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

 描述(申请人提供)：多巴胺传递的改变在大多数当代药物滥用理论中都有牵连，但这些变化的方式甚至方向都很有争议。从娱乐性吸毒转向吸毒的最显著的行为特征是对寻找毒品的关注增加和毒品消费的增加。我们最近证明，长期使用后药物消耗量的增加是由特定的多巴胺信号的减少所驱动的：药物线索的反应相关的呈现引起的相性多巴胺释放。然而，我们的初步数据表明，药物提示(即在戒毒期间寻求药物和复发的有力刺激)的非偶然呈现的相性多巴胺释放以相反的方向变化，实际上随着长期药物使用而增加。总而言之，多巴胺在偶然和非偶然药物提示下释放时相的直径变化这一概念，可以解决显然相互矛盾的药物成瘾理论。在这项拟议的工作中，我们将用快速扫描循环伏安法测量多巴胺的释放，并观察不同的可卡因自我给药方案和随后的药物戒断阶段对药物相关线索的行为，以检验这一假说。我们还将测试L多巴在恢复多巴胺释放到偶然呈现的药物线索以减少药物消耗方面的影响是否通过增加非偶然线索的多巴胺释放和潜在增加复发的可能性来缓解。如果不是，并且L-多巴选择性地增加枯竭的多巴胺释放(到偶然线索)，而不显著增加非枯竭的多巴胺(到偶然线索)，我们主张L-多巴作为一种减少药物消耗的减害药物，为行为和认知干预提供一个窗口。

 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.