The abuse of illegal drugs poses a worldwide problem, with a multitude of negative individual and societal consequences. Addiction to methamphetamine (MA) damages the brain, can induce psychosis, and is associated with crime and increased aggression. Military personnel, including Veterans and their families, have been identified as among key populations requiring special support to deal with their drug abuse problems. Genetic animal models for investigating risk for MA use and mechanisms that underlie risk and escalating use are lacking. This application describes research focused on a genetic mouse model for human methamphetamine (MA) use and on the identification of genetic factors and specific mechanisms that influence genetic risk for MA abuse. To be utilized are (1) unique genetic tools that consist of lines of mice selectively bred for high and low MA drinking (the MADR lines) and of interval specific congenic strains to be used for finer mapping of a gene(s) that influences MA intake;and (2) a newly developed operant oral MA self-administration method that has been used to validate the MADR lines as a genetic model that shows differential sensitivity to the reinforcing effects of MA. This program of research will develop a model of genetically-determined escalating, binge-like MA intake. It will also follow up the results of quantitative trat locus (QTL) mapping, which identified a locus on mouse chromosome 10 that accounts for ~50% of the genetic variance associated with differential MA intake, by completing finer mapping and sequence analysis that will allow progress to be made in identifying genes and gene networks that influence genetic risk for MA addiction. Preliminary data support the importance of mu-opioid receptors in this risk and pharmacological and molecular studies will be completed to further test the importance of this mechanism. In addition, molecular analyses will explore other potential candidate mechanisms and knockout mice and pharmacological approaches for druggable targets will be used to follow-up promising mechanisms. There are 3 specific aims: (1) examine genetically-determined patterns of MA intake, escalation, binge-like intake, and reinstatement. Potential differences in sensitivity to reinforcement by natural rewards will also be examined as part of this aim;(2) use an existing panel of interval specific congenic strains to more finely map the chromosome 10 QTL;measure genetically correlated traits in these congenics to test the hypothesis that a common genetic region on mouse chromosome 10 influences MA drinking and the correlated trait;(3) complete qPCR, sequence and Western blot analyses, after fine mapping of the chromosome 10 QTL, for genes that could impact MA drinking;use these data to identify specific mechanisms that should be tested for their impact on MA intake, using knockout and pharmacological approaches. Functional analysis of the mu- opioid receptor in the MADR lines, one candidate gene in the chromosome 10 interval, will also be completed. This work has the potential for developing a needed genetic animal model of high MA intake that takes advantage of existing genetic risk in the development of this model. In addition, the study of opioid system involvement dovetails nicely with ongoing clinical work that indicates concomitant changes in MA use in individuals receiving buprenorphine or methadone treatment (both opioid receptor agonists) for opiate dependence. Use of the genetic model will indicate whether animals at higher genetic risk for MA use are susceptible to opioid and other pharmacological interventions that are explored.

Public Health Relevance

The 2011 update of the United States National Drug Control Strategy identified active military personnel, Veterans, and their families as populations requiring special support to deal with their drug abuse problems. Data gathered by Drs. Ben Morasco and Linda Ganzini here at the Portland VA Medical Center estimate an increase of 50% over the last 10-year period in the number of veterans diagnosed with (meth)amphetamine (MA) use disorders and in the costs associated with treatment. Existing data also suggest that persons suffering from posttraumatic stress disorder (PTSD), commonly seen in military personnel and Veterans, are more likely to use methamphetamine than are trauma-exposed individuals without PTSD (Smith et al., 2010). This research program is focused on the development of a genetic animal model of binge MA use and identification of mechanisms associated with risk for MA addiction, with the ultimate goal of developing treatments for MA use disorders that would benefit Veterans.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX002106-01A2
Application #
8732881
Study Section
Neurobiology A (NURA)
Project Start
2014-07-01
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Portland VA Medical Center
Department
Type
DUNS #
City
Portland
State
OR
Country
United States
Zip Code
97239
Miner, Nicholas B; O'Callaghan, James P; Phillips, Tamara J et al. (2017) The combined effects of 3,4-methylenedioxymethamphetamine (MDMA) and selected substituted methcathinones on measures of neurotoxicity. Neurotoxicol Teratol 61:74-81
Greenberg, Gian D; Phillips, Tamara J; Crabbe, John C (2016) Effects of acute alcohol withdrawal on nest building in mice selectively bred for alcohol withdrawal severity. Physiol Behav 165:257-66
Shabani, Shkelzen; Houlton, Sydney K; Hellmuth, Laura et al. (2016) A Mouse Model for Binge-Level Methamphetamine Use. Front Neurosci 10:493
Hostetler, Caroline M; Phillips, Tamara J; Ryabinin, Andrey E (2016) Methamphetamine Consumption Inhibits Pair Bonding and Hypothalamic Oxytocin in Prairie Voles. PLoS One 11:e0158178
Phillips, T J; Mootz, J R K; Reed, C (2016) Identification of Treatment Targets in a Genetic Mouse Model of Voluntary Methamphetamine Drinking. Int Rev Neurobiol 126:39-85
Shi, Xiao; Walter, Nicole A R; Harkness, John H et al. (2016) Genetic Polymorphisms Affect Mouse and Human Trace Amine-Associated Receptor 1 Function. PLoS One 11:e0152581
Lominac, Kevin D; Quadir, Sema G; Barrett, Hannah M et al. (2016) Prefrontal glutamate correlates of methamphetamine sensitization and preference. Eur J Neurosci 43:689-702
Harkness, John H; Shi, Xiao; Janowsky, Aaron et al. (2015) Trace Amine-Associated Receptor 1 Regulation of Methamphetamine Intake and Related Traits. Neuropsychopharmacology 40:2175-84
Phillips, Tamara J; Shabani, Shkelzen (2015) An animal model of differential genetic risk for methamphetamine intake. Front Neurosci 9:327
Phillips, Tamara J; Reed, Cheryl (2014) Targeting GABAB receptors for anti-abuse drug discovery. Expert Opin Drug Discov 9:1307-17

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