Norepinephrine and Dopamine: Mediating Drug vs. Natural Rewards

描述（由申请人提供）：成瘾是一种主要以强迫性药物寻求和服用为特征的疾病;然而，同样具有破坏性的是对一个人的正常活动失去兴趣（例如，人际关系、工作和娱乐活动）。通常，这种减少被视为药物增强价值提高的次要结果（即，药物变得如此重要/突出，与之相比，其他一切都必然相形见绌）。我们认为，药物对动机回路至少产生两种不同的影响：1）药物的动机增强，主要通过增强的多巴胺（DA）信号传导介导，2）对自然奖励的兴趣丧失，我们假设这是由增强的去甲肾上腺素（NE）信号传导介导的。DA和NE水平的个体差异预计会使一些更容易（或更少）成瘾的发展。纹状体中的NE水平在女性中更高，并且在生殖周期中变化。因此，我们建议，一个机制，使妇女成瘾是他们的NE水平升高，这成为进一步加剧与药物使用。这导致对自然回报失去兴趣，使妇女更容易受到药物强化作用的影响。男性不太可能经历相同程度的这些影响（由于其相对较低的NE水平）;然而，长期使用，药物诱导的NE信号传导神经适应可能导致两种性别中更严重的依赖体征。为了检验这一假设，我们将检查NAc中的肾上腺素能拮抗剂对可卡因自我给药和自然奖励（例如，食物）在雄性和雌性大鼠。我们预测，NE拮抗剂将减少药物的摄入量，通过重新激发自然奖励的兴趣，这是抑制在自我管理的过程中，这种效果将是最明显的女性。我们还将研究NE系统的性别差异，包括21个肾上腺素能受体，NE生物合成酶和神经支配的NAc通过免疫组织化学，和基础和可卡因诱导的NE水平的NAc通过微透析。这些实验的总和将奠定基础，了解性别差异的功能，去甲肾上腺素能系统在基础条件下，在NAC和药物暴露后，并提供了一个理由，不同的药物治疗的男性和女性在治疗成瘾。

DESCRIPTION (provided by applicant): Addiction is a disease primarily characterized by compulsive drug seeking and taking; however, equally devastating is the loss of interest in one's normal activities (e.g., interpersonal relationships, work and recreational activities). Typically, this reduction is viewed as a secondary consequence of the heightened reinforcing value of drugs (i.e., drugs become so important/salient that everything else necessarily pales in comparison). We propose that drugs exert at least two distinct influences on motivation circuits: 1) the enhanced motivation for drugs, mediated primarily by enhanced dopamine (DA) signaling in the nucleus accumbens (NAc), and 2) the loss of interest in natural rewards, which we hypothesize is mediated by enhanced norepinephrine (NE) signaling in the NAc. Individual differences in DA and NE levels are expected to render some more (or less) vulnerable to the development of addiction. NE levels in the striatum are greater in females and vary over the reproductive cycle. Therefore, we propose that one mechanism predisposing women to addiction is their heightened NE levels, which become further exacerbated with drug use. This results in the loss of interest in natural rewards and renders women more susceptible to the reinforcing effects of drugs. Males are less likely to experience these effects to the same degree (due to their relatively lower NE levels); however, with chronic use, drug-induced neuroadaptations in NE signaling may contribute to more severe signs of dependence in both sexes. To test this hypothesis we will examine the effects of adrenergic antagonists in the NAc on the self-administration of cocaine and natural rewards (e.g., food) in male and female rats. We predict that NE antagonists will reduce drug intake by reinvigorating interest in natural rewards, which is suppressed over the course of self-administration, and that this effect will be most pronounced in females. We will also examine sex differences in the NE system, including 21 adrenergic receptors, NE biosynethetic enzymes and innervation in the NAc via immunohistochemistry, and basal and cocaine-induced NE levels in the NAc via microdialysis. The sum of these experiments will lay the groundwork for understanding sex differences in the function of the noradrenergic system in the NAc under basal conditions and following drug exposure and provide a rationale for different pharmacotherapies for men and women in the treatment of addiction.