EFFECT OF 5-HT1A RECEPTOR ANTAGONISTS ON CITALOPRAM-INDUCED INCREASE IN EXTRACELLULAR SEROTONIN IN THE FRONTAL-CORTEX, STRIATUM AND DORSAL HIPPOCAMPUS

The aim of the present study was to compare the effects of citalopram, either alone or combined with 5-HT1A receptor antagonists, on extrace llular serotonin levels in brain regions innervated by the dorsal or m edian raphe nuclei. Using intracerebral microdialysis in awake rats wi th separate probes in the frontal cortex or dorsal hippocampus, we stu died the ability of 8 mg/kg s.c. (-)penbutolol, a beta-adrenoceptor an tagonist with antagonist action at 5-HT1A and 5-HT1B receptors, and 0. 3 mg/kg s.c. WAY-100635, a selective 5-HT1A receptor blocker, to modif y the effect of 1 and 10 mg/kg i.p. citalopram on extracellular seroto nin. Both doses of citalopram had more effect on extracellular seroton in levels in the dorsal hippocampus than in the frontal cortex. The ef fect of 1 mg/kg citalopram was significantly potentiated by (-)penbuto lol in the frontal cortex only, but a clear-cut potentiation of the ef fect of citalopram was seen in both regions at a dose of 10 mg/kg. The effect of 10 mg/kg citalopram was potentiated by WAY-100635 in the fr ontal cortex but not in the dorsal hippocampus. In a second set of exp eriments, the combined effect of WAY-100635 and citalopram was studied in the same rat implanted with vertical probes in the striatum and do rsal hippocampus. Citalopram (1 and 10 mg/kg i.p.) raised extracellula r serotonin to a similar extent in both regions. However, 0.3 mg/kg s. c. WAY-100635 potentiated the effect of 10 mg/kg citalopram in the str iatum but not in the dorsal hippocampus. The results suggest that only a combined blockade of 5-HT1A and 5-HT1B receptors potentiates the ef fect of citalopram on extracellular concentrations of serotonin in the dorsal hippocampus. The findings may be relevant in designing clinica l trials aimed at enhancing the antidepressant action of selective ser otonin re-uptake inhibitors by combining them with serotonin receptor antagonists. (C) 1997 Elsevier Science Ltd.