Norepinephrine and Dopamine: Mediating Drug vs. Natural Rewards

描述(申请人提供)：上瘾是一种疾病，主要特征是强迫寻求和吸毒；然而，同样具有破坏性的是对一个人的正常活动(例如，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结果(即药物变得如此重要/突出，其他一切与之相比必然相形见绌)。我们认为，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，主要由伏核(NAC)中增强的多巴胺(DA)信号介导；2)对自然奖赏的兴趣丧失，我们推测这是由NAC中增强的去甲肾上腺素(NE)信号介导的。多巴胺和去甲肾上腺素水平的个体差异预计会使一些人更容易(或更少)地受到成瘾的影响。雌性纹状体中的去甲肾上腺素水平较高，并随生殖周期的不同而变化。因此，我们认为，女性容易上瘾的一个机制是她们体内NE水平的升高，随着药物的使用而进一步加剧。这导致人们对自然奖励失去兴趣，并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(因为他们的NE水平相对较低)；然而，随着长期使用，药物诱导的NE信号的神经适应可能会导致两性更严重的依赖迹象。为了验证这一假设，我们将检验NAC中肾上腺素能拮抗剂对雄性和雌性大鼠的可卡因自我给药和自然奖励(如食物)的影响。我们预测，去甲肾上腺素拮抗剂将通过重新激发人们对自然奖励的兴趣来减少药物摄取，这种兴趣在自我给药过程中被抑制，这种影响将在女性中最为明显。我们还将通过免疫组织化学的方法检测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的神经支配，以及通过微透析检测NAC的基础和可卡因诱导的NE水平。这些实验的总结将为了解基础条件下和药物暴露后NAC去甲肾上腺素系统功能的性别差异奠定基础，并为治疗成瘾的男性和女性提供不同药物疗法的理论基础。

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.