5-HT1A receptor antagonists increase the activity of serotonergic cells in the dorsal raphe nucleus in rats treated acutely or chronically with citalopram

Abstract

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-HT1A receptor antagonists, [(S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin [(S)-UH-301] or (+)-N-tertbutyl 3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenyl-propionamide 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-HT1A 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 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-dependently increased the activity of 5-HT cells in citalopram-treated rats, 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 receptor antagonists can augment both the acute and chronic effects of citalopram on central serotonergic neurotransmission.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential Effects of the 5-Hydroxytryptamine (5-HT)1AReceptor Inverse Agonists Rec 27/0224 and Rec 27/0074 on Electrophysiological Responses to 5-HT1AReceptor Activation in Rat Dorsal Raphe Nucleus and Hippocampus in Vitro

“…This negative feedback is believed to contribute to the slow onset of the therapeutic effect of SSRI (2-3 weeks). 5-HT 1A receptor antagonists block the inhibition of serotonergic cell discharge caused by the SSRI-elicited increase in 5-HT levels (Arborelius et al, 1995;Romero and Artigas, 1997), suggesting the potential utility of 5-HT 1A receptor antagonists in hastening the therapeutic effect of antidepressant drugs (see Artigas et al, 1996). For this purpose, an ideal antagonist should selectively block raphe 5-HT 1A autoreceptors without affecting postsynaptic 5-HT 1A heteroreceptors.…”

“…To activate 5-HT 1A receptors with endogenous 5-HT and thereby inhibit serotonergic cell firing, we used citalopram, which elicits an increase in extracellular 5-HT levels through the selective block of 5-HT transporters (Arborelius et al, 1995).…”

Desensitization of 5-HT1A Autoreceptors by a Low Chronic Fluoxetine Dose Effect of the Concurrent Administration of WAY-100635

“…Based on this rationale, selective 5-HT 1A receptor antagonists (for use with SSRIs; add-on strategy) and dual action compounds (5-HT reuptake inhibitor ϩ 5-HT 1A antagonist) are being developed for use in the treatment of major depression. The prolonged administration of SSRIs has been reported to desensitize raphe 5-HT 1A autoreceptors, as assessed by single unit recordings and brain microdialysis (Blier and de Montigny 1994;Invernizzi et al 1994;Arborelius et al 1995;Le Poul et al 1995). This reduces the efficacy of the above negative feedback and increases extracellular 5-HT (Bel and Artigas 1993;Invernizzi et al 1994;Rutter et al 1994;Arborelius et al 1996).…”

Sleep deprivation reduces the citalopram –induced inhibition of serotoninergic neuronal firing in the nucleus raphe dorsalis of the rat

“…1995) antagonized the inhibitory action of citalopram in rats of all three groups. Recently, another 5-HTIA receptor blocker, WAY 1001 35, was also found by Arborelius et al (1995) to antagonize the effects of citalopram, but at doses I0 times higher than those of WAY 100635 used in the present work. In fact, this difference correlates perfectly with the respective affinities of these two antagonists for 5-HT,, receptors (Fletcher et a!.…”