Department of Psychiatry, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.
Department of Basic Neurosciences, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.
Int J Mol Sci. 2023 Aug 26;24(17):13238. doi: 10.3390/ijms241713238.
Current research indicates that altered dopamine (DA) transmission in the striatum contributes to impulsivity and novelty-seeking, and it may mediate a link concerning a higher susceptibility to drug abuse. Whether increased susceptibility to drug abuse results from a hyperdopaminergic or hypodopaminergic state is still debated. Here, we simultaneously tracked changes in DA D receptor (DR) availability and amphetamine-(AMPH)-induced DA release in relation to impulsivity and novelty-seeking prior to, and following, cocaine self-administration (SA) in Roman high- (RHA) and low- (RLA) avoidance rats. We found that high-impulsive/high novelty-seeking RHA rats exhibited lower DR availabilities and higher AMPH-induced DA release in the striatum that predicted higher levels of cocaine intake compared with RLAs. Cocaine SA did not alter striatal DR availability or impulsivity in RHA or RLA rats. Critically, cocaine exposure led to a baseline-dependent blunting of stimulated DA release in high-impulsive/high novelty-seeking RHA rats only, and to a baseline-dependent increase in novelty-seeking in low-impulsive/low novelty-seeking RLA rats only. Altogether, we propose that susceptibility to drug abuse results from an innate hyper-responsive DA system, promoting impulsive action and novelty-seeking, and producing stronger initial drug-reinforcing effects that contribute to the initiation and perpetuation of drug use. However, with repeated cocaine use, a tolerance to drug-induced striatal DA elevations develops, leading to a compensatory increase in drug consumption to overcome the reduced reward effects.
目前的研究表明，纹状体中多巴胺（DA）传递的改变导致冲动性和寻求新奇，并且可能介导与更高的药物滥用易感性有关的联系。药物滥用易感性的增加是由于多巴胺能亢进还是多巴胺能低下状态仍存在争议。在这里，我们在可卡因自我给药（SA）之前和之后，同时跟踪了罗曼高回避（RHA）和低回避（RLA）大鼠中 DA D 受体（DR）可用性的变化以及安非他明（AMPH）诱导的 DA 释放与冲动性和寻求新奇性的关系。我们发现，高冲动/高寻求新奇性的 RHA 大鼠表现出较低的纹状体 DR 可用性和较高的 AMPH 诱导的 DA 释放，这预示着可卡因摄入量较高。可卡因 SA 并未改变 RHA 或 RLA 大鼠的纹状体 DR 可用性或冲动性。至关重要的是，可卡因暴露仅导致高冲动/高寻求新奇性的 RHA 大鼠的基础依赖性刺激的 DA 释放迟钝，并且仅导致低冲动/低寻求新奇性的 RLA 大鼠的基础依赖性寻求新奇性增加。总之，我们提出药物滥用易感性源于先天的高反应性 DA 系统，促进冲动性行为和寻求新奇性，并产生更强的初始药物强化效应，从而有助于药物使用的开始和持续。然而，随着重复使用可卡因，会对药物引起的纹状体 DA 升高产生耐受性，导致药物消费的代偿性增加，以克服减少的奖励效应。
