Abstract

This proposal describes a study of the mu opioid receptor (OPRM1) gene in two strains of mice (C57B1/6J and DBA/2J) which differ remarkably in voluntary morphine intake during a two-bottle choice paradigm. Quantitative trait loci mapping revealed that a segment of proximal murine chromosome 10 determines nearly 50 percent of the genetic variance in voluntary morphine consumption. The OPRM1 gene was subsequently mapped to this region. To study OPRM1 function in the rewarding aspects of opioids, reciprocal congenic strains are being created. A C57B1/6J chromosome 10 interval (containing the OPRM gene) is being bred onto a DBA/2J background. Similarly, the DBA/2J chromosome 10 interval is being transferred to a C57B1/6J background. In addition, OPRM1 null mutant mice on C57Bl/6J and DBA/2J backgrounds are being prepared. D2 transgenic mice, expressing the B6 OPRM1 allele are being created. These groups of genetically unique mice will be compared with the parental strains (C57B1/6J and DBA/2J) for several phenotypes which assess the rewarding properties of opioids. These phenotypes include operant intravenous morphine self-administration, voluntary two- bottle choice morphine drinking and morphine place preference. Differences among genetically unique groups of mice and parental inbred strains may increase our understanding of the OPRM1 role in rewarding properties of opioids. This may enhance our knowledge of genetic susceptibility to opioid dependence in human populations.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA014008-02
Application #
6612674
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Rutter, Joni
Project Start
2002-07-15
Project End
2005-04-30
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
2
Fiscal Year
2003
Total Cost
$321,929
Indirect Cost

  Institution

Name
University of Pennsylvania
Department
Psychiatry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Doyle, Glenn A; Furlong, Patrick J; Schwebel, Candice L et al. (2008) Fine mapping of a major QTL influencing morphine preference in C57BL/6 and DBA/2 mice using congenic strains. Neuropsychopharmacology 33:2801-9
Doyle, Glenn A; Rebecca Sheng, X; Lin, Sharon S J et al. (2007) Identification of three mouse mu-opioid receptor (MOR) gene (Oprm1) splice variants containing a newly identified alternatively spliced exon. Gene 388:135-47
Doyle, Glenn A; Sheng, X Rebecca; Lin, Sharon S J et al. (2007) Identification of five mouse mu-opioid receptor (MOR) gene (Oprm1) splice variants containing a newly identified alternatively spliced exon. Gene 395:98-107
Grice, Dorothy E; Reenila, Ilkka; Mannisto, Pekka T et al. (2007) Transcriptional profiling of C57 and DBA strains of mice in the absence and presence of morphine. BMC Genomics 8:76
Doyle, Glenn A; Sheng, X Rebecca; Schwebel, Candice L et al. (2006) Identification and functional significance of polymorphisms in the mu-opioid receptor gene (Oprm) promoter of C57BL/6 and DBA/2 mice. Neurosci Res 55:244-54
Smith, Rachel J; Doyle, Glenn A; Han, Angela M et al. (2005) Novel exonic mu-opioid receptor gene (OPRM1) polymorphisms not associated with opioid dependence. Am J Med Genet B Neuropsychiatr Genet 133B:105-9
Ferraro, Thomas N; Golden, Gregory T; Smith, George G et al. (2005) Confirmation of a major QTL influencing oral morphine intake in C57 and DBA mice using reciprocal congenic strains. Neuropsychopharmacology 30:742-6
Mannelli, Paolo; Patkar, Ashwin A; Murray, Heather W et al. (2005) Polymorphism in the serotonin transporter gene and response to treatment in African American cocaine and alcohol-abusing individuals. Addict Biol 10:261-8
Berrettini, Wade H; Lerman, Caryn E (2005) Pharmacotherapy and pharmacogenetics of nicotine dependence. Am J Psychiatry 162:1441-51
Patkar, Ashwin A; Mannelli, Paolo; Certa, Kenneth M et al. (2004) Relationship of serum prolactin with severity of drug use and treatment outcome in cocaine dependence. Psychopharmacology (Berl) 176:74-81

Showing the most recent 10 out of 12 publications