title: Genetically correlated effects of selective breeding for high and low methamphetamine consumption.
abstract: Improved prevention and treatment of drug addiction will require deeper understanding of genetic factors contributing to susceptibility to excessive drug use. Intravenous operant self-administration methods have greatly advanced understanding of behavioral traits related to addiction. However, these methods are not suitable for large-scale genetic experiments in mice. Selective breeding of mice can aggregate 'addiction alleles' in a model that has the potential to identify coordinated effects of multiple genes. We produced mouse lines that orally self-administer high (MAHDR) or low (MALDR) amounts of methamphetamine, representing the first demonstration of selective breeding for self-administration of any psychostimulant drug. Conditioned place preference and taste aversion results indicate that MAHDR mice are relatively more sensitive to the rewarding effects and less sensitive to the aversive effects of methamphetamine, compared to MALDR mice. These results validate the oral route of self-administration for investigation of the motivational effects of methamphetamine and provide a viable alternative to intravenous self-administration procedures. Gene expression results for a subset of genes relevant to addiction-related processes suggest differential regulation by methamphetamine of apoptosis and immune pathways in the nucleus accumbens of MAHDR and MALDR mice. In each line, methamphetamine reduced an allostatic state by bringing gene expression back toward 'normal' levels. Genes differentially expressed in the drug-naï ve state, including Slc6a4 (serotonin transporter), Htr3a (serotonin receptor 3A), Rela [nuclear factor kappaB (NFkappaB)] and Fos (cFos), represent candidates whose expression levels may predict methamphetamine consumption and susceptibility to methamphetamine reward and aversion.
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Wheeler
authors.forename: C
authors.initials: C
authors.lastname: Reed
authors.forename: S
authors.initials: S
authors.lastname: Burkhart-Kasch
authors.forename: N
authors.initials: N
authors.lastname: Li
authors.forename: C L
authors.initials: CL
authors.lastname: Cunningham
authors.forename: A
authors.initials: A
authors.lastname: Janowsky
authors.forename: F H
authors.initials: FH
authors.lastname: Franken
authors.forename: K M
authors.initials: KM
authors.lastname: Wiren
authors.forename: J G
authors.initials: JG
authors.lastname: Hashimoto
authors.forename: A C
authors.initials: AC
authors.lastname: Scibelli
authors.forename: T J
authors.initials: TJ
authors.lastname: Phillips
mesh_terms: D000284:Administration, Oral; D019969:Amphetamine-Related Disorders / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D001947:Breeding / Q000379:methods*; D000697:Central Nervous System Stimulants / Q000378:metabolism / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D007107:Immune System / Q000502:physiology; D008297:Male; D008694:Methamphetamine / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009042:Motivation / Q000187:drug effects / Q000235:genetics; D010641:Phenotype; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics; D044406:Receptors, Serotonin, 5-HT3 / Q000235:genetics; D012646:Self Administration; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics
chemical_list: D000697:Central Nervous System Stimulants; C511230:Htr3a protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D020569:Proto-Oncogene Proteins c-rel; D044406:Receptors, Serotonin, 5-HT3; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D008694:Methamphetamine
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