Uncertainty and stimulant self-administration

描述(申请人提供)：病理性赌博和吸毒可能有共同的神经基础。对可卡因和酒精依赖者的研究表明，病理性赌博的流行率高于普通人群，通常是先赌博后吸毒。在赌博期间进行的人体成像研究以及不可预测的奖励任务的执行也观察到了中脑腹侧被盖区(VTA)的神经元激活，该区域与成瘾的形成和维持密切相关。诱因敏感化提供了一个潜在的解释，说明这种神经元激活可能是如何从随意吸毒转变为吸毒渴望和滥用的基础。在这个模型中，反复间歇性接触药物，如苯丙胺，启动VTA的神经适应，导致敏感化运动和伏隔核(NAcc)多巴胺(DA)溢出，以递增比率时间表增加苯丙胺自我给药。在接触一些药物后观察到了敏化，并报告了药物与糖精等非药物增强剂之间的交叉敏化。最近，我们报道，暴露在像赌博一样的不确定而不是可预测的条件下，糖精强化可能会导致大脑中的神经可塑性变化，与反复间歇性精神刺激剂暴露所产生的变化相同23。对非剥夺雄性大鼠进行固定比例(FR)或可变比例(VR)糖精强化(FR：压力机与支出之间的固定关系；VR：压力机与支出之间的不确定关系)强化训练。在训练结束时，两组都可靠地按照时间表工作，糖精总摄入量在两组之间没有差异。尽管如此，在最后一次糖精训练后两周注射阈值苯丙胺挑战注射(0.5 mg/kg ip)，与FR大鼠相比，VR大鼠的运动反应显著增强。这一发现表明，可变的强化计划引起的神经可塑性变化类似于已知的敏化反应的反复精神刺激剂暴露所产生的变化。在两个目标中，拟议的实验将开始表征重复暴露于赌博类不可预测的强化如何促进运动对苯丙胺的交叉敏感化，并确定苯丙胺自我给药和NAcc DA溢出是否随后也会增强。首先，当大鼠对可预测或不可预测的糖精强化做出反应时，将通过测量VTA中的躯体树突DA溢出来评估中脑DA神经元在对不确定奖励的反应期间的反应性。其次，暴露在不确定强化中的长期影响将通过测试这种经历是否导致增强的药物自我管理和NAcc DA溢出来进一步表征。这些实验对于理解不同形式成瘾背后的神经适应具有重要意义，并首次在动物模型中研究了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.