的药物成瘾理论，在拟议的工作中，我们将通过以下方式检验这一假设。使用快速扫描循环伏安法测量多巴胺释放，并使用不同的可卡因自我给药方案和停药期观察药物相关线索的行为，我们还将测试左旋多巴是否对恢复多巴胺释放有影响。通过增加非偶然线索的多巴胺释放来减轻药物线索的偶然出现，从而减少药物消耗，并可能增加复发的可能性。如果没有，左旋多巴选择性地增加耗尽。如果多巴胺释放（针对偶然线索）而不显着提高未耗尽的多巴胺（针对偶然线索），我们提倡将左旋多巴作为一种减少危害的药物治疗，以减少药物消耗，为行为和认知干预提供一个窗口。