Pharmacogenomic evaluation of the antidepressant citalopram in the mouse tail suspension test.
The identification of genetic variants regulating antidepressant response in human patients would allow for more individualized, rational, and successful drug treatments. We have previously identified the BALB/cJ inbred mouse strain as highly responsive to the selective serotonin reuptake inhibitor (SSRI) citalopram in the tail suspension test (TST), a widely used and well-established screening paradigm for detecting compounds with antidepressant activity. In contrast, A/J mice did not show a significant response to citalopram in this test despite exposure to equivalent plasma levels of the drug. To identify genetic determinants of this differential response, 506 F2 mice from an intercross between BALB/cJ and A/J mice were phenotyped. Composite interval mapping of 92 mice from the phenotypic extremes revealed three loci on chromosomes 7, 12, and 19 affecting citalopram response in the TST. The quantitative trait locus (QTL) at the telomeric end of chromosome 19 showed the greatest level of significance. Three candidate genes residing in this locus include those for vesicular monoamine transporter 2 (VMAT2, slc18a2), alpha 2A adrenergic receptor (adra2a), and beta 1 adrenergic receptor (adrb1). The protein coding regions of these three genes in BALB/cJ and A/J mice were sequenced and two polymorphisms were found in VMAT2 (Leu117Pro and Ser505Pro), while the transcribed regions of adra2a and adrb1 were of identical sequence between strains. Follow-up studies are needed to determine if the VMAT2 polymorphisms are functional and if they could explain the chromosome 19 QTL. The present quantitative trait study suggests possible candidate genes for human pharmacogenetic studies of therapeutic responses to SSRIs such as citalopram.
Crowley
James J
JJ
Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Brodkin
Edward S
ES
Blendy
Julie A
JA
Berrettini
Wade H
WH
Lucki
Irwin
I
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000097:blood / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D002417:Cattle; D002874:Chromosome Mapping / Q000379:methods; D015283:Citalopram / Q000097:blood / Q000494:pharmacology*; D005260:Female; D005820:Genetic Testing / Q000379:methods; D019417:Hindlimb Suspension; D006801:Humans; D046353:Immobility Response, Tonic / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D002679:Pan troglodytes; D010597:Pharmacogenetics; D040641:Quantitative Trait Loci; D051381:Rats
D018687:Antidepressive Agents, Second-Generation; D015283:Citalopram