Pre‐ and postsynaptic effects of zimelidine and norzimelidine on the serotoninergic system: single cell studies in the rat

Abstract

The pre-and postsynaptic effects of zimelidine and norzimelidine were studied in adult male Sprague-Dawley rats. The potency of the presynap tic effect was estimated from their ability to depress the rate of firing of serotonin (5-HT)-containing raphe neurons. Chronic administration of tricyclic antidepressant drugs has been shown to sensitize forebrain postsynaptic 5-HT receptors. The effect of zimelidine on these receptors was compared to that of saline and chlorimipramine by assessing the responsiveness of hippocampal pyramidal cells to microiontophoretic applications of 5-HT, norepinephrine (NE) and y-aminobutyric acid (GABA).Consistent with their known 5-HT reuptake blocking property, acute intravenous administration of zimelidine and norzimelidine depressed the firing rate of 5-HT-containing dorsal raphe neurons. EDso of zimelidine and norzimelidine were respectively 1.1 mglkg and 0.8 mg/kg. Chronic administration of zimelidine (5 and 10 mg/kg, q.d. for 14 days) did not modify the responsiveness of hippocampal pyramidal cells to iontophoretic applications of 5-HT, NE and GABA, whereas chlorimipramine (5 mg/kg, q.d. for 14 days) increased selectively their sensitivity to 5-HT.Since the antidepressant efficacy of zimelidine is well documented, it is concluded that sensitization of forebrain postsynaptic 5-HT receptors is not a prerequisite for a drug to exert an antidepressant effect. It is suggested that an enhancement of the 5-HT-mediated synaptic transmission might be the final effect of the various types of antidepressant treatment whether their primary effect is pre-or postsynaptic.

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 .…”

“…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.…”

Current therapeutic strategies for premature ejaculation and future perspectives

“…41 Increasing 5-HT levels activates 5-HT 1A autoreceptors, resulting in less 5-HT being released into the synaptic cleft within minutes. 42 A higher 5-HT concentration increases activation of presynaptic 5-HT 1B autoreceptors, which alone can reduce the release of 5-HT. Under normal physiological conditions, the net effect of acute administration of SSRIs is little to no increase in 5-HT neurotransmission and minimal or no stimulation of postsynaptic 5-HT receptors.…”