TAAR 1 modulation of addiction-related effects of nicotine
TAAR 1 调节尼古丁成瘾相关效应
基本信息
- 批准号:9307798
- 负责人:
- 金额:$ 21.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-07-01 至 2019-06-30
- 项目状态:已结题
- 来源:
- 关键词:AbstinenceAgonistAminationAminesAmphetaminesAttenuatedBehaviorBehavioralBiochemicalBrain regionBupropionCessation of lifeClinicalCocaineCuesDataDevelopmentDopamineDopamine D2 ReceptorDopamine Uptake InhibitorsDoseDrug AddictionFDA approvedFemaleFutureHealth Care CostsIntravenousInvestigationKnock-outMaintenanceMediatingMethamphetamineMissionMusNeuronsNicotineNicotine DependenceNicotine WithdrawalNicotinic AgonistsNicotinic ReceptorsNorepinephrineOutcomePathway interactionsPharmacologyPharmacotherapyProceduresPublic HealthRattusReinforcement ScheduleResearchRewardsRiskRoleScheduleSelf AdministrationSelf-AdministeredSex CharacteristicsSignal TransductionSmokerSmokingStimulusSystemTestingTherapeuticTobaccoTobacco DependenceTobacco smokingTobacco useTrainingUnited States National Institutes of Healthaddictionbasebehavioral sensitizationcombatcost effectivedopamine transportermalemortalitynew therapeutic targetnicotine abusenicotine replacementnoveloverexpressionreceptorrelating to nervous systemreward circuitrysexsmoking cessationsuccesstransmission processvarenicline
项目摘要
ABSTRACT
Tobacco smoking remains a major public health concern globally. Although there are FDA-approved
therapeutic options available, they are far from adequate to maintain long-term smoking abstinence in most
smokers. Thus, discovering novel efficacious pharmacotherapies to aid in smoking cessation remains an
urgent clinical need. Nicotine, the major component in tobacco that is responsible for tobacco addiction,
stimulates the mesolimbic dopaminergic system via activating nicotinic acetylcholine receptors (nAChRs).
Nicotine replacement therapy and the nAChR partial agonist varenicline have achieved limited clinical success
by directly modulating the central nAChRs. Indirect modulation of dopaminergic system by non-dopaminergic
mechanism may also be able to modulate the addiction-related effects of nicotine. Trace amine associated
receptor 1 (TAAR 1) has emerged as a novel target for the development of potential pharmacotherapy to treat
drug addiction. In particular, the neuronal distribution of TAAR 1 overlaps with many key regions of the reward
pathway, and biochemical studies reveal robust interactions between TAAR 1 signaling and dopamine
transporters and D2 receptors. TAAR 1 agonists have been shown to attenuate several addiction-related
behavioral effects of cocaine and methamphetamine. However, it is unknown of the role of TAAR 1 in
mediating nicotine addiction. We recently observed that a selective TAAR 1 partial agonist, RO5263397,
markedly attenuates nicotine induced behavioral sensitization and the discriminative stimulus effects of
nicotine. The objective of the present application is to examine the hypothesis that TAAR 1 is a novel drug
target for the treatment of nicotine addiction. This hypothesis will be tested by pursuing two specific aims: 1)
examine the effects of TAAR 1 full agonist RO5166017 and partial agonist RO5263397 on nicotine self-
administration using both fixed ratio and progressive ratio schedules of reinforcement (Aim 1); 2) examine the
effects of RO5166017 and RO5263397 on nicotine-associated cue- and nicotine prime-induced reinstatement
of extinguished nicotine-seeking behavior (Aim 2). Collectively, the proposed studies systematically evaluate
the effects of TAAR 1 agonists on the addiction-related (e.g., reinforcing and reinstatement) effects of nicotine.
These data will provide valuable information on the role of TAAR 1 in mediating nicotine addiction. In addition,
data obtained in the proposed investigation may contribute to the identification of novel TAAR 1-based
pharmacotherapy for smoking cessation.
摘要
吸烟仍然是全球主要的公共卫生问题。尽管有FDA批准的
现有的治疗方案,它们远远不足以维持大多数人的长期戒烟
吸烟者。因此,发现新的有效的药物疗法来帮助戒烟仍然是一个
急切的临床需要。尼古丁是烟草中导致烟瘾的主要成分,
通过激活烟碱型乙酰胆碱受体(NAChRs)刺激中脑边缘多巴胺能系统。
尼古丁替代疗法和nAChR部分激动剂varenicline的临床成功有限
通过直接调节中枢nAChRs。非多巴胺能系统对多巴胺能系统的间接调节
这一机制也可能能够调节尼古丁成瘾的相关效应。相关的痕量胺
受体1(Taar1)已成为潜在药物治疗的新靶点。
吸毒成瘾。特别是,TAAR 1的神经元分布与奖赏的许多关键区域重叠
途径和生化研究表明TAAR-1信号和多巴胺之间有很强的相互作用
转运蛋白和D2受体。TAAR-1激动剂已被证明可以减轻几种与成瘾有关的疾病
可卡因和甲基苯丙胺的行为影响。然而,目前尚不清楚TAAR-1在
调节尼古丁成瘾。我们最近观察到一种选择性的TAAR 1部分激动剂RO5263397,
显著减弱尼古丁诱导的行为敏感化和对烟碱的辨别刺激效应
尼古丁。本申请的目的是检验TAAR-1是一种新药的假设
尼古丁成瘾治疗的靶点。这一假设将通过追求两个具体目标来检验:1)
检测TAAR-1全激动剂RO5166017和部分激动剂RO5263397对尼古丁自身的影响
使用固定比率和累进比率增强表进行管理(目标1);2)检查
RO5166017和RO5263397对尼古丁相关线索和尼古丁原诱导的恢复的影响
消除尼古丁寻觅行为(目标2)。总的来说,拟议的研究系统地评估了
TAAR-1激动剂对尼古丁成瘾相关(例如,增强和恢复)效应的影响。
这些数据将为TAAR1在调节尼古丁成瘾中的作用提供有价值的信息。此外,
在拟议的调查中获得的数据可能有助于鉴定新的基于TAAR 1的
戒烟的药物疗法。
项目成果
期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Interleukin-1 receptor-associated kinase 4 (IRAK4) in the nucleus accumbens regulates opioid-seeking behavior in male rats.
- DOI:10.1016/j.bbi.2021.12.014
- 发表时间:2022-03
- 期刊:
- 影响因子:0
- 作者:Wu R;Liu J;Vu J;Huang Y;Dietz DM;Li JX
- 通讯作者:Li JX
TAAR1 in Addiction: Looking Beyond the Tip of the Iceberg.
- DOI:10.3389/fphar.2018.00279
- 发表时间:2018
- 期刊:
- 影响因子:5.6
- 作者:Liu JF;Li JX
- 通讯作者:Li JX
Activation of trace amine-associated receptor 1 attenuates nicotine withdrawal-related effects.
- DOI:10.1111/adb.13075
- 发表时间:2022-01
- 期刊:
- 影响因子:3.4
- 作者:Wu R;Liu J;Johnson B;Huang Y;Zhang Y;Li JX
- 通讯作者:Li JX
TAAR1 and Psychostimulant Addiction.
- DOI:10.1007/s10571-020-00792-8
- 发表时间:2020-03
- 期刊:
- 影响因子:4
- 作者:Liu J;Wu R;Li JX
- 通讯作者:Li JX
Modulating reconsolidation and extinction to regulate drug reward memory.
- DOI:10.1111/ejn.14072
- 发表时间:2019-08
- 期刊:
- 影响因子:0
- 作者:Liu JF;Tian J;Li JX
- 通讯作者:Li JX
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Jun-Xu Li其他文献
Jun-Xu Li的其他文献
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LPA5 拮抗剂镇痛药的开发
- 批准号:
10638278 - 财政年份:2023
- 资助金额:
$ 21.22万 - 项目类别:
TAAR 1 modulation of addiction-related effects of nicotine
TAAR 1 调节尼古丁成瘾相关效应
- 批准号:
9182100 - 财政年份:2016
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9186516 - 财政年份:2013
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IMIDAZOLINE I2 RECEPTORS AS TARGETS FOR THE TREATMENT OF PAIN
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9170057 - 财政年份:2013
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