Effects of a selective 5-HT reuptake blocker, citalopram, on the sensitivity of 5-HT autoreceptors: Electrophysiological studies in the rat brain

Abstract

Citalopram (CIT), is a selective serotonin (5-HT) reuptake blocker and a clinically effective antidepressant. The present electrophysiological studies were undertaken to investigate in vivo the acute and long-term effects of CIT administration on 5-HT neurotransmission. In a first series of experiments, a single dose of CIT (0.05-0.5 mg/kg) was administered intravenously to naive rats while recording the activity of a 5-HT-containing neuron in the nucleus raphe dorsalis. A dose-response relationship of the inhibitory effect of CIT on the firing activity of 5-HT neurons was obtained with an ED50 of 0.23 +/- 0.03 mg/kg. In a second series of experiments, rats were treated with CIT (20 mg/kg/day, i.p.) for 2, 7 and 14 days. In rats treated for 2 days, there was a marked reduction in the firing activity of 5-HT neurons in the nucleus raphe dorsalis; there was a partial recovery after 7 days and a complete recovery after 14 days of treatment. The response of 5-HT neurons to intravenously administered LSD was decreased in rats treated for 14 days with CIT, indicating a desensitization of the somatodendritic 5-HT autoreceptor. In a third series of experiments, carried out in rats treated with CIT (20 mg/kg/day, i.p.) for 14 days, the suppression of firing activity of CA3 hippocampal pyramidal neurons produced by microiontophoretically-applied 5-HT and by the electrical activation of the ascending 5-HT pathway was measured. Long-term treatment with CIT did not modify the responsiveness of these neurons to microiontophoretically-applied 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

Potentiation by (-)Pindolol of the Activation of Postsynaptic 5-HT1A Receptors Induced by Venlafaxine

“…The acute intravenous administration of 5-HT reuptake inhibitors suppresses the firing activity of the 5-HT neurons of the dorsal and median raphe nuclei (de Montigny et al 1981;Blier et al 1984;Chaput et al 1986;Hajós et al 1995) ACh-induced firing activity in control and in 5,7-DHT-lesioned rats is shown in B. * p Ͻ .01, compared to control values using the non-paired Student's t-test.…”

“…The acute intravenous administration of 5-HT reuptake inhibitors suppresses the firing activity of the 5-HT neurons of the dorsal and median raphe nuclei (de Montigny et al 1981;Blier et al 1984;Chaput et al 1986;Hajós et al 1995) due to an enhanced activation of the somatodendritic 5-HT 1A autoreceptor by an increased level of extracellular 5-HT in the raphe (Adell and Artigas 1991;Bel and Artigas 1993;Hajós et al 1995;Gartside et al 1995;Rutter et al 1995;Béïque et al 1999). ACh-induced firing activity in control and in 5,7-DHT-lesioned rats is shown in B.…”

“…At least in the rat, this occurs only in the midst of long-term administration of antidepressant treatments, which is necessary for the development of specific adaptative changes. Indeed, acute administration of SSRI's induces a reduction of firing activity of the 5-HT neurons of the raphe nuclei due to an increased activation of the somatodendritic 5-HT 1A autoreceptors, resulting from the increased extracellular 5-HT (de Montigny et al 1981;Blier et al 1984;Chaput et al 1986;Hajós et al 1995;Béïque et al 1999). However, in the course of a long-term administration of SSRI's, 5-HT neurons recover their normal firing activity as a consequence of the desensitization of these autoreceptors .…”

“…Several studies from our laboratory have shown that, in the course of a sustained administration of a 5-HT reuptake blocking agent, the degree of suppression of firing activity of 5-HT neurons is maximal at two days of treatment (Blier et al 1984;Chaput et al 1986). We have, thus, made use of this paradigm to assess the ability of (-)pindolol to prevent the effect of venlafaxine on somatodendritic 5-HT 1A receptors.…”

“…Moreover, a pretreatment with the mixed ␤-adrenoceptor/5-HT 1A antagonist (-) pindolol, but not with the selective ␤-adrenoceptor antagonist metoprolol, potentiated the suppression of firing activity of CA 3 pyramidal neurons induced by venlafaxine. Finally, the observation that a two-day treatment with the coadministration of (-)pindolol and venlafaxine prevented the suppression of firing activity of dorsal raphe 5-HT neurons induced by a two-day treatment with venlafaxine alone, confirmed the antagonistic activity of (-)pindolol at the level of the somatodendritic 5-HT 1A autoreceptor.The acute intravenous administration of 5-HT reuptake inhibitors suppresses the firing activity of the 5-HT neurons of the dorsal and median raphe nuclei (de Montigny et al 1981;Blier et al 1984;Chaput et al 1986;Hajós et al 1995) ACh-induced firing activity in control and in 5,7-DHT-lesioned rats is shown in B. * p Ͻ .01, compared to control values using the non-paired Student's t-test.…”