Dopaminergic and Glutamatergic Mechanisms of Cocaine Addiction: Sex Differences

项目摘要 物质使用障碍（SUD）是一种主要的流行病，其影响可能对妇女特别严重。一 最突出的例子是“伸缩效应”，其中女性符合SUD和/或寻求 与男性相比，使用药物的时间更短。已报告多种药物的这种效应 包括精神兴奋剂和阿片类药物。我们从上一个资助期获得的数据表明， 在可卡因使用障碍（CUD）大鼠模型中也发生了类似的现象，雌性大鼠出现了 成瘾样表型在禁欲期间比男性更快。我们将成瘾样表型定义为 对可卡因的强烈动机该特征在延长使用后的禁欲中发展（ExA， >6小时/天），但不是短距离（ShA）自我给药，并且像人类的SUD一样，它代表了持久的转变 走向更高的激励状态。我们的数据表明，7天的禁欲足以诱导这种情况。 在雌性表型中，而雄性需要14天。禁欲7天后测试的雌性也显示 更大的可卡因强迫使用，如使用惩罚程序测量，但通过14天的禁欲， 男性达到女性水平。我们在此竞争性R 01更新应用程序中的目标是 分子位移的基础伸缩效应，并确定是否，类似于人类， 阿片类药物也会产生套叠效应。我们的主要假设是，从核的转移， (NAc)多巴胺D1受体（D1 R）到谷氨酸AMPA受体（AMPAR）在戒断过程中发生得更快， 女性多于男性，这是伸缩效应的基础。这一假设是基于我们的发现， 随着成瘾样表型的发展，可卡因使用的动机机制在两个方面都发生了变化， 男性和女性从NAc D1 R到AMPAR，在女性中，雌二醇是发展所必需的。 这种表型和NAc D1 R作用减弱的转变。在目的1中，使用NAc的位点特异性拮抗作用， D1 R和AMPAR，我们将确定随着增强的 可卡因的动机和强迫性可卡因使用。将在ExA自我给药后检查效应 和1天的禁欲，这不会诱导成瘾样表型或分子转变，在任何性别，或7- 禁欲的天数，这将在雌二醇的雌性中诱导这种表型和分子转变，但在雄性中不会 或没有雌二醇的女性。在目标2中，我们将使用RNA和ChIP测序来测试雌激素 受体调节伴随成瘾样表型发展的转录事件。 最后，在目标3中，我们将使用ExA芬太尼自我给药程序优化研究性别差异 为了验证这一假设，与人类相似，雌性大鼠更快地发展出阿片类成瘾样表型， 比男性更容易禁欲。这些研究将提供全新的信息的机制， 的伸缩效应，并确定可能的目标，以防止其发生在妇女。他们还将建立 阿片类药物的伸缩效应的生物学基础。

PROJECT SUMMARY Substance use disorder (SUD) is a major epidemic, and its impact may be particularly severe for women. One of the most striking examples is “the telescoping effect” wherein women meet criteria for SUD and/or seek treatment after fewer years of drug use as compared to men. This effect has been reported for multiple drug classes, including psychostimulants and opioids. Our data obtained from the previous funding period establish that a similar phenomenon occurs in a rat model of cocaine use disorder (CUD) with females developing an addiction-like phenotype sooner during abstinence than males. We have defined an addiction-like phenotype as an enhanced motivation for cocaine. This feature develops over abstinence following extended-access (ExA, >6-hr/day) but not short-access (ShA) self-administration, and like SUD in humans, it represents a lasting shift toward a higher motivational state. Our data show that 7 days of abstinence is sufficient for inducing this phenotype in females, whereas males require 14 days. Females tested after 7 days of abstinence also display greater compulsive cocaine use, as measured using a punishment procedure, but by 14 days of abstinence, males reach the female-level. Our goals with this competitive R01 renewal application are to characterize molecular shifts that underlie the telescoping effect, and to determine whether, similar to humans, the telescoping effect also occurs with opioids. Our primary hypothesis is that a shift from nucleus accumbens (NAc) dopamine D1 receptors (D1R) to glutamate AMPA receptors (AMPAR) occurs sooner during abstinence in females than males and underlies the telescoping effect. This hypothesis is based on our findings showing that following the development of an addiction-like phenotype, the mechanisms motivating cocaine use shift in both males and females from NAc D1R to AMPAR, and that in females, estradiol is necessary for the development of this phenotype and the shift to a diminished role of NAc D1R. In Aim 1, using site-specific antagonism of NAc D1R and AMPAR, we will determine mechanistic shifts that occur with the development of an enhanced motivation for cocaine and compulsive cocaine use. Effects will be examined following ExA self-administration and 1-day of abstinence, which will not induce an addiction-like phenotype or molecular shift in either sex, or 7- days of abstinence, which will induce this phenotype and molecular shift in females with estradiol, but not males or females without estradiol. In Aim 2, we will use RNA- and ChIP-sequencing to test the hypothesis that estrogen receptors regulate the transcriptional events that accompany the development of an addiction-like phenotype. Finally, in Aim 3, we will use an ExA fentanyl self-administration procedure optimized for studying sex differences to test the hypothesis that, similar to humans, female rats develop an opioid addiction-like phenotype sooner during abstinence than males. These studies will provide entirely novel information of the mechanism underlying the telescoping effect and identify possible targets to prevent its occurrence in women. They will also establish the biological basis for the telescoping effect with opioids.