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，在可卡因成瘾的某些方面，女性比男性更容易受到伤害，这表明女性和男性可能需要不同的战略来预防和治疗可卡因成瘾。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的反应的机制过程，以便更好地了解男性和女性的可卡因成瘾。除多巴胺(DA)外，谷氨酸能信号失控的分子基础可能不同地参与调节对可卡因的反应，特别是在成瘾的后期(即，在慢性过量使用和可卡因复发期间)。虽然有证据表明，在最初的可卡因暴露后，性别和卵巢激素对中边缘DAR能信号的调节，但关于成瘾后期的性别差异或谷氨酸能信号的性别差异的信息很少，这可能会导致男性和女性对可卡因的不同反应。因此，作为成瘾阶段的功能，调节对可卡因的反应的多巴能和谷氨酸能过程在男性和女性之间可能有所不同，这是该项目的主要重点。在目标1中，我们将确定性别和荷尔蒙影响相关的条件，重点放在两个被认为对维持可卡因成瘾至关重要的行为过程：可卡因强化和可卡因恢复。将在24小时连续试验程序(每小时注射4次可卡因，注射1.5毫克/公斤可卡因)下，在延长准入自我给药之前和之后，按照累进比率时间表检查可卡因强化情况。在可卡因引发和线索诱导的条件下，将在延长准入自我给药后检查可卡因的恢复情况。在目标2中，将通过阻断伏核中的D_1和D_2多巴胺受体以及AMPA/海人藻酸和N-甲基-D-天冬氨酸和N-甲基-D-天冬氨酸受体的作用，来确定DA能和谷氨酸能信号在介导可卡因强化和恢复过程中的相对作用。在目标3中，我们将确定大通道自我给药后伏隔核内发生的神经适应在雄性和雌性之间是否相同或不同，重点放在DA(即酪氨酸羟基酶和DARPP-32的PKA磷酸化)和谷氨酸(NMDA和AMPA谷氨酸受体的NR1和GluR1亚单位的PKA磷酸化)信号以及ERK信号上，因为这一通路需要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，并将为开发针对性别的药物治疗提供亟需的基础。公共卫生相关性：这里提出的对男性和女性的研究将扩大我们对成瘾的生物学基础的理解，包括与女性成瘾的发展和表达相关的生物过程。到目前为止的研究表明，女性对可卡因的有益作用有更大的生物脆弱性，有关雌激素的数据对青春期女性、服用避孕药的女性可卡因滥用者和接受雌激素替代的绝经后女性有影响。这些研究将为开发荷尔蒙、药理学和/或基于分子的可卡因滥用疗法提供急需的基础，特别是在妇女中。

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.