Effect of cocaine sensitization on cue-evoked reward seeking and dopamine release

描述(由申请人提供)：与奖励相关的环境线索可能会影响涉及对奖励做出回应的行动和决定。环境线索对行为选择的影响与上瘾尤其相关，在上瘾中，我们看到行为控制的丧失，以及习惯性寻求毒品行为的增加。呈现与奖赏相关的线索会在伏核(NA)内引起多巴胺(DA)的释放，这一效应被认为是奖赏寻求增加的基础。激励敏感化理论 成瘾研究认为，反复接触精神刺激剂会使这一系统变得敏感，从而使刺激更容易激活DA系统，增强动力。因此，药物暴露应该允许线索与奖励配对对行为施加更大的控制，解释了线索诱导的成瘾个体寻求毒品行为的敏感性质。拟议实验的第一个目标将是确定，在大鼠身上，可卡因敏化是否会增强NA中线索诱发的奖赏反应和DA释放，并将为我提供快速扫描循环伏安法和巴甫洛夫-仪器范式的训练。成本与大额奖励选项的关联可能会降低其价值，并将选择转向更小、成本更低的奖励，而成瘾者一再被证明，与健康对照组相比，更有可能对更大、更昂贵的奖励打折。有趣的是，与奖励相关的线索的存在与否似乎会将行为转向不同的选择。然而，目前尚不清楚在可卡因敏化后线索诱发的DA释放的变化如何影响线索的存在或不存在对选择偏好的影响。因此，该实验的第二个目标将是确定可卡因诱导的敏感化如何影响报酬相关线索对延迟和努力折扣任务中选择偏好的影响。快速扫描循环伏安法将再次被用来确定在提示呈现和选择偏好期间大脑中多巴胺水平的相关变化。成本效益决策的障碍可能会促使行为转向需要较少努力的即时奖励，例如与药物使用有关的奖励(欣快感，戒断症状的缓解)，而不是与禁欲有关的更努力但最终更有益的奖励(例如，更好的健康、就业、家庭关系)，从而导致上瘾。了解线索的作用，以及多巴胺在奖赏反应中的作用，特别是在有不同的奖赏-成本选择的情况下，对于我们理解滥用药物如何改变行为和决策以及制定治疗策略非常重要。

DESCRIPTION (provided by applicant): Environmental cues associated with reward can impact actions and decisions that involve responding for rewards. The influence of environmental cues on action selection is particularly relevant to addiction, in which we see a loss of behavioral control, and increases in habitual drug seeking behavior. Presentation of reward associated cues elicits dopamine (DA) release within the nucleus accumbens (NA), an effect that is believed to underlie increases in reward seeking. The incentive sensitization theory of addiction posits that repeated psychostimulant exposure sensitizes this system, allowing stimuli to more easily activate the DA system and enhance motivation. Thus, drug exposure should allow cues paired with reward to exert greater control over behavior, explaining the sensitive nature of cue-induced drug seeking behavior in addicted individuals. The first objective of the proposed experiments will be to determine, in rats, if cocaine sensitization potentiates cue- evoked reward responding and DA release in the NA and will provide me with training in fast-scan cyclic voltammetry and the Pavlovian-to-instrumental paradigm. The association of a cost with a large reward option can decrease its value and shift choice toward a smaller, less costly reward, and addicted individuals have been repeatedly shown to be more likely to discount larger, more costly rewards, than healthy controls. Interestingly, the presence or absence of reward-related cues appears to shift behavior towards different options. However, it is currently not clear how alterations in cue-evoked DA release, following cocaine sensitization, impacts the effects of cue presence or absence on choice preference. The second objective of the proposed experiments will therefore be to determine how cocaine induced sensitization impacts the effects of reward-associated cues on choice preference, in delay and effort discounting task. Fast-scan cyclic voltammetry will again be used to determine associated changes in dopamine levels within the brain, during cue presentation and choice preference. Impairments in cost-benefit decision making may contribute to addiction by driving behavior towards immediate rewards requiring less effort, such as those associated with drug use (euphoria, relief from withdrawal symptoms), over more effortful, but ultimately more beneficial, rewards associated with abstinence (e.g. - better health, employment, family relationships). Understanding the role of cues, as well as the role of dopamine, in responding for rewards, particularly when different reward-cost options are available, is important to our understanding of how drugs of abuse modify behavior and decision making, as well as for the development of treatment strategies.