Genetically correlated effects of selective breeding for high and low methamphetamine consumption

J. M. Wheeler, C. Reed, S. Burkhart-Kasch, N. Li, Christopher Cunningham, Aaron Janowsky, F. H. Franken, Kristine Wiren, J. G. Hashimoto, A. C. Scibelli, Tamara Phillips

Research output: Contribution to journalArticle

49 Citations (Scopus)

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 κB (NFκB)] and Fos (cFos), represent candidates whose expression levels may predict methamphetamine consumption and susceptibility to methamphetamine reward and aversion.

Original languageEnglish (US)
Pages (from-to)758-771
Number of pages14
JournalGenes, Brain and Behavior
Volume8
Issue number8
DOIs
StatePublished - Nov 2009

Fingerprint

Methamphetamine
Self Administration
Pharmaceutical Preparations
Genes
Gene Expression
Serotonin Plasma Membrane Transport Proteins
Serotonin Receptors
Nucleus Accumbens
Selective Breeding
Reward
Intravenous Administration
Substance-Related Disorders
Alleles
Apoptosis

Keywords

  • Addiction
  • Conditioned place preference
  • Conditioned taste aversion
  • Drug reward
  • EQTL
  • Gene expression
  • Preference drinking
  • Selective breeding

ASJC Scopus subject areas

  • Behavioral Neuroscience
  • Genetics
  • Neurology

Cite this

Genetically correlated effects of selective breeding for high and low methamphetamine consumption. / Wheeler, J. M.; Reed, C.; Burkhart-Kasch, S.; Li, N.; Cunningham, Christopher; Janowsky, Aaron; Franken, F. H.; Wiren, Kristine; Hashimoto, J. G.; Scibelli, A. C.; Phillips, Tamara.

In: Genes, Brain and Behavior, Vol. 8, No. 8, 11.2009, p. 758-771.

Research output: Contribution to journalArticle

Wheeler, J. M. ; Reed, C. ; Burkhart-Kasch, S. ; Li, N. ; Cunningham, Christopher ; Janowsky, Aaron ; Franken, F. H. ; Wiren, Kristine ; Hashimoto, J. G. ; Scibelli, A. C. ; Phillips, Tamara. / Genetically correlated effects of selective breeding for high and low methamphetamine consumption. In: Genes, Brain and Behavior. 2009 ; Vol. 8, No. 8. pp. 758-771.
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