Association between tryptophan hydroxylase-2 genotype and the antidepressant effect of citalopram and paroxetine on immobility time in the forced swim test in mice.

Tryptophan hydroxylase-2 (TPH2) is the rate limiting enzyme of serotonin synthesis in the brain. The 1473G allele of the C1473G polymorphism in mTPH2 gene is associated with reduced enzyme activity and serotonin synthesis rate in the mouse brain. Here, the influence of the 1473G allele on the antidepressant effect of selective serotonin reuptake inhibitors (SSRIs), citalopram (2.5 or 5.0mg/kg) and paroxetine (5.0 or 10.0mg/kg), in the forced swim test was studied using B6-1473G and B6-1473C congenic mouse lines with the 1473G (decreased TPH2 activity) or 1473C (normal TPH2 activity) alleles, respectively, transferred to the genome of C57BL/6 mouse strain. Paroxetine (5.0 or 10.0mg/kg) and citalopram (2.5 or 5.0mg/kg) decreased immobility time in B6-1473C mice, while both doses of paroxetine and 2.5mg/kg of citaloprame did not alter immobility time in B6-1473G mice. However, 5.0mg/kg of citalopram reduced immobility in B6-1473G mice. The results provided genetic evidence of moderate association between 1473G allele and reduced sensitivity to SSRIs in mice.