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.
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.
Laboratory of Neurochemistry and Behavior, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
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Invernizzi
D000818:Animals; D015283:Citalopram / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D005838:Genotype; D006624:Hippocampus / Q000378:metabolism*; D007527:Isoenzymes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D017551:Microdialysis; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000096:biosynthesis* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013045:Species Specificity; D014364:Tryptophan / Q000378:metabolism / Q000494:pharmacology; D014365:Tryptophan Hydroxylase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D015283:Citalopram; D007527:Isoenzymes; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D014364:Tryptophan; D014365:Tryptophan Hydroxylase; C487802:Tph2 protein, mouse