Strain differences in basal and post‐citalopram extracellular 5‐HT in the mouse medial prefrontal cortex and dorsal hippocampus: relation with tryptophan hydroxylase‐2 activity

Abstract We used the microdialysis technique to compare basal extracellular serotonin (5‐HT) and the response to citalopram in different strains of mice with functionally different allelic forms of tryptophan hydroxylase‐2 (TPH‐2), the rate‐limiting enzyme in brain 5‐HT synthesis. DBA/2J, DBA/2N and BALB/c mice carrying the 1473G allele of TPH‐2 had less dialysate 5‐HT in the medial prefrontal cortex and dorsal hippocampus (DH) (20–40% reduction) than C57BL/6J and C57BL/6N mice carrying the 1473C allele. Extracellular 5‐HT estimated by the zero‐net flux method confirmed the result of conventional microdialysis. Citalopram, 1.25, 5 and 20 mg/kg, dose‐dependently raised extracellular 5‐HT in the medial prefrontal cortex of C57BL/6J mice, with maximum effect at 5 mg/kg, but had significantly less effect in DBA/2J and BALB/c mice and in the DH of DBA/2J mice. A tryptophan (TRP) load enhanced basal extracellular 5‐HT in the medial prefrontal cortex of DBA/2J mice but did not affect citalopram’s ability to raise cortical and hippocampal extracellular 5‐HT. The impairment of 5‐HT synthesis quite likely accounts for the reduction of basal 5‐HT and the citalopram‐induced rise in mice carrying the mutated enzyme. These findings might explain why DBA/2 and BALB/c mice do not respond to citalopram in the forced swimming test. Although TRP could be a useful strategy to improve the antidepressant effect of citalopram ( Cervo et al. 2005 ), particularly in subjects with low 5‐HT synthesis, the contribution of serotonergic and non‐serotonergic mechanisms to TRP’s effect remains to be elucidated.