Inhibition of hippocampal 5-HT synthesis by fluoxetine and paroxetine: Evidence for the involvement of both 5-HT1A and 5-HT1B/D autoreceptors

Hippocampal serotonin (5-hydroxytryptamine, 5-HT) synthesis, as determined by the accumulation of 5-hydroxytryptophan (5-HTP) following inhibition of L-aromatic amino acid decarboxylase with NSD 1015, was inhibited by systemi c administration of the selective serotonin reuptake inhibitors fluoxetine (10 mg/kg i.p.) and paroxetine (3 mg/kg i.p.). Pretreatment of rats with th e selective 5-HT1A receptor antagonist WAY 100635 for a period of 7 days us ing subcutaneously implanted osmotic minipumps (1 mg/kg/day) was sufficient to block the inhibition of 5-HT synthesis following the 5-HT1A receptor ag onist 8-OH-DPAT (0.3 mg/kg s.c.), but failed to inhibit the decrease of hip pocampal 5-HT synthesis by fluoxetine (10 mg/kg i.p.) or paroxetine (3 mg/k g i.p.). Similarly, pretreatment of rats with GR 121935 (5 mg/kg i.p.), an antagonist with high affinity for 5-HT1B/D receptors, blocked the reduction of hippocampal 5-HT synthesis following the 5-HT receptor agonist TFMPP (3 mg/kg s.c.) without affecting the reduction of hippocampal 5-HT synthesis by either fluoxetine or paroxetine. In contrast, pretreatment with WAY 1006 35 (1 mg/kg/day, for 7 days s.c. in osmotic minipumps) in combination with CTR 127935 (5 mg/kg i.p.) significantly attenuated the decrease of hippocam pal 5-HT synthesis by both fluoxetine and paroxetine. These results indicat e that both 5-HT1A and 5-HT1B/1D receptors, which function in the rat as in hibitory somatodendritic and nerve terminal autoreceptors, independently re gulate hippocampal 5-HT synthesis and must be simultaneously blocked to pre vent the inhibition of 5-HT synthesis by selective serotonin reuptake inhib itors which increase 5-HT availability at both nerve terminals in hippocamp us and 5-HT cell bodies in the raphe nuclei. Synapse 31:13-19, 1999. (C) 19 99 Wiley-Liss, Inc.