A major QTL on chromosome 11 influences psychostimulant and opioid sensitivity in mice.
The identification of genes influencing sensitivity to stimulants and opioids is important for determining their mechanism of action and may provide fundamental insights into the genetics of drug abuse. We used a panel of C57BL/6J (B6; recipient)x A/J (donor) chromosome substitution strains (CSSs) to identify quantitative trait loci (QTL) for both open field activity and sensitivity to the locomotor stimulant response to methamphetamine (MA). Mice were injected with saline (days 1 and 2) and MA (day 3; 2 mg/kg i.p.). We analyzed the total distance traveled in the open field for 30 min following each injection. CSS-8, -11 and -16 showed reduced MA-induced locomotor activity relative to B6, whereas CSS-10 and -12 showed increased MA-induced locomotor activity. Further analysis focused on CSS-11 because it was robustly different from B6 following MA injection, but did not differ in activity following saline injection and because it also showed reduced locomotor activity in response to the mu-opioid receptor agonist fentanyl (0.2 mg/kg i.p.). Thus, CSS-11 captures QTLs for the response to both psychostimulants and opioids. Using a B6 x CSS-11 F(2) intercross, we identified a dominant QTL for the MA response on chromosome 11. We used haplotype association mapping of cis expression QTLs and bioinformatic resources to parse among genes within the 95% confidence interval of the chromosome 11 QTL. Identification of the genes underlying QTLs for response to psychostimulants and opioids may provide insights about genetic factors that modulate sensitivity to drugs of abuse.
Bryant
C D
CD
Department of Human Genetics, University of Chicago, Chicago, IL, USA.
Chang
H P
HP
Zhang
J
J
Wiltshire
T
T
Tarantino
L M
LM
Palmer
A A
AA
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000235:genetics; D019966:Substance-Related Disorders / Q000235:genetics*
D000701:Analgesics, Opioid; D000697:Central Nervous System Stimulants; D017450:Receptors, Opioid, mu; D008694:Methamphetamine
Genes Brain Behav. 2008 Oct;7(7):720-9
18518925
Science. 2004 Apr 16;304(5669):445-8
15031436
J Pharmacol Exp Ther. 1998 Sep;286(3):1171-6
9732375
J Biol Chem. 2000 Dec 29;275(52):41521-7
11024017
Neuropsychopharmacology. 2007 Sep;32(9):1995-2003
17251906
Biochem Biophys Res Commun. 2002 Nov 29;299(2):299-304
12437986
Psychopharmacology (Berl). 2009 May;203(4):703-11
19050854
J Neurosci. 1984 Jan;4(1):111-24
6319625
PLoS Biol. 2006 Nov;4(12):e395
17105354
J Neurochem. 2006 Apr;97 Suppl 1:3-10
16635244
Nat Genet. 2000 Mar;24(3):221-5
10700173
Mamm Genome. 2003 Nov;14(11):723-32
14722722
J Nihon Univ Sch Dent. 1989 Jun;31(2):451-7
2570826
Nature. 2002 Aug 15;418(6899):774-8
12181566
Eur J Pharmacol. 1990 Nov 6;190(1-2):217-21
2076753
Neurosci Biobehav Rev. 2008;32(4):707-59
18207241
Science. 1998 Aug 7;281(5378):838-42
9694658
Science. 2001 Nov 2;294(5544):1024-30
11691979
Ann N Y Acad Sci. 1998 May 30;844:201-7
9668678
Bioinformatics. 2003 May 1;19(7):889-90
12724300
Neuropsychopharmacology. 2006 Mar;31(3):555-62
16123776
Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3380-5
12612341
BMC Bioinformatics. 2006 Feb 09;7:61
16466585
Proc Natl Acad Sci U S A. 1988 Jul;85(14):5274-8
2899326
Biol Psychiatry. 2002 Apr 15;51(8):612-20
11955461
PLoS Biol. 2004 Dec;2(12):e393
15534693
Mol Pharmacol. 2008 Oct;74(4):1101-8
18617632
Brain Res Bull. 1991 Mar;26(3):445-7
1828708
Nat Neurosci. 2004 May;7(5):485-6
15114364
Pharmacology. 1998 Apr;56(4):165-74
9566018
J Neurosci. 2000 Jun 15;20(12):4480-8
10844017
Nature. 1983 Jan 6;301(5895):69-71
6296685
Drug Alcohol Depend. 2009 Jul 1;103(1-2):74-83
19419821
Neuropsychopharmacology. 2006 May;31(5):1056-63
16237383
Mamm Genome. 2005 May;16(5):291-305
16104378
J Appl Physiol (1985). 2003 Oct;95(4):1335-7
12970372
Genes Brain Behav. 2005 Oct;4(7):401-11
16176386
Psychopharmacology (Berl). 1999 Jun;144(3):295-300
10435398
Psychol Rev. 1987 Oct;94(4):469-92
3317472
Brain Res. 1998 Sep 14;805(1-2):55-68
9733917