Dopaminergic and glutamatergic mechanisms of cocaine addiction: sex differences

可卡因成瘾的多巴胺能和谷氨酸能机制：性别差异

• 批准号: 8245829
• 负责人: Wendy Jean Lynch
• 金额: $ 25.46万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245829
• 关键词: Abstinence; Animal Model; Animals; Behavior; Behavioral; Biological; Biological Process; Chronic; Cocaine; Cocaine Abuse; Cocaine Dependence; Cues; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; DARPP; Data; Development; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Drug abuse; Estrogen Replacements; Estrogens; Female; Female Adolescents; Foundations; Future; Glutamate Receptor; Glutamates; Goals; Gonadal Steroid Hormones; Health; Hormonal; Hormones; Hour; Infusion procedures; Maintenance; Mediating; Mitogen-Activated Protein Kinases; Modeling; Molecular; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR1 gene; Neurobiology; Nucleus Accumbens; Oral Contraceptives; Ovarian hormone; Pathway interactions; Pharmacotherapy; Phosphorylation; Postmenopause; Prevention strategy; Procedures; Process; Psychological reinforcement; Rattus; Receptor Signaling; Relapse; Relative (related person); Research; Rewards; Schedule; Self Administration; Sex Characteristics; Sexual Development; Signal Pathway; Signal Transduction; Staging; System; Techniques; Therapeutic; Tyrosine 3-Monooxygenase; Western Blotting; Woman; Work; addiction; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; base; cocaine exposure; innovation; kainate; male; men; neuroadaptation; neurotransmission; novel; phosphoprotein 32; preclinical study; sex

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.

描述（由申请人提供）：新兴数据表明，与男性相比，女性在可卡因成瘾的某些方面更容易受到伤害，这表明男女可能需要不同的策略来预防和治疗可卡因成瘾。该项目的主要目的是了解性和卵巢激素影响可卡因成瘾的不同方面和阶段的机械过程，以便更好地了解男性和女性中的可卡因成瘾。除多巴胺（DA）外，还提出，谷氨酸能信号失调的分子基础可能与可卡因的反应有关，尤其是在成瘾的后期阶段（即，在慢性过度使用过后和可卡因复发期间和在可卡因复发期间）。虽然有证据表明最初可卡因暴露后，性别和卵巢激素调节了中性脱脂脂肪脂能信号传导，但很少有有关成瘾后期的性别差异或谷氨酸能信号传导性别差异的信息，可能会导致雄性和女性对cocaine的反应不同。因此，介导可卡因反应的daergic和谷氨酸能过程可能会因成瘾阶段而有所不同，这是该项目的主要重点。在AIM 1中，我们将确定性别和激素影响的条件相关，重点是两个行为过程，这些过程被认为对于维持可卡因成瘾至关重要：可卡因增强和可卡因恢复。可卡因的加固将在24小时访问离散试验程序（4个可卡因输注/HR，1.5 mg/kg的可卡因输注）下进行渐进式收视时间表进行检查。在可卡因培养的和提示诱导的条件下，将检查可卡因的恢复原状。在AIM 2中，通过检查男性和雌性的介导可卡因增强和恢复介导对可卡因增强和恢复原状的相对贡献，可以通过检查D1和D2 DA受体的阻断以及AMPA/Kainate和NMDA谷氨酸受体的封锁作用。在目标3中，我们将确定在扩展访问自我给药后，伏调核中发生的神经适应是否相同或不同，男性和女性之间的关注于DA的标记（即酪氨酸酪氨酸羟化酶和Darpp-32）和glutamamate（pka nrpa n nrm1 of the pa paplation）和glur pa磷酸化和glurpa nrm1和glur pa papa pka磷酸化（即PKA磷酸化）。谷氨酸受体）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。这里提出的研究将使我们对成瘾的神经生物学基础的理解扩大，以包括女性的相关过程，它们将为开发性别特定的药物疗法提供急需的基础。公共卫生相关性：与男性和女性提出的研究将扩大我们对成瘾生物学基础的理解，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，研究的含义是，女性对可卡因的奖励作用具有增加的生物学脆弱性，并且关于雌激素的数据对青少年女性，女性可卡因虐待者服用避孕药和绝经后妇女对雌激素的替代具有影响。这些研究将为可卡因滥用，尤其是女性的荷尔蒙，药理和/或分子疗法的发展提供急需的基础。