Brain Cannabinoid Signaling: Selectivity and Adaptation

大脑大麻素信号传导:选择性和适应

基本信息

  • 批准号:
    7741166
  • 负责人:
  • 金额:
    $ 29.9万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2002
  • 资助国家:
    美国
  • 起止时间:
    2002-05-01 至 2011-07-31
  • 项目状态:
    已结题

项目摘要

69-tetrahydrocannabinol (THC), the psychoactive component of marijuana, produces a variety of effects by activating cannaibinoid CBl receptors (CB1R) in specific CNS regions. THC is widely used illicitly for its psychoactive properties, which can lead to addiction, and is the primary component of antiemetic, appetite stimulating and anti-spasticity medications. Chronic THC use produces tolerance and dependence, which might contribute to addiction and limit the therapeutic use of cannabinoids. Our previous studies revealed brain region-specific CB1R desensitization and downregulation after THC administration, and this receptor neuroadaptation was associated with tolerance to in vivo effects. The proposed studies will elucidate the role of specific signaling proteins, J3-arrestin and 6FosB in regulation of acute and chronic CB1R signaling using mouse models with abrogated or overexpressed proteins. CBl R function will be assessed by functional neuroanatomy and biochemical pharmacology. Parallel in vivo studies will determine whether altered CB1R signaling translates into behavioral and physiological effects. Specific Aim 1 will assess CB1R function and in vivo effects in wild-type and J3-arrestin-2 null mice to test the hypothesis that J3-arrestin regulates acute and chronic CB1R signaling, THC-mediated in vivo effects (antinociception, locomotor inhibition, catalepsy, hypothermia) and tolerance. Preliminary data show that CB1R-mediated G-protein activity is increased in na'ive J3-arrestin-2 null mouse spinal cord and CBl R desensitization following chronic THC is reduced in 13-arrestin-2 null mice. Previous studies showed that CBl R desensitization and down regulation recover by 2 weeks following chronic THC treatment and therefore lack the stability to underlie persistent changes associated with addiction. Specific Aim 2 hypothesizes that 6FosB, a stable transcription factor, is involved in chronic THC-mediated effects. The regional expression of 6FosB after THC treatment will first be examined. Then CB1R signaling and THC in vivo effects will be assessed in transgenic mice with inducible overexpression or dominant negative inactivation of 6FosB in the striatum. Preliminary studies show increased 6FosB in nucleus accumbens following chronic THC treatment, and administration of THC to 6FosB overexpressing mice revealed attenuated tolerance and CB1R desensitization in mice. These studies will elucidate cellular and molecular mechanisms that regulate CBl R signaling and neuroadaptation and translate these effects to the in vivo level. This project will determine roles of specific signaling proteins in the effects of acute and long-term CB1R activation by THC and are relevant to cannabinoid therapeutics and drug abuse.
69-四氢大麻酚(THC)是大麻的精神活性成分,通过激活特定中枢神经系统区域的大麻素CBl受体(CB1R)产生多种作用。四氢大麻酚因其可导致成瘾的精神活性而被广泛非法使用,是止吐、食欲刺激和抗痉挛药物的主要成分。长期使用四氢大麻酚会产生耐受性和依赖性,这可能会导致成瘾并限制大麻素的治疗使用。我们之前的研究揭示了四氢大麻酚给药后大脑区域特异性CB1R脱敏和下调,以及该受体

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Laura J Sim-Selley其他文献

FAAH−/− Mice Display Differential Tolerance, Dependence, and Cannabinoid Receptor Adaptation After Δ9-Tetrahydrocannabinol and Anandamide Administration
FAAH−/− 小鼠在给予 Δ9-四氢大麻酚和花生四烯酸乙醇胺后表现出差异耐受性、依赖性和大麻素受体适应性
  • DOI:
    10.1038/npp.2010.44
  • 发表时间:
    2010-03-31
  • 期刊:
  • 影响因子:
    7.100
  • 作者:
    Katherine W Falenski;Andrew J Thorpe;Joel E Schlosburg;Benjamin F Cravatt;Rehab A Abdullah;Tricia H Smith;Dana E Selley;Aron H Lichtman;Laura J Sim-Selley
  • 通讯作者:
    Laura J Sim-Selley

Laura J Sim-Selley的其他文献

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{{ truncateString('Laura J Sim-Selley', 18)}}的其他基金

Brain Cannabinoid Signaling: Selectivity and Adaptation
大脑大麻素信号传导:选择性和适应
  • 批准号:
    6727639
  • 财政年份:
    2002
  • 资助金额:
    $ 29.9万
  • 项目类别:
Brain Cannabinoid Signaling: Selectivity and Adaptation
大脑大麻素信号传导:选择性和适应
  • 批准号:
    6624182
  • 财政年份:
    2002
  • 资助金额:
    $ 29.9万
  • 项目类别:
Brain Cannabinoid Signaling: Selectivity and Adaptation
大脑大麻素信号传导:选择性和适应
  • 批准号:
    7894922
  • 财政年份:
    2002
  • 资助金额:
    $ 29.9万
  • 项目类别:
Brain Cannabinoid Signaling: Selectivity and Adaptation
大脑大麻素信号传导:选择性和适应
  • 批准号:
    7060755
  • 财政年份:
    2002
  • 资助金额:
    $ 29.9万
  • 项目类别:
Brain Cannabinoid Signaling: Selectivity and Adaptation
大脑大麻素信号传导:选择性和适应
  • 批准号:
    6888151
  • 财政年份:
    2002
  • 资助金额:
    $ 29.9万
  • 项目类别:
Brain Cannabinoid Signaling: Selectivity and Adaptation
大脑大麻素信号传导:选择性和适应
  • 批准号:
    6472884
  • 财政年份:
    2002
  • 资助金额:
    $ 29.9万
  • 项目类别:
ALCOHOL EFFECTS ON RECEPTOR G PROTEIN COUPLING
酒精对受体 G 蛋白偶联的影响
  • 批准号:
    2894293
  • 财政年份:
    1998
  • 资助金额:
    $ 29.9万
  • 项目类别:
ALCOHOL EFFECTS ON RECEPTOR G PROTEIN COUPLING
酒精对受体 G 蛋白偶联的影响
  • 批准号:
    2875359
  • 财政年份:
    1998
  • 资助金额:
    $ 29.9万
  • 项目类别:
LOCALIZATION OF RECEPTOR ACITIVITY FOR DRUGS OF ABUSE
滥用药物受体活性的定位
  • 批准号:
    2012774
  • 财政年份:
    1996
  • 资助金额:
    $ 29.9万
  • 项目类别:
LOCALIZATION OF RECEPTOR ACITIVITY FOR DRUGS OF ABUSE
滥用药物受体活性的定位
  • 批准号:
    2897612
  • 财政年份:
    1996
  • 资助金额:
    $ 29.9万
  • 项目类别:

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