Pharmacological characteristics of GABAA responses in postnatal suprachiasmatic neurons in culture

Kawahara, Futoshi; Saito, Hiroshi; Katsuki, Hiroshi

doi:10.1016/0304-3940(93)90913-6

Cited by 34 publications

(18 citation statements)

References 18 publications

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“…GABA is known to block photic phase shifts (Ralph and Menaker, 1989;Mintz et al, 2002). However, ethanol was shown to not enhance GABA currents in SCN neurons (Kawahara et al, 1993), and it is not clear how excess BDNF would be able to reverse GABAergic inhibition of glutamate phase shifts, as seen here. Thus, the data are more consistent with ethanol acting on glutamate signaling.…”

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confidence: 51%

Acute ethanol modulates glutamatergic and serotonergic phase shifts of the mouse circadian clock in vitro

2008

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Alcohol abuse is associated with sleep problems, which are often linked to circadian rhythm disturbances. However, there is no information on the direct effects of ethanol on the mammalian circadian clock. Acute ethanol inhibits glutamate signaling, which is the primary mechanism through which light resets the mammalian clock in the suprachiasmatic nucleus (SCN). Glutamate and light also inhibit circadian clock resetting induced by non-photic signals, including serotonin. Thus, we investigated the effects of acute ethanol on both glutamatergic and serotoninergic resetting of the SCN clock in vitro. We show that ethanol dose-dependently inhibits glutamate-induced phase shifts and enhances serotonergic phase shifts. The inhibition of glutamate-induced phase shifts is not affected by excess glutamate, glycine or D-serine, but is prevented by excess brain-derived neurotrophic factor (BDNF). BDNF is known to augment glutamate signaling in the SCN and to be necessary for glutamate/light-induced phase shifts. Thus, ethanol may inhibit glutamate-induced clock resetting at least in part by blocking BDNF enhancement of glutamate signaling. Ethanol enhancement of serotonergic phase shifts is mimicked by treatments that suppress glutamate signaling in the SCN, including antagonists of glutamate receptors, BDNF signaling and nitric oxide synthase. The combined effect of ethanol with these treatments is not additive, suggesting they act through a common pathway. Our data indicate further that the interaction between serotonin and glutamate in the SCN may occur downstream from nitric oxide synthase activation. Thus, acute ethanol disrupts normal circadian clock phase regulation, which could contribute to the physiological and psychological problems associated with alcohol abuse. Keywords suprachiasmatic nucleus; circadian rhythms; ethanol; glutamate; serotonin; brain-derived neurotrophic factorThe development of alcoholism and the likelihood of relapse drinking are associated with poor sleep quality and the deleterious effects of ethanol on sleep (Landolt and Gillin, 2001;Brower et al., 2001). Alcohol consumption reduces sleep quality (Kubota et al., 2002;Ehler and Slawecki, 2000;Landolt et al., 1996), which is closely linked to the circadian system. For example, the inability to fall asleep at the desired time can result from improper synchronization *Corresponding author: Dept. Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996, phone: (865) 974-2722, FAX: (865)-974-6306, rprosser@utk.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal per...

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confidence: 51%

Acute ethanol modulates glutamatergic and serotonergic phase shifts of the mouse circadian clock in vitro

2008

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“…A variety of GABA receptor subunits are expressed in the SCN (Gao et al, 1995;Naum et al, 2001;O'Hara et al, 1995;Belenky et al, 2003), and GABA receptors are seen in pre-, post- and extra-synaptic locations (Belenky et al, 2003). Pharmacological studies have provided evidence for the presence of both δ- and δ-subunit-containing GABA receptors in the SCN (Kawahara et al, 1993;Shimura et al, 1996). …”

Section: Discussionmentioning

confidence: 99%

Ethanol modulates mammalian circadian clock phase resetting through extrasynaptic gaba receptor activation

et al. 2009

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Ethanol modulates the actions of multiple neurotransmitter systems, including GABA. However, its enhancing effects on GABA signaling typically are seen only at high concentrations. In contrast, although GABA is a prominent neurotransmitter in the circadian clock of the suprachiasmatic nucleus (SCN), we see ethanol modulation of clock phase resetting at low concentrations (<50 mM). A possible explanation is that ethanol enhances GABAergic signaling in the SCN through activating GABA A receptors that contain the δ subunit (GABA Aδ receptors), which are sensitive to low ethanol concentrations. Therefore, we investigated whether ethanol acts on GABA Aδ receptors in the SCN. Here we show that acute application of the GABA Aδ receptor antagonist, RO15-4513, to mouse hypothalamic slices containing the SCN prevents ethanol inhibition of nighttime glutamate-induced (photic-like) phase delays of the circadian clock. Diazepam, which enhances activity of GABA Aγ receptors, does not modulate these phase shifts. Moreover, we find that RO15-4513 prevents ethanol enhancement of daytime serotonergic (non-photic) phase advances of the circadian clock. Furthermore, diazepam phase-advances the SCN circadian clock when applied alone in the daytime, while ethanol has no effect by itself at that time. These data support the hypothesis that ethanol acts on GABA Aδ receptors in the SCN to modulate photic and non-photic circadian clock phase resetting. They also reveal distinct modulatory roles of different GABA A receptor subtypes in circadian clock phase regulation.Keywords suprachiasmatic nucleus; circadian rhythms; GABA; alcohol; benzodiazepine Alcoholism and alcohol abuse pose major health concerns that are difficult to treat in part due to ethanol's diverse actions throughout the central nervous system. One of the neurotransmitter systems modulated by ethanol is GABA: Ethanol increases GABA release, and enhances the activity of both GABA A and GABA B receptors (see (Weiner and Valenzuela, 2006) Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2010 December 1. (Mihic et al., 1997;Sigel et al., 1993;Vengeliene et al., 2008). At levels typically associated with social ethanol consumption (< 50 mM), however, the GABAergic effects of ethanol appear to be restricted primarily to a subset of GABA A receptors that contain the δ subunit (GABA Aδ receptors) (Mihic et al., 1997;Wallner et al., 2003;Glykys et al., 2007;Wei et al., 2004;Olsen et al., 2007;Santhakumar et al., 2007). These receptors are thought to...

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“…Results from studies of SCN neurons obtained from early postnatal rats are not consistent. One study found that GABA-induced inward current in the SCN was inhibited by Zn 2+ in a dose-dependent manner, and that there was no potentiation of the current response by the BDZ diazepam as would be expected if the γ subunit was present (Kawahara et al, 1993). Another study also using SCN neurons from early postnatal rats found that diazepam potentiates GABA-induced currents, thereby suggesting that the SCN does contain γ subunits (Shimura et al, 1996).…”

Section: Gaba Receptorsmentioning

confidence: 99%

The dynamics of GABA signaling: Revelations from the circadian pacemaker in the suprachiasmatic nucleus

Albers

Walton

Gamble

et al. 2017

Frontiers in Neuroendocrinology

133

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Virtually every neuron within the suprachiasmatic nucleus (SCN) communicates via GABAergic signaling. The extracellular levels of GABA within the SCN are determined by a complex interaction of synthesis and transport, as well as synaptic and non-synaptic release. The response to GABA is mediated by GABAA receptors that respond to both phasic and tonic GABA release and that can produce excitatory as well as inhibitory cellular responses. GABA also influences circadian control through the exclusively inhibitory effects of GABAB receptors. Both GABA and neuropeptide signaling occur within the SCN, although the functional consequences of the interactions of these signals are not well understood. This review considers the role of GABA in the circadian pacemaker, in the mechanisms responsible for the generation of circadian rhythms, in the ability of non-photic stimuli to reset the phase of the pacemaker, and in the ability of the day-night cycle to entrain the pacemaker.

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Pharmacological characteristics of GABAA responses in postnatal suprachiasmatic neurons in culture

Cited by 34 publications

References 18 publications

Acute ethanol modulates glutamatergic and serotonergic phase shifts of the mouse circadian clock in vitro

Acute ethanol modulates glutamatergic and serotonergic phase shifts of the mouse circadian clock in vitro

Ethanol modulates mammalian circadian clock phase resetting through extrasynaptic gaba receptor activation

The dynamics of GABA signaling: Revelations from the circadian pacemaker in the suprachiasmatic nucleus

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