Differential changes in brain and platelet 5-HT concentrations after steady-state achievement and repeated administration of antidepressant drugs in mice.

Abstract The aim of the study was to compare in male NMRI mice the simultaneous evolution of blood serotonin (5-HT) concentrations, which correspond to 99% of platelet 5-HT content, and 5-HT parameters in the dorsal raphe, caudate nucleus and frontal cortex after clomipramine, fluoxetine and moclobemide treatments. After steady-state concentrations of the three compounds were reached, the 5-HT levels were significantly enhanced vs. saline-treated mice in the three brain areas studied. Tryptophan (TRP) levels in the three brain areas were significantly increased with clomipramine and fluoxetine but not with moclobemide. A significant decrease in the metabolite 5-hydroxyindoleacetic acid (5-HIAA) levels was observed only with moclobemide. After 14 days of treatment, 5-HT levels in all areas studied were found to be enhanced only with moclobemide while TRP and 5-HIAA levels were not different under the three drug regimes from those of controls. After 21 days of treatment, 5-HT levels were found enhanced only with moclobemide in the nerve terminal regions. An important depletion in platelet 5-HT content was observed after clomipramine and fluoxetine treatments at day 14 and day 21 and a significant increase was observed after moclobemide treatment at day 14 with a return to initial values after 21 days. Our results show significantly different effects between central and peripheral indices of 5-HT metabolism according to time and to the antidepressant assessed: (i) an enhancement of total tissue 5-HT levels in the three brain areas studied after steady-state achievement of the 3 antidepressants, (ii) the return to initial values of brain 5-HT levels after repeated administration of the two 5-HT re-uptake inhibitors, consistent with the presence of brain adaptative mechanisms, with a concomittant dramatic decrease of platelet 5-HT content and (iii) an apparent gradual attenuation of the brain and periphery MAOI-A effect induced by moclobemide with 5-HT levels remaining elevated only in 5-HT nerve terminal regions.