Uncertainty and stimulant self-administration

不确定性和刺激性自我管理

• 批准号: 8696842
• 负责人: Paul R Vezina
• 金额: $ 23.7万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696842
• 关键词: Addictive Behavior; Affect; Alcohol dependence; Amphetamines; Animal Model; Animals; Behavioral; Biochemical; Brain; Brain region; Chronic; Cocaine; Cues; Development; Disease; Dopamine; Dose; Drug Addiction; Drug abuse; Drug usage; Exposure to; Fire - disasters; Gambling; General Population; Health; High Prevalence; Human; Image; Incentives; Individual; Injection of therapeutic agent; Intake; Lead; Locomotion; Maintenance; Measures; Midbrain structure; Modeling; Motivation; Neurons; Nucleus Accumbens; Pathological Gambling; Pathway interactions; Performance; Pharmaceutical Preparations; Process; Productivity; Psychological reinforcement; Rattus; Reading; Reinforcement Schedule; Reporting; Rewards; Saccharin; Schedule; Self Administration; Societies; Sucrose; System; Testing; Time; Training; Uncertainty; Ventral Tegmental Area; addiction; age group; craving; demographics; dopaminergic neuron; drug craving; experience; male; neuroadaptation; non-drug; novel; psychostimulant; public health relevance; reinforcer; research study; response; working group

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.

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元底物。对可卡因和酒精依赖者的研究表明，病态赌博的流行率高于一般人群，通常赌博先于吸毒。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。激励敏化提供了一个潜在的解释，这种神经元激活可能是从偶然使用药物的过渡到药物渴望和滥用。在该模型中，重复间歇性暴露于药物，如安非他明，引发腹侧被盖区的神经适应，导致敏化运动和神经核（NAcc）多巴胺（DA）溢出，以响应药物的挑战，以及增强安非他明自我管理的渐进比例时间表。在暴露于多种药物后观察到致敏作用，并报告了药物和非药物致敏剂（如糖精）之间的交叉致敏作用。最近，我们报告说，暴露于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相同的神经可塑性变化，这些变化是由反复间歇性精神兴奋剂刺激产生的。非剥夺雄性大鼠进行训练，逐步升级的固定比例（FR）或可变比例（VR）的糖精强化（FR：固定的压力和支出之间的关系; VR：不确定的压力和支出之间的关系）。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，阈值安非他明挑战注射（0.5毫克/公斤IP）后两周的最后一次糖精训练期产生了显着更大的运动反应，VR相比，FR大鼠。这一发现表明，可变强化时间表引起的神经可塑性变化类似于已知的敏感反应的重复精神兴奋剂暴露所产生的变化。在两个目标，拟议的实验将开始，以表征如何重复暴露于赌博样不可预测的强化促进运动交叉致敏安非他明，并确定是否安非他明自我管理和NAcc DA溢出也随后增强。首先，中脑DA神经元的反应性将评估在响应不确定的奖励通过测量体树突DA溢出的腹侧被盖区，而大鼠响应可预测或不可预测的糖精强化。第二，暴露于不确定强化的长期效应将通过测试这种经历是否导致增强的药物自我施用和NAcc DA溢出来进一步表征。这些实验对于理解不同形式成瘾的神经适应具有重要意义，并且是第一个在动物模型中研究从病理性赌博到药物成瘾的潜在转变的实验。