Abstract
Acute systemic injection of selective serotonin reuptake inhibitors (SSRIs) decreases 5-HT neuronal firing in the dorsal raphe nucleus (DRN). Recent data, however, question whether these drugs also inhibit the firing of 5-HT neurones in the median raphe nucleus (MRN). Using in vivo extracellular electrophysiological recording techniques in the chloral hydrate anaesthetised rat, we have tested the effect of acute administration of the SSRI, paroxetine, on 5-HT neuronal activity in the MRN and DRN. Presumed 5-HT neurones in the MRN displayed the same electrophysiological characteristics as those in the DRN, the only detectable difference being that MRN neurones showed a significantly (p < 0.001) slower mean ( ± SEM(n)) spontaneous firing rate (MRN, 5.6 ± 0.9 (14) spikes/10 s; DRN, 13.5 ± 1.6 (24) spikes/10 s). Paroxetine caused a dose-related (0.1–0.8 mg/kg i.v.) inhibition of all MRN neurones tested (n = 8), producing a complete cessation of cell-firing at the highest doses. DRN neurones (n = 9) responded in a similar fashion. Furthermore, paroxetine inhibited MRN and DRN neurones with almost identical potency (MRN ED50 259 ± 57 μg/kg i.v.: DRN ED50 243 ± 49 μg/kg i.v.). In the majority of cells tested, the effect of paroxetine was reversed by the 5-HT1A receptor antagonists spiperone or (+)WAY100135, implicating the involvement of the 5-HT1A autoreceptor. The selective 5-HT1A receptor agonist 8-OH-DPAT also inhibited the firing of MRN (n = 5) and DRN (n = 12) neurones and with equal potency (MRN ED50, 1.32 ± 0.40 μg/kg i.v.: DRN ED50, 1.19 ± 0.23 μg/kg i.v.). Our data indicate that paroxetine not only inhibits the firing of 5-HT neurones in the MRN but does so with equal potency to those in the DRN.
Similar content being viewed by others
References
Aghajanian GK, Foote WF, Sheard MH (1968) Lysergic acid diethylamide: Sensitive neuronal units in the midbrain raphe. Science 161: 706–708
Aghajanian GK, VanderMaelen CP (1982) Intracellular identification of central noradrenergic and serotonergic neurons by a new double labeling procedure. J Neurosci 2:1786–1792
Aghajanian GK, Wang RY, Baraban J (1978) Serotonergic and non-serotonergic neurons of the dorsal raphe: reciprocal changes in firing induced by peripheral nerve stimulation. Brain Res 153:169–175
Artigas F, Perez V, and Alvarez E (1994) Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors. Arch Gen Psychiatry 51:248–251
Bel N, Artigas F (1992) Fluvoxamine preferentially increases extracellular 5-hydroxytryptamine in the raphe nuclei: an in vivo microdialysis study. Eur J Pharmacol 229:101–103
Blier P, de Montigny C, Tardif D (1987) Short-term lithium treatment enhances responsiveness of postsynaptic 5-HT1A receptors without altering 5-HT autoreceptor sensitivity: An electrophysiological study in the rat brain. Synapse 1: 225–232
Blier P, Serrano A, Scatton B (1990) Differential responsiveness of the rat dorsal and median raphe 5-HT systems to 5-HT1, receptor agonists and p-chloramphetamine. Synapse 5:120–133
Bramwell GJ (1974) The effects of antidepressants on unit activity in the midbrain raphe of rats. Arch Int Pharmacodyn Ther 211: 24–33
Ceci A, Baschirotto A, Borsini F (1994) The inhibitory effect of 8-OH-DPAT on the firing activity of dorsal raphe serotoninergic neurons in rats is attenuated by lesion of the frontal cortex. Neuropharmacology 33: 709–713
Chaput Y, Blier P, de Montigny C (1986) In vivo electrophysiological evidence for the regulatory role of autoreceptors on serotonergic terminals. J Neurosci 6:2796–2801
Fletcher A, Bill DJ, Bill SJ, Brammer NT, Cliffe IA, Dover GM, Forster EA, Haskins JT, Jones D, Mansell HL, Reilly Y (1993) ( + )WAY100135: a novel, selective antagonist at presynaptic and postsynaptic 5-HT1A receptors. Eur J Pharmacol 237: 283–291
Gallager DW, Aghajanian GK (1975) Effects of chlorimipramine and lysergic acid diethylamide on efflux of precursor-formed 3H-serotonin: correlations with serotonergic impulse flow. J Pharmacol Exp Ther 193: 785–795
Haigler HJ, Aghajanian GK (1974) Lysergic acid diethylamide and serotonin: A comparison of effects on serotonergic neurons and neurons receiving a serotonergic input. J Pharmacol Exp Ther 188:688–699
Hjorth S (1993) Serotonin 5-HT1Aautoreceptor blockade potentiates the ability of the 5-HT reuptake inhibitor citalopram to increase nerve terminal output of 5-HT in vivo: a microdialysis study. J Neurochem 60:776–779
Hjorth S, Sharp T (1991) Effect of the 5-HT1A receptor agonist 8-OH-DPAT on the release of 5-HT in dorsal and median raphe-innervated rat brain regions as measured by in vivo microdialysis. Life Sci 48:1779–1786
Invernizzi R, Belli S, Samanin R (1992) Citalopram's ability to increase the extracellular concentrations of serotonin in the dorsal raphe prevents the drug's effect in the frontal cortex. Brain Res 584:322–324.
Lum JT, Piercey, MF (1989) Neuropharmacology of 5-HT1A agonists: effects on firing rates of norepinephrine cells more related to effects on dopamine cells than to effects on 5-HT. Soc Neurosci Abstr 15:485.6.
Moore RY (1981) The anatomy of central serotonin neuron systems in the rat brain. In: Jacobs BL, Gelpin A (eds) Serotonin neurotransmission and behaviour. MIT Press, Cambridge, Mass., pp 35–71
Paxinos G, Watson C (1982) The Rat Brain in Stereotaxic Coordinates. Academic Press, Sydney
Rigdon GC, Wang CM (1991) Serotonin uptake blockers inhibit the firing of presumed serotonergic dorsal raphe neurons in vitro. Drug Dev Res 22:135–140
Scuvée-Moreau J, Dresse AR (1979) Effect of various antidepressant drugs on the spontaneous firing rate of locus coeruleus and dorsal raphe neurons of the rat. Eur. J. Pharmacol 57: 690–694
Sheard MH, Zolovick A, Aghajanian GK (1972) Raphe neurones: effect of tricyclic antidepressant drugs. Brain Res. 43: 690–694.
Sinton CM, Fallon SC (1988) Electrophysiological evidence for a functional differentiation between subtypes of the 5-HT1 receptor. Eur J Pharmacol 157:173–181
Sotelo C, Cholley B, El Mestikawy S, Gozlan H, Hamon M (1990) Direct immunocytochemical evidence of the existence of 5-HT1A autoreceptors on serotonergic neurons in the midbrain raphe nuclei. Eur J Neuroscience 2: 1144–1154
Starkey SJ, Skingle M (1994) 5-HT1D as well as 5-HT1A autoreceptors modulate 5-HT release in the guinea pig dorsal raphe nucleus. Neuropharmacology 33: 393–402.
VanderMaelen CP, Braselton JP (1990) Intravenously administered buspirone inhibits dorsal and median raphe 5-HT neurones with about equal potency. 2nd IUPHAR Satellite Meeting on Serotonin, Basel, Switzerland
Werner G, Mountcastle VB (1963) The variability of central neural activity in a sensory system and its implications for the central reflection of sensory events. J Neurophysiol 26:958–977
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hajós, M., Gartside, S.E. & Sharp, T. Inhibition of median and dorsal raphe neurones following administration of the selective serotonin reuptake inhibitor paroxetine. Naunyn-Schmiedeberg's Arch Pharmacol 351, 624–629 (1995). https://doi.org/10.1007/BF00170162
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00170162