Dopaminergic and Glutamatergic Mechanisms of Cocaine Addiction: Sex Differences

描述(申请人提供)：吸毒成瘾是美国可预防死亡的主要原因。迫切需要有效的治疗方法，但开发治疗方法具有挑战性，因为成瘾的潜在神经生物学随着疾病的进展而变化。我们过去15年的工作揭示了成瘾不同阶段中重要的性和激素效应，这表明其潜在的神经生物学也可能在男性和女性之间有所不同。在过去5年的资助期内，我们扩大了我们的行为研究，将性别差异背后的神经生物学研究包括在内。现在，在这场竞争性的更新中，我们转向对成瘾发展基础上的性别特定行为和神经生物学变化的描述。这一点很重要，因为绝大多数关于可卡因成瘾的神经生物学数据都是基于在男性身上进行的短期自我给药研究。然而，由于其稳定性，短访问条件(1-2小时/天)会 没有捕捉到人类成瘾的关键特征，包括更强的使用药物的动机和更容易复发。扩展通路程序(6-24小时/天)已经被开发出来，它们产生了这些特征，并揭示了潜在的神经生物学不同于在短通路程序下观察到的。在累进比率时间表下测量的对可卡因的增强动机已被用来定义大鼠成瘾的发展。这一特征在长时间但不是短时间的自我管理之后的一段禁欲时期内发展起来，女性比男性发展得更早。我们最近发现，虽然伏核(NAC)中的多巴胺(DA)D1受体信号是短期给药后可卡因动机的关键中介，但一旦成瘾建立，其作用就会减弱，谷氨酸AMPA/KA受体信号似乎是关键参与其中。在女性中，雌二醇似乎对于成瘾表型的发展和DA作用的减弱是必要的。我们假设，从NAC DA向AMPA传递的转变是成瘾发展的基础，而在女性，这种转变是加速的，雌二醇是发生这种转变所必需的。为了解决这一假设，在目标1中，我们将确定禁欲期间这种转变的时间点，以确定它是否支持女性成瘾的发展和加速的时间进程。在目标2中，我们将针对涉及的多巴胺和谷氨酸受体，在目标3中，我们将评估雌激素在其发育过程中的需求。这些结果不仅有助于我们了解与成瘾的发展和表达相关的神经生物学过程，而且还有助于了解性激素和卵巢激素如何影响这些过程。

DESCRIPTION (provided by applicant): Drug addiction is the leading cause of preventable death in the United States. Effective treatments are critically needed, but developing treatments is challenging because the underlying neurobiology of addiction varies over time as the disease progresses. Our work over the past 15 years has revealed important sex and hormone effects in the different phases of addiction suggesting that its underlying neurobiology may also vary between males and females. In the last 5-yr grant period we expanded our behavioral work to include studies of the neurobiology underlying sex differences. Now, in this competitive renewal, we turn to characterization of sex-specific behavioral and neurobiological changes that underlie the development of addiction. This is important because the vast majority of data on the neurobiology of cocaine addiction is based on short access self-administration studies conducted in males. Short access conditions (1-2 hr/day), however, by virtue of their stability, do not capture critical features of addiction in humans, including an enhanced motivation to use the drug and enhanced relapse vulnerability. Extended access procedures (6-24 hr/day) have been developed that produce these characteristics and reveal that the underlying neurobiology is different from that observed under short access procedures. An enhanced motivation for cocaine, as measured under a progressive-ratio schedule, has been used to define the development of addiction in rats. This characteristic develops over an abstinence period following extended, but not short access self- administration, and develops sooner in females compared to males. We recently showed that while dopamine (DA) D1 receptor signaling in the nucleus accumbens (NAc) is a critical mediator of motivation for cocaine following short access self-administration, once addiction is established, its role is diminished and glutamate AMPA/KA receptor signaling appears to be critically involved. In females, estradiol appears to be necessary for the development of an addicted phenotype and the shift to a diminished role for DA. We hypothesize that a shift from NAc DA to AMPA transmission underlies the development of addiction, and that in females, this shift is accelerated, and estradiol is necessary for it to occur. To address this hypothesis, in Aim 1 we will determine the time-point during abstinence for this shift to determine if it underlies the development of addiction and the accelerated time-course in females. In Aim 2, we will pin-point the dopamine versus glutamate receptors involved, and in Aim 3 we will evaluate the requirement of estradiol in its development. These results will greatly contribute to our understanding of not only the neurobiological processes relevant for the development and expression of addiction, but also how sex and ovarian hormones influence these processes.