Uncertainty and stimulant self-administration

描述（由申请人提供）：病理性赌博和药物成瘾可能具有共同的神经基质。对可卡因和酒精依赖个体的研究表明，病态赌博的患病率高于一般人群，通常在吸毒成瘾之前赌博。在赌博和执行不可预测的奖励任务期间进行的人类成像研究也观察到中脑腹侧被盖区（VTA）的神经元激活，该区域与成瘾的发展和维持密切相关。激励敏化提供了一种潜在的解释，解释了这种神经元激活是如何从偶然的药物使用过渡到药物渴望和滥用的。在该模型中，反复间歇性暴露于药物，如安非他明，启动VTA的神经适应，导致致敏运动和伏隔核（NAcc）多巴胺（DA）溢出，以应对药物挑战，并增强安非他明自我给药的递进比例计划。暴露于多种药物后已观察到致敏现象，并且有报道称药物与非药物强化剂（如糖精）之间存在交叉致敏现象。最近，我们报道，暴露在赌博般的不确定条件下，而不是可预测的，糖精强化可能导致大脑中与反复间歇性精神兴奋剂暴露所产生的相同的神经可塑性变化23。对未被剥夺的雄性大鼠进行糖精固定比（FR）或变比（VR）强化训练（FR：按下与支付之间的固定关系；VR：按下与支付之间的不确定关系）。在训练结束时，两组都能可靠地按照时间表工作，两组之间的总糖精摄入量没有差异。尽管如此，在最后一次糖精训练后两周给予阈值安非他明激发注射（0.5 mg/kg IP），与FR大鼠相比，VR大鼠的运动反应明显更大。这一发现表明，可变强化时间表引发的神经可塑性变化类似于反复暴露于已知的致敏反应的精神兴奋剂所产生的变化。在两个目标中，本实验将开始描述反复暴露于赌博样的不可预测强化如何促进运动对安非他明的交叉敏化，并确定安非他明自我给药和NAcc DA溢出是否也随之增强。首先，当大鼠对可预测或不可预测的糖精强化作出反应时，中脑DA神经元的反应性将通过测量VTA的体树突DA溢出来评估。其次，暴露于不确定强化的长期影响将通过测试这种经历是否会导致药物自我给药增强和NAcc DA溢出来进一步表征。这些实验对于理解不同形式的成瘾背后的神经适应具有重要意义，并且是首次在动物模型中研究从病理性赌博到药物成瘾的潜在转变。

DESCRIPTION (provided by applicant): Pathological gambling and drug addiction may share common neuronal substrates. Studies of cocaine- and alcohol-dependent individuals have revealed a higher prevalence of pathological gambling than seen in the general population often with gambling preceding drug addiction. Human imaging studies conducted during gambling and the performance of unpredictable reward tasks have also observed neuronal activation in the midbrain ventral tegmental area (VTA), a region intimately involved in the development and maintenance of addiction. Incentive sensitization provides a potential explanation for how this neuronal activation may underlie the transition from casual drug use to drug craving and abuse. In this model, repeated intermittent exposure to drugs, such as amphetamine, initiates neuroadaptations in the VTA that lead to sensitized locomotion and nucleus accumbens (NAcc) dopamine (DA) overflow in response to a drug challenge as well as enhanced amphetamine self-administration on a progressive ratio schedule. Sensitization has been observed following exposure to a number of drugs and cross-sensitization between drugs and non-drug reinforcers such as saccharin has been reported. Recently, we reported that exposure to conditions of gambling-like uncertain, rather than predictable, saccharin reinforcement may lead to the same neuroplastic changes in the brain that are produced by repeated intermittent psychostimulant exposure23. Non-deprived male rats were trained with escalating schedules of fixed-ratio (FR) or variable-ratio (VR) reinforcement for saccharin (FR: fixed relationship between presses and payout; VR: uncertain relationship between presses and payout). At the end of training, both groups worked reliably on the schedules and total saccharin intake did not differ between groups. Nonetheless, a threshold amphetamine challenge injection (0.5 mg/kg IP) administered two weeks after the last saccharin training session produced a significantly greater locomotor response in VR compared to FR rats. This finding suggests that the variable reinforcement schedule elicited neuroplastic changes similar to those produced by repeated psychostimulant exposure known to sensitize responding. In two aims, the proposed experiments will begin to characterize how repeated exposure to gambling-like unpredictable reinforcement promotes locomotor cross-sensitization to amphetamine and determine whether amphetamine self-administration and NAcc DA overflow are also subsequently enhanced. First, midbrain DA neuron reactivity will be assessed during responding for uncertain reward by measuring somatodendritic DA overflow in the VTA while rats respond for predictable or unpredictable saccharin reinforcement. Second, the long- lasting effects of exposure to uncertain reinforcement will be further characterized by testing whether this experience leads to both enhanced drug self-administration and NAcc DA overflow. These experiments have important implications for understanding the neuroadaptations that underlie different forms of addiction and are the first to investigate this potential transition from pathological gambling to drug addiction in an animal model.