Mechanisms of stimulatory effects of mecamylamine on the dorsal raphe neurons.

Autor: Hernández-González O; Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), PO Box 70250, Ciudad de México, 04510, Mexico., Mondragón-García A; Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), PO Box 70250, Ciudad de México, 04510, Mexico., Hernández-López S; Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), PO Box 70250, Ciudad de México, 04510, Mexico. Electronic address: salvadorhl@comunidad.unam.mx., Castillo-Rolon DE; Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), PO Box 70250, Ciudad de México, 04510, Mexico., Arenas-López G; Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), PO Box 70250, Ciudad de México, 04510, Mexico., Tapia D; División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, 04510, Mexico., Mihailescu S; Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), PO Box 70250, Ciudad de México, 04510, Mexico.
Jazyk: angličtina
Zdroj: Brain research bulletin [Brain Res Bull] 2020 Nov; Vol. 164, pp. 289-298. Date of Electronic Publication: 2020 Sep 07.
DOI: 10.1016/j.brainresbull.2020.08.031
Abstrakt: Previous studies showed that mecamylamine a noncompetitive and nonspecific blocker of nicotinic acetylcholine receptors (nAChRs), stimulates the activity of the dorsal raphe nucleus (DRN) serotonergic neurons and DRN serotonin (5-HT) release. In the present study, the mechanisms involved in these mecamylamine-induced effects were examined using electrophysiology and calcium-imaging studies, both performed in Wistar rat midbrain slices. Mecamylamine (0.5-9 μM), bath administered, increased the firing frequency of identified 5-HT DRN neurons by a maximum of 5% at 3 μM. This effect was accompanied by a 112 % increase in the frequency of spontaneous excitatory postsynaptic currents of 5-HT DRN neurons. It was blocked by the AMPA/kainate receptor blocker CNQX (10 μM) and by the specific α4β2 nAChRs blocker dihydro-β-erythroidine (100 nM) but was not affected by tetrodotoxin (TTX, 500 nM). Simultaneously, mecamylamine produced a 58 % decrease in the frequency of GABAergic spontaneous inhibitory postsynaptic currents, an effect that was not influenced by TTX. Calcium-imaging studies support the results obtained with the electrophysiological studies by showing that mecamylamine (3 μM) increases the activity of a cell population located in the midline of the DRN, which was sensitive to the inhibitory effects of 8-OH-DPAT, an agonist at 5-HT 1A receptors. It is assumed that mecamylamine, in low concentrations, acts as an agonist of α4β2 nAChRs present on the glutamatergic DRN terminals, thus increasing intra-raphe glutamate release. This stimulatory effect is reinforced by the decrease in DRN GABA release, which is dependent on the mecamylamine-induced blockade of α7 nAChRs located on DRN GABAergic terminals. We hypothesize that at least a part of mecamylamine antidepressant effects described in animal models of depression are mediated by an increase in DRN 5-HT release.
(Copyright © 2020. Published by Elsevier Inc.)
Databáze: MEDLINE
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