Differential changes in brain and platelet 5-HT concentrations after steady-state achievement and repeated administration of antidepressant drugs in mice.
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 concomitant 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.
Alvarez
J C
JC
Faculté de Médecine Paris-Ouest-Université Paris V Département de Biochimie-Pharmacologie-Toxicologie, Centre Hospitalier de Versailles, Le Chesnay, France.
Sanceaume
M
M
Advenier
C
C
Spreux-Varoquaux
O
O
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage*; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002421:Caudate Nucleus / Q000378:metabolism; D002997:Clomipramine / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005473:Fluoxetine / Q000008:administration & dosage; D005625:Frontal Lobe / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D020912:Moclobemide / Q000008:administration & dosage; D011903:Raphe Nuclei / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D013997:Time Factors; D014364:Tryptophan / Q000378:metabolism
D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D005473:Fluoxetine; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D014364:Tryptophan; D002997:Clomipramine; D020912:Moclobemide