Evidence for involvement of 5-hydroxytryptamine(1B) autoreceptors in the enhancement of serotonin turnover in the mouse brain following repeated treatment with fluoxetine.
The effect of repeated treatment with the selective serotonin reuptake inhibitor fluoxetine on synthesis and turnover of 5-hydroxytryptamine (5-HT) was studied in the mouse brain in vivo. The concentration of 5-hydroxytryptophan (5-HTP), 5-hydroxyindoleacetic acid (5-HIAA) and 5-HT was measured in hypothalamus, hippocampus and frontal cortex after inhibition of the aromatic amino acid decarboxylase activity with m-hydroxybenzylhydrazine (NSD 1015). Fluoxetine 6.9 mg/kg s.c. was injected once daily for three weeks. Three days after the final daily injection of fluoxetine 5-HT synthesis (5-HTP accumulation) and turnover (5-HIAA/5-HT ratio) were significantly enhanced compared with saline-treated mice. The 5-HIAA/5-HT ratio was already significantly elevated after 3 days of fluoxetine treatment and continued to increase during treatment for 2-3 weeks. The increase in 5-HIAA/5-HT ratio was considerably larger (150-200% of controls) than the increase in 5-HTP accumulation (110-120%), which reached significance only after 3 weeks of treatment. The increase in 5-HT synthesis may be secondary to that of the turnover. The 5-HIAA/5-HT ratio returned to control values after a 14 days washout period. Simultaneous treatment with the long-acting 5-HT(1B)-receptor antagonist, SB 224289 for 14 days counteracted the fluoxetine-induced increase in 5-HIAA/5-HT ratio that indicates involvement of 5-HT(1B) autoreceptors in the development of this increase. It is proposed that the fluoxetine-induced enhancement of 5-HT turnover was evoked by the long-lasting stimulation of 5-HT(1B) autoreceptors that resulted in an intraneuronal compensatory adaptation of the basal 5-HT release.
Stenfors
Carina
C
Bioscience, Local Discovery, Astra Zeneca R&D Södertälje, S-151 85, Södertälje, Sweden. carina.stenfors@astrazeneca.com
Ross
Svante B
SB
D006916:5-Hydroxytryptophan / Q000378:metabolism; D000818:Animals; D017660:Autoreceptors / Q000378:metabolism*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004347:Drug Interactions; D005473:Fluoxetine / Q000494:pharmacology*; D006834:Hydrazines / Q000494:pharmacology; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010881:Piperidones / Q000008:administration & dosage; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013141:Spiro Compounds / Q000008:administration & dosage
D006916:5-Hydroxytryptophan; D017660:Autoreceptors; D005473:Fluoxetine; D006834:Hydrazines; D006897:Hydroxyindoleacetic Acid; D010881:Piperidones; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D013141:Spiro Compounds; C108518:SB 22489G; C004297:3-hydroxybenzylhydrazine