Sex differences in the aversive effects of kappa-opioid receptor activation

κ-阿片受体激活的厌恶效应存在性别差异

基本信息

批准号：
8444087
负责人：
ELENA H CHARTOFF
金额：
$ 7.9万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8444087
关键词：
Address Affect Affective Agonist Alcohol abuse Anhedonia Attenuated Behavior Behavioral Binding Biological Brain Brain region Cavia Chronic Coupling Data Dependence Drug Addiction Drug abuse Dynorphins Exposure to FOS gene Female Foundations Future GRK Gender Role Goals Gonadal Hormones Gonadal Steroid Hormones Human Hypothalamic structure In Situ Hybridization Intake Knowledge Laboratories Laboratory Animals Lead Ligands Link Measurement Mediating Mental Depression Messenger RNA Molecular Nature Neuropeptides Operant Conditioning Opioid Outcome Pathway interactions Pharmaceutical Preparations Pharmacodynamics Phase Phosphorylation Pilot Projects Play Procedures Rattus Receptor Activation Regulation Relapse Reporting Research Rewards Rodent Role Self Stimulation Sex Characteristics Stimulus Stress Structure of terminal stria nuclei of preoptic region System Testing Time TimeLine Training Western Blotting Woman Writing addiction base craving depressive symptoms disturbance in affect drug addict drug of abuse drug withdrawal effective therapy immunoreactivity indexing kappa opioid receptors mRNA Expression male men mood regulation negative emotional state neuroadaptation paraventricular nucleus prodynorphin public health relevance receptor receptor function research and development response sex

项目摘要

DESCRIPTION (provided by applicant): This R03 proposal was written in response to PA-11-049, "Women and Sex/Gender Differences in Drug and Alcohol Abuse/Dependence". Growing evidence shows that drug-dependent women express greater negative affect than men (1, 2, 3, 4) and negative emotional states such as stress and depression are more likely to trigger craving and relapse in women (5, 6). Research in males has shown that aversive and depressive-like states are mediated, in part, by the neuropeptide dynorphin, an endogenous ligand that acts at kappa opioid receptors (7). Chronic exposure to drugs of abuse promotes the synthesis and release of dynorphin that is coincident with the emergence of depressive-like effects (8, 9, 10). The purpose of this proposal is to examine sex differences in the regulation and role of kappa-opioid receptors in mediating negative affective states in rats. Understanding the biological basis of these differences is crucial to developing better treatments for both men and women. Chartoff and colleagues have begun to examine the role of kappa-opioid receptors in males and females using intracranial self-stimulation (ICSS), an operant conditioning paradigm that is sensitive to increases or decreases in reward function "in real time". Kappa- opioid receptor agonists increase stimulation thresholds in ICSS, which is indicative of a decrease in reward function (anhedonia). Preliminary results show that females are less sensitive to the threshold-increasing effects of the kappa-opioid receptor agonist U50,488. Given that the majority of sex differences have been linked to actions of circulating gonadal steroid hormones, this proposal uses two complementary approaches to test the role of gonadal hormones in kappa-opioid receptor function. First, the effects of U50,488 on ICSS thresholds will be determined in gonadectomized rats. If gonadectomy abolishes the sex difference in the depressive-like effects of KOR activation, then it is likely that activational effects of gonadal steroid hormones are required. Although a fairly basic question, it is fundamental to the understanding of mood dysfunction in drug addiction. Second, the role of sex and gonadal steroid hormones on kappa-opioid receptor mRNA levels and U50,488-induced coupling to downstream effectors will be determined within brain regions that regulate reward function. If receptor levels or coupling are modulated by sex or sex hormones, then it is likely that differences in the behavioral effects of kappa-opioid receptor activation are due, in part, to receptor pharmacodynamics. Data from these studies will lead to a better understanding of how kappa-opioid receptors regulate affective states in males and females and will form a foundation for future research on sex differences in the role of kappa-opioid receptors in drug addiction.

描述（由申请人提供）：该R03提案是针对PA-11-049，“毒品和酒精滥用/依赖性的妇女以及性别/性别差异”而编写的。越来越多的证据表明，依赖药物的女性比男性（1、2、3、4）表现出更大的负面影响，而压力和抑郁等负面情绪状态更有可能引发女性的渴望和复发（5，6）。对男性的研究表明，厌恶和抑郁状态是由神经肽dynorphin介导的，神经肽Dynorphin是一种在Kappa阿片类受体上作用的内源性配体（7）。长期暴露于滥用药物会促进与抑郁样作用的出现相吻合（8、9、10）的合成和释放。该提案的目的是检查Kappa-阿片受体在大鼠中介导负面情感状态中的调节和作用中的性别差异。了解这些差异的生物学基础对于为男女开发更好的治疗至关重要。 Chartoff及其同事已经开始使用颅内自刺激（ICS）（ICSS）来检查Kappa-阿片受体在男性和女性中的作用，这是一种操作范围，对奖励功能的增加或减少“实时”。 Kappa-阿片类药物受体激动剂增加ICS中的刺激阈值，这表明奖励功能降低（ANHEDONIA）。初步结果表明，女性对kappa-阿片受体激动剂U50,488的阈值增长效应的敏感性较小。鉴于大多数性别差异与循环性腺类固醇激素的作用有关，因此该提案采用了两种互补方法来检验性腺激素在Kappa-阿片类受体功能中的作用。首先，将在Gonadectomized大鼠中确定U50,488对ICSS阈值的影响。如果性腺切除术废除了Kor激活的抑郁样作用的性别差异，那么可能需要性腺类固醇激素的活化作用。尽管这是一个相当基本的问题，但这是对吸毒成瘾中情绪功能障碍的理解至关重要的。其次，在调节奖励功能的大脑区域内，将确定性和性腺类固醇激素对Kappa-阿片受体mRNA水平和U50,488诱导的耦合与下游效应子的作用。如果受体水平或耦合是通过性别或性激素调节的，那么Kappa-阿片受体激活的行为影响差异可能部分归因于受体药效学。来自这些研究的数据将使人们更好地了解Kappa-阿片类受体如何调节男性和女性的情感状态，并将为对Kappa-阿片类受体在药物成瘾中作用的性别差异的未来研究奠定基础。