Exploring a role for organic transporter 3 in the mechanism of action of drugs of abuse

探索有机转运蛋白 3 在滥用药物作用机制中的作用

基本信息

  • 批准号:
    9788402
  • 负责人:
  • 金额:
    $ 19.06万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-09-15 至 2021-08-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT Co-abuse of cocaine and alcohol is one of the most common, and dangerous drug pairings, as evidenced by their concurrent use being a major cause for emergency hospitalization. Thus, this drug combination is not only a serious health threat to the individual user, but a major public health burden. Currently, there are no effective treatments for addiction to cocaine and ethanol, underscoring the vital need to understand the mechanistic basis of this highly addictive drug pairing in order to discover new targets for therapeutic intervention. It is well-known that cocaine and ethanol each increase extracellular levels of dopamine (DA), serotonin (5-HT), and norepinephrine (NE), biogenic amine neurotransmitters that are strongly linked to the rewarding properties of drugs. Cocaine does this by inhibiting the high-affinity, low-capacity transporters for these neurotransmitters, DAT, SERT, and NET, respectively. However, the mechanisms by which ethanol does so are unclear. It is known that ethanol inhibits uptake of DA, 5-HT, and NE, however our published data, together with literature evidence, show this inhibition to be DAT-, SERT-, and NET-independent. Organic cation transporter 3 (OCT3) is a low-affinity, high-capacity transporter for DA, 5-HT, and NE, and is emerging as an important player in regulation of biogenic amine homeostasis. Interestingly, recent reports show that corticosterone, a blocker of OCT3, enhances cocaine-induced DA signaling and potentiates reinstatement of cocaine seeking via an OCT3-dependent mechanism. Moreover, we found that OCT3 expression is increased in mice lacking SERT (-/-), and that ethanol, and corticosterone, both inhibit 5-HT clearance in SERT-/- mice to a much greater extent than in their wild-type counterpart. Together, these findings raise the possibility that ethanol may interact with OCT3 to inhibit uptake of biogenic amines, thereby increasing the addictive properties of cocaine, and propagating the concurrent use of these drugs. To this end, the studies proposed in this exploratory R21 will test the overarching hypothesis that one mechanism by which ethanol increases extracellular DA, 5-HT and NE is by inhibition of their uptake via OCT3, and that this inhibition enhances the increase in biogenic amines produced by cocaine, which blocks their uptake via DAT, SERT and NET. Importantly, we will determine the OCT3-dependency of ethanol’s ability to enhance the rewarding properties of cocaine. We will use pharmacological and genetic approaches, combined with in vivo neurochemistry, and behavioral assays relevant for reward. Regardless of the outcome of these exploratory studies, results will fill fundamental knowledge gaps about the mechanism(s) through which ethanol inhibits uptake of biogenic amines and enhances rewarding effects of cocaine. Results from these studies will improve our understanding of mechanisms that make the abuse potential of concurrent alcohol and cocaine use so high. Importantly, these studies will form an essential platform on which to base larger scale studies probing novel molecular targets, putatively OCT3, for medications to treat abuse of alcohol and cocaine.
摘要

项目成果

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LYNETTE C DAWS其他文献

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{{ truncateString('LYNETTE C DAWS', 18)}}的其他基金

Uptake2 transporters: Novel sex-dependent molecular targets to treat stimulant use disorder
Uptake2转运蛋白:治疗兴奋剂使用障碍的新型性别依赖性分子靶标
  • 批准号:
    10595444
  • 财政年份:
    2023
  • 资助金额:
    $ 19.06万
  • 项目类别:
Organic cation transporter 3: a novel molecular target to treat amphetamine abuse
有机阳离子转运蛋白 3:治疗苯丙胺滥用的新型分子靶点
  • 批准号:
    9808668
  • 财政年份:
    2019
  • 资助金额:
    $ 19.06万
  • 项目类别:
Age-related differences in serotonin clearance: novel targets for antidepressants
血清素清除率与年龄相关的差异:抗抑郁药的新目标
  • 批准号:
    9062518
  • 财政年份:
    2015
  • 资助金额:
    $ 19.06万
  • 项目类别:
The dopamine transporter in eating disorders: Uncovering new therapeutic targets
饮食失调中的多巴胺转运蛋白:发现新的治疗靶点
  • 批准号:
    8771759
  • 财政年份:
    2014
  • 资助金额:
    $ 19.06万
  • 项目类别:
The dopamine transporter in eating disorders: Uncovering new therapeutic targets
饮食失调中的多巴胺转运蛋白:发现新的治疗靶点
  • 批准号:
    8845537
  • 财政年份:
    2014
  • 资助金额:
    $ 19.06万
  • 项目类别:
Organic Cation Transporters as Targets for Novel Antidepressant Drugs
有机阳离子转运蛋白作为新型抗抑郁药物的靶标
  • 批准号:
    8424968
  • 财政年份:
    2012
  • 资助金额:
    $ 19.06万
  • 项目类别:
Serotonin Club Meetings 2012-2016
2012-2016 年血清素俱乐部会议
  • 批准号:
    8446340
  • 财政年份:
    2012
  • 资助金额:
    $ 19.06万
  • 项目类别:
Organic Cation Transporters as Targets for Novel Antidepressant Drugs
有机阳离子转运蛋白作为新型抗抑郁药物的靶标
  • 批准号:
    8262100
  • 财政年份:
    2012
  • 资助金额:
    $ 19.06万
  • 项目类别:
Organic Cation Transporters as Targets for Novel Antidepressant Drugs
有机阳离子转运蛋白作为新型抗抑郁药物的靶标
  • 批准号:
    8581356
  • 财政年份:
    2012
  • 资助金额:
    $ 19.06万
  • 项目类别:
Organic Cation Transporters as Targets for Novel Antidepressant Drugs
有机阳离子转运蛋白作为新型抗抑郁药物的靶标
  • 批准号:
    8969703
  • 财政年份:
    2012
  • 资助金额:
    $ 19.06万
  • 项目类别:
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