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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：
LYNETTE C DAWS
金额：
$ 19.06万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
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：
https://reporter.nih.gov/project-details/9788402
关键词：
1-Methyl-4-phenylpyridinium Adrenergic alpha-Antagonists Adult Affinity Alcohol abuse Alcohol consumption Alcohols Anesthesia procedures Behavior Behavioral Behavioral Assay Biogenic Amine Neurotransmitters Biogenic Amines Brain Brain region Cations Cells Chemosensitization Cocaine Cocaine Abuse Corpus striatum structure Corticosterone Dangerousness Data Dependence Dopamine Dorsal Dose Drug Combinations Drug effect disorder Drug usage Emergency Situation Ethanol Ethanol dependence Female Genotype Health Homeostasis Hospitalization Human Individual Knock-out Knowledge Link Literature Mediator of activation protein Molecular Target Mus National Institute of Drug Abuse Neurotransmitters Norepinephrine Nucleus Accumbens Organic Cation Transporter Outcome Overdose POU2F1 gene POU2F2 gene Pharmaceutical Preparations Pharmacology Prefrontal Cortex Property Protein Isoforms Public Health Publishing Regulation Reporting Rewards Rodent Role Sedation procedure Serotonin Signal Transduction Testing Therapeutic Intervention addiction alcohol effect base cocaine use dopamine transporter drug of abuse effective therapy extracellular genetic approach improved in vivo male neurochemistry new therapeutic target novel overexpression preference targeted treatment uptake

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