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

 描述（由申请人提供）：多巴胺传递的改变与大多数当代药物滥用理论有关，但这些变化的方式甚至方向都存在争议。从娱乐性药物使用转向药物滥用的最突出的行为特征是更加注重寻求药物和增加药物消费。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驱动的：由药物线索的响应-视情况呈现诱发的阶段性多巴胺释放。然而，我们的初步数据表明，阶段性多巴胺释放对药物线索的非偶然呈现（即，在戒毒期间对寻求毒品和吸毒复吸的一种强有力的刺激）向相反的方向变化，实际上随着长期吸毒而增加。总的来说，这个概念的直径变化阶段多巴胺释放的偶然性和非偶然的药物线索，分别可以解决明显矛盾的理论药物成瘾。在拟议的工作中，我们将测试这一假设，通过测量多巴胺的释放与快速扫描循环伏安法和观察行为的药物相关的线索使用不同的方案可卡因自我管理和以下时期的药物戒断。我们还将测试左旋多巴对恢复多巴胺释放到药物线索的偶然呈现以减少药物消耗的影响是否通过增加多巴胺释放到非偶然线索并潜在地增加复发的可能性来减轻。如果没有，并且L-DOPA选择性地增加耗尽的多巴胺释放（对偶然线索）而不显著升高未耗尽的多巴胺（对偶然线索），我们将提倡L-DOPA作为减少药物消耗的减少伤害的药剂，以提供行为和认知干预的窗口。

 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.