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寻求和服用药物为特征的疾病；然而，同样毁灭性的是对正常活动（如人际关系、工作和娱乐活动）失去兴趣。通常，这种减少被视为药物强化价值提高的次要后果（即，药物变得如此重要/突出，以至于其他一切都必然相形见绌）。我们提出，药物对动机回路至少有两种不同的影响：1)药物动机的增强，主要由伏隔核（NAc）中多巴胺（DA）信号的增强介导；2)对自然奖励的兴趣丧失，我们假设这是由伏隔核（NAc）中去甲肾上腺素（NE）信号的增强介导的。DA和NE水平的个体差异预计会使一些人更容易（或更不容易）上瘾。纹状体中的NE水平在女性中更高，并且在生殖周期中有所不同。因此，我们提出一种使女性容易上瘾的机制是她们的NE水平升高，这种升高会随着药物的使用而进一步加剧。这导致对自然奖励失去兴趣，使妇女更容易受到药物强化作用的影响。男性不太可能经历同样程度的这些影响（由于他们的NE水平相对较低）；然而，在长期使用中，药物诱导的NE信号的神经适应可能导致两性更严重的依赖迹象。为了验证这一假设，我们将研究NAc中肾上腺素能拮抗剂对雄性和雌性大鼠自我给药可卡因和自然奖励（如食物）的影响。我们预测，NE拮抗剂将通过重新激活对自然奖励的兴趣来减少药物摄入量，这种兴趣在自我给药过程中被抑制，并且这种效果将在女性中最为明显。我们还将通过免疫组织化学检查NE系统的性别差异，包括21种肾上腺素能受体、NE生物合成酶和NAc中的神经支配，以及通过微透析检查NAc中基础和可卡因诱导的NE水平。这些实验的总结将为了解NAc中去甲肾上腺素能系统在基础条件下和药物暴露后功能的性别差异奠定基础，并为治疗成瘾的男女不同药物治疗提供依据。

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.