In this study we have examined the acute effects of systemic administration of the selective serotonin reuptake inhibitor (SSRI), citalopram, in combination with either of the two selective 5-HT
1A receptor antagonists, (S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin [(S)-UH-301] or (+)-N-tertbutyl 3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylpropionamide dihydrochloride [(+)-WAY100135], on the activity of single 5-HT neurons in the dorsal raphe nucleus (DRN) of anesthetized rats using extracellular recording techniques. Acute administration of citalopram (0.3 mg/kg i.v.) significantly decreased the firing rate of DRN-5-HT cells most likely as a result of indirect stimulation of inhibitory somatodendritic 5-HT
1A autoreceptors located on 5-HT cells in the DRN. This effect of citalopram was completely reversed by (S)-UH-301 (0.5 mg/kg i.v.) and partly by (+)WAY100135 (0.5 mg/kg i.v.). Furthermore, the inhibitory effect of citalopram on the activity of 5-HT neurons was significantly attenuated by pretreatment with (S)-UH-301 (0.25 mg/kg i.v.) or (+)-WAY100135 (0.25 mg/kg i.v.).
We have also studied the effects of (S)-UH-301 (0.03–0.50 mg/kg i.v.) on the firing rate of single DRN5-HT cells in rats chronically treated with citalopram (20 mg/kg/day i.p. × 14 days). Administration of (S)UH-301 significantly and dose-dependently increased the activity of 5-HT cells in citalopram-treated rats, but did not affect these neurons in saline-treated (1 m1/kg/day i.p. × 14 days), control rats. Our results thus suggest that 5-HT1A receptor antagonists can augment both the acute and chronic effects of citalopram on central serotonergic neurotransmission. Since the antidepressant effect of SSRIs is critically linked to the availability of 5-HT, these findings support the notion that 5-HT1A receptor antagonists may not only shorten the latency of onset of SSRIs in the treatment of depression, but also increase their efficacy.
Key words 5-HT1A receptor antagonist - Citalopram - Antidepressant - Electrophysiology - Dorsal raphe nucleus - (S)-UH-301 - (+)-WAY100135