The Journal of Neuroscience, April 15, 1998, 18(8):3023-3034
Localization of Genes Mediating Acute and Sensitized Locomotor
Responses to Cocaine in BXD/Ty Recombinant Inbred Mice
Tamara J.
Phillips1, 2, 3,
Mary G.
Huson2, and
Carrie
S.
McKinnon2
1 Veterans Affairs Medical Center,
2 Behavioral Neuroscience Department, and
3 Portland Alcohol Research Center, Oregon Health Sciences
University, Portland, Oregon 97201
Sensitization to the psychostimulant effects of cocaine has
received widespread attention because concomitant changes occur in
neurochemical pathways that are part of the brain reward pathway. The
current study was undertaken with the purpose of mapping genes determining sensitivity to the acute stimulant and sensitizing effects
of cocaine. Sensitivity and sensitization to cocaine (5, 10, and 40 mg/kg) were measured in 25 BXD/Ty recombinant inbred (BXD RI) strains
and the progenitor C57BL/6J (B6) and DBA/2J (D2) strains. Quantitative
trait locus (QTL) mapping provisionally localized cocaine sensitivity
genes to regions on all chromosomes except 6, 11, 17, and X;
sensitization QTLs were localized to chromosomes 1-10, 13, 15, 18, 19, and X. Provisional QTLs for locomotion after saline injection in a
novel setting were mapped to chromosomes 1, 3-6, 9, 12, 13, 18, and 19 and in a familiar setting to chromosomes 4-7, 9, 13, and 19. There
were both common and unique QTL regions across the phenotypes. Evidence
for a genetic association between magnitude of acute cocaine response
and sensitization was obtained for only the 10 mg/kg dose. Some common
QTL regions for cocaine, ethanol, and methamphetamine responses suggest
the possibility that these drugs induce stimulant effects or
sensitization through some common mechanisms. However, independent
mechanisms were also indicated. Many candidate genes reside near the
provisional QTLs mapped for cocaine responses, including genes coding a
variety of neurotransmitter and hormone receptors. These data, once
confirmed, should prove useful for directing investigations of acute
and chronic cocaine effects down already suspected and novel
avenues.
Key words:
cocaine; locomotor activity; behavioral sensitization; mice; BXD recombinant inbred strains; quantitative trait locus; QTL; C57BL/6; DBA/2
Copyright © 1998 Society for Neuroscience 0270-6474/98/1883023-12$05.00/0
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