Using a genetic murine model for opioid addiction and linkage analysis, we identified a chromosome 10 locus (later defined as the mu opioid receptor [OPRM] gene) that determines 50% of the variance in how much morphine a mouse consumes during a two-bottle choice paradigm experiment. If the murine addiction model partially reflects a human genetic vulnerability to opioid dependence (OD), then study of the human OPRM gene will reveal DNA sequence variants which predispose individuals to OD. This application proposes to study-200 OD patients with parents, to examine OPRM gene sequence variants as potential susceptibility factors for OD. OPRM gene variants which predispose to OD should be transmitted to OD individuals by their parents more often than expected by chance in a haplotype relative risk analysis. Single-stranded conformational polymorphism (SSCP) and DNA sequencing has been used to examine exons one and two of the human OPRM gene. OPRM exonic nucleotide variation (which alters amino acid sequence) was seen in exons 1 and 2 among 55 OD individuals. One or more of these exonic variants may represent a genetic susceptibility factor for OD. These data indicate that exonic variation in the human OPRM gene exists, and a more extensive examination of the OPRM gene sequence may be useful in understanding genetic susceptibility to OD. Genes for dopamine neurotransmission will also be studied, because independent lines of evidence suggest that dopamine neurotransmission in the mesocorticolimbic pathway is important in the rewarding aspects of opioid drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA011835-02
Application #
2770170
Study Section
Human Development Research Subcommittee (NIDA)
Project Start
1997-09-30
Project End
2001-08-31
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Psychiatry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
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
Crowley, James J; Oslin, David W; Patkar, Ashwin A et al. (2003) A genetic association study of the mu opioid receptor and severe opioid dependence. Psychiatr Genet 13:169-73
Patkar, Ashwin A; Berrettini, Wade H; Hoehe, Margret et al. (2002) No association between polymorphisms in the serotonin transporter gene and susceptibility to cocaine dependence among African-American individuals. Psychiatr Genet 12:161-4
Patkar, Ashwin A; Berrettini, Wade H; Hoehe, Margret et al. (2002) Serotonin transporter polymorphisms and measures of impulsivity, aggression, and sensation seeking among African-American cocaine-dependent individuals. Psychiatry Res 110:103-15
Hoehe, M R; Kopke, K; Wendel, B et al. (2000) Sequence variability and candidate gene analysis in complex disease: association of mu opioid receptor gene variation with substance dependence. Hum Mol Genet 9:2895-908