Hypothalamic-Pituitary-Adrenal Axis and Alcoholism

下丘脑-垂体-肾上腺轴和酒精中毒

• 批准号: 8071116
• 负责人: GARY S WAND
• 金额: $ 53.07万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8071116
• 关键词: Affinity; Age; Alcoholism; Amphetamines; Anxiety; Binding; Binding Sites; Clinical; Cocaine; Corpus striatum structure; Dimensions; Disease; Dopamine; Dopamine D2 Receptor; Epidemiology; Estradiol; Ethanol; Etiology; Family history of; Female; Funding; Gender; Gonadal Steroid Hormones; High Prevalence; Household; Human; Huntington Disease; Image; Imaging Techniques; Individual; Ligands; Literature; Measurement; Measures; Methods; Methylphenidate; Neurobiology; Neurotic Disorders; Obsessive-Compulsive Disorder; Parkinson Disease; Personality; Pharmaceutical Preparations; Physiological; Positron-Emission Tomography; Procedures; Progesterone; Progress Reports; Raclopride; Request for Proposals; Research Personnel; Rewards; Risk; Risk Factors; Role; Scanning; Schizophrenia; Sex Characteristics; Stress; Surveys; System; Techniques; Testosterone; Ventral Striatum; Woman; addiction; alcohol abuse therapy; alcohol effect; alcohol measurement; alcohol research; alcohol response; alcohol sensitivity; alcohol use disorder; base; clinically relevant; drug of abuse; human subject; hypothalamic-pituitary-adrenal axis; male; men; neuropsychiatry; neurosteroids; pregnenolone sulfate; receptor

DESCRIPTION (provided by applicant): Sex differences have been observed in the clinical presentation of and vulnerability to various neuropsychiatric illnesses involving the striatum, including Parkinson's disease (Scott et al., 2000) and schizophrenia (Aleman et al., 2003). The striatum also is important in the rewarding effects of alcohol and other drugs of abuse. Interestingly, there is a higher prevalence of alcohol use disorders in males than females (National Household Survey, 2004). In attempts to elucidate the neurobiology underlying disorders that involve the striatum, researchers have thus focused on sex differences in the striatal dopaminergic system. We have recently demonstrated robust sex differences in ventral striatum dopamine release (DAR) following amphetamine administration in healthy, age-matched men and women. This is the first demonstration of gender-based DAR differences in human subjects. In this competitive renewal proposal, we are requesting funds to extend these important findings. Using PET imaging, we have established our ability to measure ethanol-induced DAR as oppose to the standard method of employing a stimulant drug to provoke DAR. Measurement of ethanol-induced DAR has greater utility for the field of alcohol research since it employs the actual substance administered by individuals with alcohol use disorders and does not rely on extrapolation from the techniques that administer amphetamine, methylphenidate or cocaine. Using PET imaging, we propose to compare the magnitude of ethanol-induced mesolimbic dopamine release in men and women. We will also examine the relationship between alcohol sensitivity (subjective and physiologic measures) and mesolimbic dopamine release. Finally, we will examine possible mechanisms for gender-based differences in dopamine release by studying the relationship between baseline and ethanol-stimulated sex hormones and neurosteroids with mesolimbic dopamine release. If our hypotheses of the roles of sex hormones/neurosteroid in DAR are supported, these findings will be important in understanding the etiology, epidemiology and treatment of alcohol abuse disorders. The scientific and clinical importance of the results also extends beyond addiction to include other disorders involving the striatum, such as schizophrenia, Parkinson's disease, Huntington's disease (Tamir et al., 1969), and obsessive-compulsive disorder (Bogetto et al., 1999).

描述（由申请人提供）：在涉及纹状体的各种神经精神疾病的临床表现和脆弱性中，已经观察到性别差异，包括帕金森氏病（Scott等，2000）和精神分裂症（Aleman等，2003）。纹状体在酒精和其他滥用药物的奖励作用中也很重要。有趣的是，男性的酒精使用障碍的患病率高于女性（全国家庭调查，2004年）。为了阐明涉及纹状体的神经生物学的潜在疾病，研究人员因此重点关注纹状体多巴胺能系统的性别差异。最近，在健康，年龄匹配的男性和女性中给药后，我们最近显示了腹膜多巴胺释放（DAR）的牢固性别差异。这是人类受试者基于性别的DAR差异的首次演示。在这个竞争性更新提案中，我们要求资金扩大这些重要发现。使用PET成像，我们确定了测量乙醇诱导的DAR的能力，而不是使用刺激性药物引起DAR的标准方法。乙醇诱导的DAR的测量对酒精研究领域具有更大的效用，因为它采用了酒精使用障碍的个体给予的实际物质，并且不依赖于施用苯丙胺，甲基苯甲酸酯或可卡因的技术外推。使用PET成像，我们建议比较男性和女性中乙醇诱导的中唇多巴胺释放的大小。我们还将检查酒精敏感性（主观和生理测量）与中唇多巴胺释放之间的关系。最后，我们将通过研究基线与乙醇刺激的性激素与神经蛋白酶释放的基线与乙醇刺激的性激素与神经固醇之间的关系，研究多巴胺释放中基于性别的差异的可能机制。如果我们对性激素/神经固醇在DAR中的作用的假设得到了支持，那么这些发现对于理解酗酒障碍的病因，流行病学和治疗将很重要。结果的科学和临床重要性也超出了成瘾的范围，包括涉及纹状体的其他疾病，例如精神分裂症，帕金森氏病，亨廷顿氏病（Tamir等，1969）和强迫症（Bogetto等人，1999年）。

项目成果

Striatal dopamine release and family history of alcoholism.

纹状体多巴胺释放和酗酒家族史。

• DOI: 10.1111/j.1530-0277.2006.00130.x
• 发表时间: 2006
• 期刊: Alcoholism, clinical and experimental research
• 作者: Munro,CynthiaA;McCaul,MaryE;Oswald,LynnM;Wong,DeanF;Zhou,Yun;Brasic,James;Kuwabara,Hiroto;Kumar,Anil;Alexander,Mohab;Ye,Weiguo;Wand,GaryS
• 通讯作者: Wand,GaryS

Reports of drinking to self-medicate anxiety symptoms: longitudinal assessment for subgroups of individuals with alcohol dependence.

• DOI: 10.1002/da.22024
• 发表时间: 2013-02
• 期刊: DEPRESSION AND ANXIETY
• 影响因子: 7.4
• 作者: Crum, Rosa M.;La Flair, Lareina;Storr, Carla L.;Green, Kerry M.;Stuart, Elizabeth A.;Alvanzo, Anika A. H.;Lazareck, Samuel;Bolton, James M.;Robinson, Jennifer;Sareen, Jitender;Mojtabai, Ramin
• 通讯作者: Mojtabai, Ramin

Glucocorticoid-induced loss of DNA methylation in non-neuronal cells and potential involvement of DNMT1 in epigenetic regulation of Fkbp5.

• DOI: 10.1016/j.bbrc.2012.03.035
• 发表时间: 2012-04-13
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Yang X;Ewald ER;Huo Y;Tamashiro KL;Salvatori R;Sawa A;Wand GS;Lee RS
• 通讯作者: Lee RS

Genetic association of FKBP5 and CRHR1 with cortisol response to acute psychosocial stress in healthy adults.

• DOI: 10.1007/s00213-012-2956-x
• 发表时间: 2013-05
• 期刊: PSYCHOPHARMACOLOGY
• 影响因子: 3.4
• 作者: Mahon, Pamela Belmonte;Zandi, Peter P.;Potash, James B.;Nestadt, Gerald;Wand, Gary S.
• 通讯作者: Wand, Gary S.

Endogenous opioid activity is associated with obsessive-compulsive symptomology in individuals with a family history of alcoholism.

内源性阿片类药物活性与有酗酒家族史的个体的强迫症状有关。

• DOI: 10.1016/s0893-133x(99)00149-9
• 发表时间: 2000
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
• 作者: Mangold,DL;Peyrot,M;Giggey,P;Wand,GS
• 通讯作者: Wand,GS