Methamphetamine (MA) is remarkably addictive and relapse to excessive use is highly probable and poses serious health concerns. Genetic factors have been little studied with regard to their role in susceptibility to MA addiction or relapse. A key goal will be to utilize a validated animal model of genetically-determined high and low susceptibility to MA use to improve genetic mapping resolution and to study an already identified neuroimmune gene network that influences MA response in this genetic model.
In Aim 1, in coordination with Animal Core 3, replicated sets of selected mouse lines bred for high and low voluntary consumption of MA will be produced and QTL mapping will be performed by the Biostatistics and Genetics Core 2. These mice will be used for studies proposed in Components 7, 8 and 9.
In Aim 2, neurocircuitry will be examined in the selected lines, using cFos mapping after acute and repeated MA treatment, and these data will be used to identify brain regions for immune factor analysis, and will be compared to imaging results from Scientific Component 7 for brains from the MA consumption selected lines.
In Aim 3, qPCR immunology arrays will be used to examine brain and peripheral blood mononuclear cell gene expression for immune specific genes using samples from selectively bred MA drinking line mice that have been acutely or repeatedly treated with MA or with saline, or are in "remission". These data will be used in additional network analysis by the Biostatistics and Genetics Core 2 and compared to human peripheral gene expression results for controls, chronic MA users and user in remission.
In Aim 4, cognitive, anxiety-like, and impulsivity-like traits will be examined in drug naive, acute, and repeated MA-exposed MADR mice, as well as mice in remission from MA exposure. Tissue from mice treated in the same way will be transferred to Translational Service Core 5 for analysis of immune factors and to Component 7 for imaging;half of each brain will be sent for each purpose to allow individual animal correlations to be performed. These data will also be examined for correspondence between behavior, neurocircuitry and immune system alterations. In addition, impulsivity-like measures in mice will be compared to similar measures in humans from Component 7. Finally, data collected in Component 9 will inform Component 8, with regard to traits and which of the selected lines to be studied for immunotherapeutic intervention. Cross-species analyses across components will identify key immune factors associated with chronic MA exposure (and remission) and MA-induced neuropsychiatric impairments, with the goal of ultimately identifying novel immunotherapeutic interventions.

Public Health Relevance

Many individuals try MA, but only some become addicted and continue to use MA even though it has profoundly adverse effects on their health and relationships. Genetic differences could influence who is at greater risk for developing MA addiction. If the important genetic pathways were known, researchers and clinicians would be better able to develop treatments for the prevention and treatment of MA addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Specialized Center (P50)
Project #
2P50DA018165-06A1
Application #
8355342
Study Section
Special Emphasis Panel (ZDA1-EXL-T (02))
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-06-30
Support Year
6
Fiscal Year
2012
Total Cost
$194,250
Indirect Cost
$38,400
Name
Oregon Health and Science University
Department
Type
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Szumlinski, Karen K; Lominac, Kevin D; Campbell, Rianne R et al. (2016) Methamphetamine Addiction Vulnerability: The Glutamate, the Bad, and the Ugly. Biol Psychiatry :
Li, Minghua; Underhill, Suzanne M; Reed, Cheryl et al. (2016) Amphetamine and Methamphetamine Increase NMDAR-GluN2B Synaptic Currents in Midbrain Dopamine Neurons. Neuropsychopharmacology :
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
Loftis, Jennifer M; Lim, Miranda M (2016) Sleep disturbance in substance use disorders and comorbid chronic viral infections. Addiction 111:1093-4
Ellis, Carilyn; Hoffman, William; Jaehnert, Sarah et al. (2016) Everyday problems with executive dysfunction and impulsivity in adults recovering from methamphetamine addiction. Addict Disord Their Treat 15:1-5
Kim, Hyunjee; Hartung, Daniel M; Jacob, Reside L et al. (2016) The Concentration of Opioid Prescriptions by Providers and Among Patients in the Oregon Medicaid Program. Psychiatr Serv 67:397-404
Janowsky, Aaron; Tosh, Dilip K; Eshleman, Amy J et al. (2016) Rigid Adenine Nucleoside Derivatives as Novel Modulators of the Human Sodium Symporters for Dopamine and Norepinephrine. J Pharmacol Exp Ther 357:24-35
Greenberg, G D; Huang, L C; Spence, S E et al. (2016) Nest building is a novel method for indexing severity of alcohol withdrawal in mice. Behav Brain Res 302:182-90
Zou, Mu-Fa; Keck, Thomas M; Kumar, Vivek et al. (2016) Novel Analogues of (R)-5-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (Sumanirole) Provide Clues to Dopamine D2/D3 Receptor Agonist Selectivity. J Med Chem 59:2973-88
Abraham, Antony D; Neve, Kim A; Lattal, K Matthew (2016) Effects of D1 receptor knockout on fear and reward learning. Neurobiol Learn Mem 133:265-73

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