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
- 来源:
- 关键词:1-Methyl-4-phenylpyridiniumAdrenergic alpha-AntagonistsAdultAffinityAlcohol abuseAlcohol consumptionAlcoholsAnesthesia proceduresBehaviorBehavioralBehavioral AssayBiogenic Amine NeurotransmittersBiogenic AminesBrainBrain regionCationsCellsChemosensitizationCocaineCocaine AbuseCorpus striatum structureCorticosteroneDangerousnessDataDependenceDopamineDorsalDoseDrug CombinationsDrug effect disorderDrug usageEmergency SituationEthanolEthanol dependenceFemaleGenotypeHealthHomeostasisHospitalizationHumanIndividualKnock-outKnowledgeLinkLiteratureMediator of activation proteinMolecular TargetMusNational Institute of Drug AbuseNeurotransmittersNorepinephrineNucleus AccumbensOrganic Cation TransporterOutcomeOverdosePOU2F1 genePOU2F2 genePharmaceutical PreparationsPharmacologyPrefrontal CortexPropertyProtein IsoformsPublic HealthPublishingRegulationReportingRewardsRodentRoleSedation procedureSerotoninSignal TransductionTestingTherapeutic Interventionaddictionalcohol effectbasecocaine usedopamine transporterdrug of abuseeffective therapyextracellulargenetic approachimprovedin vivomaleneurochemistrynew therapeutic targetnoveloverexpressionpreferencetargeted treatmentuptake
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
期刊论文数量(0)
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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:
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: