Dopaminergic and glutamatergic mechanisms of cocaine addiction: sex differences

描述（由申请人提供）：新出现的数据表明，女性在可卡因成瘾的某些方面比男性更脆弱，这表明女性和男性可能需要不同的预防和治疗可卡因成瘾的策略。该项目的主要目的是了解性激素和卵巢激素影响可卡因成瘾不同方面和阶段反应的机制过程，以便更好地了解男性和女性的可卡因成瘾。除了多巴胺（DA）之外，已经提出失调的多巴胺能信号传导的分子基础可能差异性地参与调节对可卡因的响应，特别是在成瘾的后期阶段（即，在长期过量使用和可卡因复吸期间）。虽然有证据表明，性别和卵巢激素调制的中脑边缘DA能信号后，最初的可卡因暴露，非常少的信息是在成瘾的后期阶段的性别差异或性别差异，可能会导致男性和女性的反应不同的可卡因。因此，作为成瘾阶段的函数，介导对可卡因的反应的DA能和多巴胺能过程在男性和女性之间可能不同的可能性是该项目的主要焦点。在目标1中，我们将确定性和激素影响相关的条件，重点关注被认为对维持可卡因成瘾至关重要的两个行为过程：可卡因强化和可卡因恢复。在24小时连续试验程序（4次可卡因输注/小时，1.5 mg/kg可卡因输注）下，在扩展给药自我给药之前和之后，将根据累进比时间表检查可卡因强化。在可卡因预激和线索诱导条件下，将在扩展使用自我给药后检查可卡因恢复情况。在目的2中，将通过检查阻断D1和D2 DA受体以及AMPA/红藻氨酸和NMDA谷氨酸受体在中脑核中的作用，确定雄性和雌性中DA能和NMDA能信号传导在介导可卡因强化和恢复中的相对贡献。在目标3中，我们将确定在扩展进入自我施用后在丘脑核中发生的神经适应在男性和女性之间是相同还是不同，重点是DA的标志物（即，酪氨酸羟化酶和DARPP-32的PKA磷酸化）和谷氨酸（NMDA和AMPA谷氨酸受体的NR 1和GluR 1亚基的PKA磷酸化）信号传导以及ERK信号传导，因为该途径需要DA和谷氨酸受体的同时激活。这里提出的研究将扩大我们对成瘾的神经生物学基础的理解，包括女性的相关过程，它们将为性别特异性药物治疗的发展提供急需的基础。公共卫生相关性：这里提出的研究与男性和女性将扩大我们的理解成瘾的生物学基础，包括相关的发展和表达的成瘾在女性的生物过程。到目前为止的研究表明，女性对可卡因的奖励效应有更大的生物脆弱性，关于雌激素的数据对青春期女性、服用避孕药的可卡因滥用者和绝经后女性的雌激素替代有影响。这些研究将为开发用于可卡因滥用（尤其是女性）的激素、药理学和/或分子疗法提供急需的基础。

DESCRIPTION (provided by applicant): Emerging data demonstrate that women are more vulnerable on certain aspects of cocaine addiction than are men, suggesting that women and men may require different strategies for the prevention and treatment of cocaine addiction. The primary objective of this project is to understand the mechanistic process by which sex and ovarian hormones influence responding on different aspects and stages of cocaine addiction in order to better understand cocaine addiction in males and females. In addition to dopamine (DA), it has been proposed that the molecular underpinnings of dysregulated glutamatergic signaling may be differentially involved in modulating responding for cocaine, particularly at later stages of addiction (i.e., following chronic excessive use and during cocaine relapse). While there is evidence demonstrating sex and ovarian hormone modulation of mesolimbic DAergic signaling following initial cocaine exposure, very little information is available on sex differences at later stages of addiction or on sex differences in glutamatergic signaling that may cause males and females to respond differently to cocaine. The possibility that the DAergic and glutamatergic processes that mediate responding for cocaine may differ between males and females as a function of stage of addiction is thus a primary focus of this project. In Aim 1 we will determine the conditions under which sex and hormonal influences are relevant focusing on two behavioral processes that are thought to be critical for maintaining cocaine addiction: cocaine reinforcement and cocaine reinstatement. Cocaine reinforcement will be examined under a progressive-ratio schedule prior to and following extended access self-administration under a 24- hr access discrete trial procedure (4 cocaine infusions/hr, 1.5 mg/kg infusions of cocaine). Cocaine reinstatement will be examined following extended access self-administration under both cocaine-primed and cue-induced conditions. In Aim 2 the relative contribution of DAergic and glutamatergic signaling in mediating cocaine reinforcement and reinstatement will be determined in both males and females by examining the effects of blockade of D1 and D2 DA receptors and AMPA/kainate and NMDA glutamate receptors in the nucleus accumbens. In Aim 3 we will determine whether the neuroadaptations that occur in the nucleus accumbens following extended access self-administration are the same or different between males and females focusing on markers of DA (i.e., PKA phosphorylation of tyrosine hydroxylase and DARPP-32) and glutamate (PKA phosphorylation of NR1 and GluR1 subunits of the NMDA and AMPA glutamate receptors) signaling as well as ERK signaling because this pathway requires coincident activation by DA and glutamate receptors. The studies proposed here will expand our understanding of the neurobiological basis of addiction to include the relevant processes in females, and they will provide a much needed foundation for the development of sex-specific pharmacotherapy. PUBLIC HEALTH RELEVANCE: The studies proposed here with both males and females will expand our understanding of the biological basis of addiction to include the biological processes relevant for the development and expression of addiction in females. The implication of studies thus far is that women have an increased biological vulnerability to cocaine's rewarding effects, and the data with regard to estrogen have implications for adolescent females, women cocaine abusers taking birth control pills, and postmenopausal women on estrogen replacement. These studies will provide a much needed foundation for the development of hormonal, pharmacological, and/or molecular based therapeutics for cocaine abuse, especially in women.