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      Ethanol inhibits histaminergic neurons in mouse tuberomammillary nucleus slices via potentiating GABAergic transmission onto the neurons at both pre- and postsynaptic sites

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          Abstract

          Aim:

          Ethanol, one of the most frequently used and abused substances in our society, has a profound impact on sedation. However, the neuronal mechanisms underlying its sedative effect remain unclear. In this study, we investigated the effects of ethanol on histaminergic neurons in the tuberomammillary nucleus (TMN), a brain region thought to be critical for wakefulness.

          Methods:

          Coronal brain slices (250 μm thick) containing the TMN were prepared from GAD67-GFP knock-in mice. GAD67-GFP was used to identify histaminergic neurons in the TMN. The spontaneous firing and membrane potential of histaminergic neurons, and GABAergic transmission onto these neurons were recorded using whole-cell patch-clamp recordings. Drugs were applied through superfusion.

          Results:

          Histaminergic and GAD67-expressing neurons in the TMN of GAD67-GFP mice were highly co-localized. TMN GFP-positive neurons exhibited a regular spontaneous discharge at a rate of 2–4 Hz without burst firing. Brief superfusion of ethanol (64, 190, and 560 mmol/L) dose-dependently and reversibly suppressed the spontaneous firing of the neurons in the TMN; when synaptic transmission was blocked by tetrodotoxin (1 μmol/L), ethanol caused hyperpolarization of the membrane potential. Furthermore, superfusion of ethanol markedly increased the frequency and amplitude of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs), which were abolished in the presence of the GABA A receptor antagonist bicuculline (20 μmol/L). Finally, ethanol-mediated enhancement of sIPSCs and mIPSCs was significantly attenuated when the slices were pretreated with the GABA B agonist baclofen (30 μmol/L).

          Conclusion:

          Ethanol inhibits the excitability of histaminergic neurons in mouse TMN slices, possibly via potentiating GABAergic transmission onto the neurons at both pre- and postsynaptic sites.

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          Green fluorescent protein expression and colocalization with calretinin, parvalbumin, and somatostatin in the GAD67-GFP knock-in mouse.

          Takeshi Kaneko, Kunihiko Obata, Jun-Ichi Miyazaki … (2003)
          Gamma-aminobutyric acid (GABA)ergic neurons in the central nervous system regulate the activity of other neurons and play a crucial role in information processing. To assist an advance in the research of GABAergic neurons, here we produced two lines of glutamic acid decarboxylase-green fluorescence protein (GAD67-GFP) knock-in mouse. The distribution pattern of GFP-positive somata was the same as that of the GAD67 in situ hybridization signal in the central nervous system. We encountered neither any apparent ectopic GFP expression in GAD67-negative cells nor any apparent lack of GFP expression in GAD67-positive neurons in the two GAD67-GFP knock-in mouse lines. The timing of GFP expression also paralleled that of GAD67 expression. Hence, we constructed a map of GFP distribution in the knock-in mouse brain. Moreover, we used the knock-in mice to investigate the colocalization of GFP with NeuN, calretinin (CR), parvalbumin (PV), and somatostatin (SS) in the frontal motor cortex. The proportion of GFP-positive cells among NeuN-positive cells (neocortical neurons) was approximately 19.5%. All the CR-, PV-, and SS-positive cells appeared positive for GFP. The CR-, PV, and SS-positive cells emitted GFP fluorescence at various intensities characteristics to them. The proportions of CR-, PV-, and SS-positive cells among GFP-positive cells were 13.9%, 40.1%, and 23.4%, respectively. Thus, the three subtypes of GABAergic neurons accounted for 77.4% of the GFP-positive cells. They accounted for 6.5% in layer I. In accord with unidentified GFP-positive cells, many medium-sized spherical somata emitting intense GFP fluorescence were observed in layer I. Copyright 2003 Wiley-Liss, Inc.
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            Sleep, sleepiness, sleep disorders and alcohol use and abuse.

            Thomas Roth, T Roehrs (2001)
            The study of ethanol's effects on sleep has a long history dating back to the work of Nathaniel Kleitman. This paper reviews the extensive literature describing ethanol's effects on the sleep of healthy normals and alcoholics and the newer literature that describes its interactive effects on daytime sleepiness, physiological functions during sleep, and sleep disorders. Ethanol initially improves sleep in non-alcoholics at both low and high doses with disturbance in the second half of the night sleep at high doses. Tolerance develops to the initial beneficial effects. In alcoholics sleep is disturbed both while drinking and for months of abstinence and the nature of the abstinent sleep disturbance is predictive of relapse. Ethanol interacts to exacerbate daytime sleepiness and sleep-disordered breathing, even inducing apnea in persons at risk. Ethanol's effects on other physiological functions during sleep and other sleep disorders has yet to be documented. 2001 Harcourt Publishers Ltd
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              Ethanol increases GABAergic transmission at both pre- and postsynaptic sites in rat central amygdala neurons.

              Marisa Roberto, Samuel Madamba, Scott D. Moore … (2003)
              We examined the interaction of ethanol with the gamma-aminobutyric acid (GABA)ergic system in neurons of slices of the rat central amygdala nucleus (CeA), a brain region thought to be critical for the reinforcing effects of ethanol. Brief superfusion of 11-66 mM ethanol significantly increased GABA type A (GABA(A)) receptor-mediated inhibitory postsynaptic potentials (IPSPs) and currents (IPSCs) in most CeA neurons, with a low apparent EC(50) of 20 mM. Acute superfusion of 44 mM ethanol increased the amplitude of evoked GABA(A) IPSPs and IPSCs in 70% of CeA neurons. The ethanol enhancement of IPSPs and IPSCs occurred to a similar extent in the presence of the GABA type B (GABA(B)) receptor antagonist CGP 55845A, suggesting that this receptor is not involved in the ethanol effect on CeA neurons. Ethanol superfusion also decreased paired-pulse facilitation of evoked GABA(A) IPSPs and IPSCs and always increased the frequency and sometimes the amplitude of spontaneous miniature GABA(A) IPSCs as well as responses to local GABA application, indicating both presynaptic and postsynaptic sites of action for ethanol. Thus, the CeA is the first brain region to reveal, without conditional treatments such as GABA(B) antagonists, consistent, low-dose ethanol enhancement of GABAergic transmission at both pre- and postsynaptic sites. These findings add further support to the contention that the ethanol-GABA interaction in CeA plays an important role in the reinforcing effects of ethanol.
              Article 0 comments Cited 72 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Acta Pharmacol Sin
                Journal ID (iso-abbrev): Acta Pharmacol. Sin
                Title: Acta Pharmacologica Sinica
                Publisher: Nature Publishing Group
                ISSN (Print): 1671-4083
                ISSN (Electronic): 1745-7254
                Publication date (Print): September 2016
                Publication date (Electronic): 08 August 2016
                Volume: 37
                Issue: 10
                Pages: 1325-1336
                Affiliations
                [1 ]Department of Pharmacology, State Key Laboratory of Medical Neurobiology, and Shanghai Key Laboratory of Bioactive Small Molecules, School of Basic Medical Sciences; Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Fudan University , Shanghai 200032, China
                [2 ]Laboratory of Quantitative Pharmacology, Department of Pharmacology, Wannan Medical College , Wuhu 241002, China
                [3 ]Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine , 3-39-22 Showa-machi, Maebashi 371–8511, Japan
                Author notes
                Article
                Publisher Item ID: aps201666
                DOI: 10.1038/aps.2016.66
                PMC ID: 5057237
                PubMed ID: 27498778
                SO-VID: 201fb057-29e9-4115-97e4-6be5bc6278c9
                Copyright © Copyright © 2016 CPS and SIMM
                History
                Date received : 04 April 2016
                Date accepted : 24 May 2016
                Categories
                Subject: Original Article

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: ethanol,tuberomammillary nucleus,histaminergic neurons,gaba receptor,ipscs,bicuculline,baclofen,tetrodotoxin
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: ethanol, tuberomammillary nucleus, histaminergic neurons, gaba receptor, ipscs, bicuculline, baclofen, tetrodotoxin

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