Department of Psychology, State University of New York - Binghamton University, PO Box 6000, Binghamton, NY, 13902-6000, USA.
The Jackson Laboratory, Bar Harbor, ME, USA.
Psychopharmacology (Berl). 2023 Mar;240(3):561-573. doi: 10.1007/s00213-022-06256-9. Epub 2022 Oct 14.
Cocaine use disorder (CUD) is a highly heritable form of substance use disorder, with genetic variation accounting for a substantial proportion of the risk for transitioning from recreational use to a clinically impairing addiction. With repeated exposures to cocaine, psychomotor and incentive sensitization are observed in rodents. These phenomena are thought to model behavioral changes elicited by the drug that contribute to the progression into addiction, but little is known about how genetic variation may moderate these consequences.
Here, we describe the use of two Collaborative Cross (CC) recombinant inbred mouse strains that either exhibit high (CC018/UncJ) or no (CC027/GeniUncJ) psychomotor sensitization in response to cocaine to measure phenotypes related to incentive sensitization after repeated cocaine exposures; given the relationship of incentive motivation to nucleus accumbens core (NAc) dopamine release and reuptake, we also assessed these neurochemical mechanisms.
Adult male and female CC018/UncJ and CC027/GeniUncJ mice underwent Pavlovian conditioning to associate a visual cue with presentation of a palatable food reward, then received five, every-other-day injections of cocaine or vehicle. Following Pavlovian re-training, they underwent testing acquisition of a new operant response for the visual cue, now serving as a conditioned reinforcer. Subsequently, electrically evoked dopamine release was assessed using fast-scan cyclic voltammetry from acute brain slices containing the NAc.
While both strains acquired the Pavlovian association, only CC018/UncJ mice showed conditioned reinforcement and incentive sensitization in response to cocaine, while CC027/GeniUncJ mice did not. Voltammetry data revealed that CC018/UncJ, compared to CC027/GeniUnc, mice exhibited higher baseline dopamine release and uptake. Moreover, chronic cocaine exposure blunted tonic and phasic dopamine release in CC018/UncJ, but not CC027/GeniUncJ, mice.
Genetic background is a moderator of cocaine-induced neuroadaptations in mesolimbic dopamine signaling, which may contribute to both psychomotor and incentive sensitization and indicate a shared biological mechanism of variation.
可卡因使用障碍（CUD）是一种高度遗传性的物质使用障碍，遗传变异在从娱乐性使用向临床致瘾的转变中占很大比例。在反复接触可卡因后，啮齿动物会出现运动和激励敏化。这些现象被认为模拟了药物引起的行为变化，这些变化导致了成瘾的发展，但对于遗传变异如何调节这些后果知之甚少。
本研究使用两种协同交叉（CC）重组近交系小鼠品系，即表现出可卡因诱导的运动敏化（CC018/UncJ）或无运动敏化（CC027/GeniUncJ），来测量与反复可卡因暴露后激励敏化相关的表型；鉴于激励动机与伏隔核核心（NAc）多巴胺释放和再摄取的关系，我们还评估了这些神经化学机制。
成年雄性和雌性 CC018/UncJ 和 CC027/GeniUncJ 小鼠接受条件反射训练，将视觉线索与美味食物奖励的呈现联系起来，然后接受五次每两天一次的可卡因或载体注射。在条件反射再训练后，它们接受了新的视觉线索操作性反应的测试获取，现在作为条件强化剂。随后，使用快速扫描循环伏安法从含有 NAc 的急性脑切片中评估电诱发多巴胺释放。
虽然两种品系都获得了条件反射关联，但只有 CC018/UncJ 小鼠在可卡因刺激下表现出条件强化和激励敏化，而 CC027/GeniUncJ 小鼠则没有。伏安法数据显示，与 CC027/GeniUncJ 小鼠相比，CC018/UncJ 小鼠的多巴胺基线释放和摄取更高。此外，慢性可卡因暴露在 CC018/UncJ 小鼠中削弱了多巴胺的紧张和相位释放，但在 CC027/GeniUncJ 小鼠中则没有。
遗传背景是中脑边缘多巴胺信号传导中可卡因诱导的神经适应性的调节剂，这可能导致运动和激励敏化，并表明存在共享的变异生物学机制。
