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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

基本信息

批准号：
9808668
负责人：
LYNETTE C DAWS
金额：
$ 23.06万
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：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9808668
关键词：
1-Methyl-4-phenylpyridinium Address Age Amphetamine Abuse Amphetamine Addiction Amphetamines Attenuated Bathing Behavioral Brain region Cocaine Data Development Dopamine Drug Combinations Drug Design Drug abuse Drug usage Extracellular Space Financial compensation Future Genetic Genome engineering Goals Health Sciences Intention Knock-out Knockout Mice Knowledge Legal Literature Locomotion LoxP-flanked allele Mediating Methamphetamine Molecular Molecular Target Mus Neurotransmitters Organic Cation Transporter Pharmaceutical Preparations Pharmacology Play Property Psychostimulant dependence Public Health Rewards Role Salts Self Administration Speed System Tamoxifen Testing Texas Therapeutic Universities addiction base cathinone cell type dopamine transporter drug of abuse effective therapy in vivo inhibitor/antagonist monoamine mouse genome neurotransmission noradrenaline transporter novel preference psychostimulant response serotonin transporter stereotypy stimulant abuse synthetic drug therapeutic target

项目摘要

Medications to help treat addiction exist for many major drugs of abuse, but not for psychostimulants, such as amphetamine, and its congeners. They are also lacking for increasingly used synthetic drugs designed to mimic the actions of known psychostimulants. Both known and new psychoactive substances continue to pose a major and increasing public health threat. To develop effective treatments, the mechanisms by which these stimulants produce their abuse-related effects need to be fully understood. Many stimulants interact with the dopamine (DA) transporter (DAT), which is thought to mediate their abuse-related effects. However, strategies targeting DAT have yielded little to no benefit in the treatment of psychostimulant addiction, raising the possibility that these stimulants have significant actions elsewhere to modulate dopaminergic neurotransmission. Consistent with this, a rapidly growing literature supports a prominent role for organic cation transporter 3 (OCT3) in regulating dopaminergic neurotransmission. Our preliminary data support this idea, showing that an OCT3 inhibitor, decynium-22 (D22), inhibits amphetamine-evoked hyperlocomotion and DA release in vivo, effects that were lost in constitutive OCT3 knockout (KO, -/-) mice. Furthermore, amphetamine-induced substrate efflux could be inhibited by D22 in a manner independent of cocaine-sensitive transporters. These data raise the exciting possibility that OCT3 is a critical player in the actions of amphetamine, which may help to explain why DAT-based therapeutics have not been successful in treating amphetamine abuse. Our intention is to submit an R01 to build on these exciting findings, but before doing so, additional preliminary data are needed. First, we need to determine if potential compensation in constitutive OCT3-/- mice accounts for the lack of difference in their locomotor and DA releasing responses to amphetamine compared with wild-type (OCT3+/+) mice. To do this, OCT3 floxed mice have recently been generated at the University of Texas Health Science Center at San Antonio (UTHSCSA). We will cross these mice with a commercially available Cre line to generate a tamoxifen inducible global OCT3 KO. In this way, we can temporally control OCT3 KO, and in future studies, use different Cre lines to create brain region specific inducible KOs. We will use these mice to test the hypothesis that amphetamine-induced DA release, locomotion, and stereotypy will be attenuated in inducible OCT3 KO mice compared with control mice. Moreover, if OCT3 is to be a useful target in the treatment of amphetamine abuse, we need to demonstrate that OCT3 is important in mediating the rewarding and reinforcing effects of amphetamine. To this end, we will use conditioned place preference (CPP), and self-administration in mice to test the hypotheses that the rewarding and reinforcing effects of amphetamine are less in inducible OCT3 KO mice than control mice, and that D22 will attenuate development of CPP to amphetamine and amphetamine self-administration in control mice, but not in the inducible OCT3 KO. These proposed studies will provide data essential for an R01 submission, and will begin to fill crucial knowledge gaps about the role of OCT3 in abuse-related effects of amphetamine.

许多主要滥用药物都有治疗成瘾的药物，但精神兴奋剂却没有，比如