title: Identification of Treatment Targets in a Genetic Mouse Model of Voluntary Methamphetamine Drinking.
abstract: Methamphetamine has powerful stimulant and euphoric effects that are experienced as rewarding and encourage use. Methamphetamine addiction is associated with debilitating illnesses, destroyed relationships, child neglect, violence, and crime; but after many years of research, broadly effective medications have not been identified. Individual differences that may impact not only risk for developing a methamphetamine use disorder but also affect treatment response have not been fully considered. Human studies have identified candidate genes that may be relevant, but lack of control over drug history, the common use or coabuse of multiple addictive drugs, and restrictions on the types of data that can be collected in humans are barriers to progress. To overcome some of these issues, a genetic animal model comprised of lines of mice selectively bred for high and low voluntary methamphetamine intake was developed to identify risk and protective alleles for methamphetamine consumption, and identify therapeutic targets. The mu opioid receptor gene was supported as a target for genes within a top-ranked transcription factor network associated with level of methamphetamine intake. In addition, mice that consume high levels of methamphetamine were found to possess a nonfunctional form of the trace amine-associated receptor 1 (TAAR1). The Taar1 gene is within a mouse chromosome 10 quantitative trait locus for methamphetamine consumption, and TAAR1 function determines sensitivity to aversive effects of methamphetamine that may curb intake. The genes, gene interaction partners, and protein products identified in this genetic mouse model represent treatment target candidates for methamphetamine addiction.
authors.affiliation: Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, OR, United States; Veterans Affairs Portland Health Care System, Portland, OR, United States. Electronic address: phillipt@ohsu.edu.
authors.forename: T J
authors.initials: TJ
authors.lastname: Phillips
authors.affiliation: Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, OR, United States.
authors.forename: J R K
authors.initials: JR
authors.lastname: Mootz
authors.affiliation: Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, OR, United States.
authors.forename: C
authors.initials: C
authors.lastname: Reed
mesh_terms: D000818:Animals; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D004195:Disease Models, Animal; D004298:Dopamine / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008822:Mice, Transgenic; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D019966:Substance-Related Disorders / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics / Q000378:metabolism; D000095383:Trace Amine-Associated Receptors
chemical_list: D000697:Central Nervous System Stimulants; D004298:Dopamine; D008694:Methamphetamine; D043562:Receptors, G-Protein-Coupled; D050493:Vesicular Monoamine Transport Proteins; D000095383:Trace Amine-Associated Receptors
keywords: Addiction; Aversion; Medication; Polymorphism; Quantitative trait locus; Reward; Selected lines; Therapeutic