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，这表明女性和男性在预防和治疗可卡因成瘾方面可能需要不同的策略。该项目的主要目标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情况。除了多巴胺（DA）外，已经提出谷氨酸能信号失调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阶段（即长期过度使用和可卡因复发期间）。虽然有证据表明，在初次接触可卡因后，性激素和卵巢激素调节中脑边缘能信号，但关于成瘾后期阶段的性别差异或可能导致男性和女性对可卡因反应不同的谷氨酸能信号的性别差异的信息很少。因此，作为成瘾阶段的功能，调节可卡因反应的DAergic和glutamatic过程在男性和女性之间可能存在差异的可能性是本项目的主要焦点。在目标1中，我们将确定性别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小时离散试验程序（4次可卡因输注/小时，1.5 mg/kg可卡因输注）下，在延长可获得性自我给药之前和之后，将按照渐进比率计划检查可卡因强化。在可卡因启动和线索诱导条件下，在延长自我给药途径后，将检查是否恢复可卡因。在Aim 2中，通过检测阻断伏隔核中D1和D2 DA受体以及AMPA/kainate和NMDA谷氨酸受体的作用，将确定雄性和雌性中DAergic和glutamic信号在介导可卡因强化和恢复中的相对贡献。在目标3中，我们将确定在长时间自我给药后发生在伏隔核中的神经适应在男性和女性之间是否相同或不同，重点关注DA标记(即，PKA磷酸化酪氨酸羟化酶和DARPP-32)和谷氨酸（PKA磷酸化NMDA和AMPA谷氨酸受体的NR1和GluR1亚基）信号以及ERK信号，因为这一途径需要DA和谷氨酸受体的同时激活。本文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，并将为发展性别特异性药物治疗提供急需的基础。公共卫生相关性：这里提出的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学过程。迄今为止的研究表明，妇女对可卡因的有益作用具有更大的生物学脆弱性，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妇女和服用雌激素替代的绝经后妇女有影响。这些研究将为开发以激素、药理学和/或分子为基础的治疗可卡因滥用，特别是妇女可卡因滥用的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.