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: 7588042
• 负责人: Wendy Jean Lynch
• 金额: $ 26.51万
• 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 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7588042
• 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; Data; Development; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Drug abuse; Estrogen Replacements; Estrogens; Extracellular Signal Regulated Kinases; Female; Female Adolescents; Foundations; Future; Glutamate Receptor; Glutamates; Goals; Gonadal Steroid Hormones; 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; public health relevance; 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）：新数据表明，女性在可卡因成瘾的某些方面比男性更容易受到影响，这表明女性和男性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。除了多巴胺 (DA) 之外，有人提出，谷氨酸能信号失调的分子基础可能不同地参与调节可卡因的反应，特别是在成瘾的后期阶段（即长期过度使用后和可卡因复发期间）。虽然有证据表明，初次接触可卡因后，性别和卵巢激素对中脑边缘 DAergic 信号进行调节，但关于成瘾后期的性别差异或谷氨酸能信号的性别差异（可能导致男性和女性对可卡因的反应不同）的信息很少。因此，作为成瘾阶段的函数，介导可卡因反应的 DAergic 和 glutamatergic 过程可能在男性和女性之间有所不同，因此是该项目的主要焦点。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种行为过程：可卡因强化和可卡因恢复。可卡因强化将在24小时访问离散试验程序（4次可卡因输注/小时，1.5mg/kg可卡因输注）下的扩展访问自我给药之前和之后按照渐进比例时间表进行检查。在可卡因引发和提示诱导的条件下延长自我给药后，将检查可卡因恢复情况。在目标 2 中，通过检查伏隔核中 D1 和 D2 DA 受体以及 AMPA/红藻氨酸和 NMDA 谷氨酸受体的阻断效果，确定男性和女性中 DAergic 和谷氨酸信号在介导可卡因强化和恢复中的相对贡献。在目标 3 中，我们将确定男性和女性在延长自我给药后伏隔核中发生的神经适应是否相同或不同，重点关注 DA 标记（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 NR1 和 GluR1 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 和谷氨酸受体同时激活。这里提出的研究将扩大我们对成瘾神经生物学基础的理解，包括女性的相关过程，并且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：这里提出的针对男性和女性的研究将扩大我们对成瘾生物学基础的理解，包括与女性成瘾发展和表达相关的生物过程。迄今为止的研究表明，女性对可卡因的奖励作用的生物脆弱性增加，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以及接受雌激素替代的绝经后妇女具有影响。这些研究将为可卡因滥用（尤其是女性滥用）的激素、药理学和/或分子疗法的开发提供急需的基础。