5-HT1A RECEPTOR ANTAGONISTS INCREASE THE ACTIVITY OF SEROTONERGIC CELLS IN THE DORSAL RAPHE NUCLEUS IN RATS TREATED ACUTELY OR CHRONICALLY WITH CITALOPRAM

In this study we have examined the acute effects of systemic administr ation of the selective serotonin reuptake inhibitor (SSRI), citalopram , in combination with either of the two selective 5-HT1A receptor anta gonists, (S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin [(S)-UH-301 ] or (+)-N-tertbutyl methoxyphenyl)piperazin-1-yl)-2-phenylpropionamid e dihydrochloride [(+)-WAY100135], on the activity of single 5-HT neur ons in the dorsal raphe nucleus (DRN) of anesthetized rats using extra cellular 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 somatod endritic 5-HT1A autoreceptors located on 5-HT cells in the DRN. This e ffect 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 in hibitory effect of citalopram on the activity of 5-HT neurons was sign ificantly 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 DRN- 5-HT cells in rats chronically treated with citalopram (20 mg/kg/day i .p. x 14 days). Administration of (S)-UH-301 significantly and dose-de pendently increased the activity of 5-HT cells in citalopram-treated r ats, but did not affect these neurons in saline-treated (1 ml/kg/day i .p. x 14 days), control rats. Our results thus suggest that 5-HT1A rec eptor antagonists can augment both the acute and chronic effects of ci talopram on central serotonergic neurotransmission. Since the antidepr essant effect of SSRIs is critically linked to the availability of 5-H T, 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.