Extrasynaptic Glycine Receptors of Rodent Dorsal Raphe Serotonergic Neurons: A Sensitive Target for Ethanol

Maguire, Edward P; Mitchell, Elizabeth A.; Greig, Scott J; Corteen, Nicole L.; Balfour, David J.K.; Swinny, Jerome D.; Lambert, Jeremy J.; Belelli, Delia

doi:10.1038/npp.2013.326

Cited by 36 publications

(38 citation statements)

References 61 publications

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“…1C and 2A) produced significant shifts in the holding current of MSNs, confirming the presence of tonic currents in our study. The small amplitude of these currents likely reflects lower expression levels, as the overall relative abundance of GlyRs in the NAc is lower than in the dorsal raphé, with nearly 40% of accumbal GlyRs being located outside the synapse (21). Furthermore, the different findings might be attributed to longer-duration applications of low-nanomolar concentrations of strychnine being required to reveal the tonic GlyR conductance that we observed.…”

Section: Discussionmentioning

confidence: 77%

“…Recent work in the dorsal raphé nucleus has revealed a large tonic GlyR conductance (∼45 pA), which, based on preliminary pharmacological measures, was proposed to be mediated by extrasynaptic α1 subunit-containing GlyRs expressed in this brain region (21). In the same study, no tonic GlyR currents were seen in the NAc.…”

Section: Discussionmentioning

confidence: 86%

“…Glycine was first identified as the inhibitory transmitter at the Renshaw cell-motoneuron synapse, where it produces inhibition via strychnine-sensitive glycine receptors (GlyRs) (14)(15)(16)(17). GlyRs also mediate synaptic inhibition in the auditory brainstem (18)(19)(20) and extrasynaptic inhibition in the dorsal raphé (21). There have been a number of reports of glycine responses and expression of strychnine-sensitive GlyRs in higher brain regions (22)(23)(24)(25)(26)(27).…”

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confidence: 99%

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Glycine receptor α3 and α2 subunits mediate tonic and exogenous agonist-induced currents in forebrain

McCracken

Lowes

Salling

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Neuronal inhibition can occur via synaptic mechanisms or through tonic activation of extrasynaptic receptors. In spinal cord, glycine mediates synaptic inhibition through the activation of heteromeric glycine receptors (GlyRs) composed primarily of α1 and β subunits. Inhibitory GlyRs are also found throughout the brain, where GlyR α2 and α3 subunit expression exceeds that of α1, particularly in forebrain structures, and coassembly of these α subunits with the β subunit appears to occur to a lesser extent than in spinal cord. Here, we analyzed GlyR currents in several regions of the adolescent mouse forebrain (striatum, prefrontal cortex, hippocampus, amygdala, and bed nucleus of the stria terminalis). Our results show ubiquitous expression of GlyRs that mediate large-amplitude currents in response to exogenously applied glycine in these forebrain structures. Additionally, tonic inward currents were also detected, but only in the striatum, hippocampus, and prefrontal cortex (PFC). These tonic currents were sensitive to both strychnine and picrotoxin, indicating that they are mediated by extrasynaptic homomeric GlyRs. Recordings from mice deficient in the GlyR α3 subunit (Glra3 −/− ) revealed a lack of tonic GlyR currents in the striatum and the PFC. In Glra2 −/Y animals, GlyR tonic currents were preserved; however, the amplitudes of current responses to exogenous glycine were significantly reduced. We conclude that functional α2 and α3 GlyRs are present in various regions of the forebrain and that α3 GlyRs specifically participate in tonic inhibition in the striatum and PFC. Our findings suggest roles for glycine in regulating neuronal excitability in the forebrain.glycine receptor | tonic inhibition | Cys-loop receptor | strychnine | alpha subunits

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 86%

mentioning

confidence: 99%

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Glycine receptor α3 and α2 subunits mediate tonic and exogenous agonist-induced currents in forebrain

McCracken

Lowes

Salling

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Currently, there is little direct evidence of enhanced or reduced transmitter release from affected regions of the brain or whether excitatory or inhibitory neurons are involved. Multiple studies have measured changes in synaptic transmission between neurons following addition of alcohol, but most propose a postsynaptic target (17,(32)(33)(34). Additionally, the vast majority of studies are done in whole animal or tissue slice preparations where observation of an ethanol effect depends on a sequence of both pre-and postsynaptic events involving many proteins.…”

Section: Introductionmentioning

confidence: 99%

Drunken Membranes: Short-Chain Alcohols Alter Fusion of Liposomes to Planar Lipid Bilayers

Paxman

Hunt

Hallan

et al. 2017

Biophysical Journal

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Although the effects of ethanol on protein receptors and lipid membranes have been studied extensively, ethanol's effect on vesicles fusing to lipid bilayers is not known. To determine the effect of alcohols on fusion rates, we utilized the nystatin/ergosterol fusion assay to measure fusion of liposomes to a planar lipid bilayer (BLM). The addition of ethanol excited fusion when applied on the cis (vesicle) side, and inhibited fusion on the trans side. Other short-chain alcohols followed a similar pattern. In general, the inhibitory effect of alcohols (trans) occurs at lower doses than the excitatory (cis) effect, with a decrease of 29% in fusion rates at the legal driving limit of 0.08% (w/v) ethanol (IC 50 ¼ 0.2% v/v, 34 mM). Similar inhibitory effects were observed with methanol, propanol, and butanol, with ethanol being the most potent. Significant variability was observed with different alcohols when applied to the cis side. Ethanol and propanol enhanced fusion, butanol also enhanced fusion but was less potent, and low doses of methanol mildly inhibited fusion. The inhibition by trans addition of alcohols implies that they alter the planar membrane structure and thereby increase the activation energy required for fusion, likely through an increase in membrane fluidity. The cis data are likely a combination of the above effect and a proportionally greater lowering of the vesicle lysis tension and hydration repulsive pressure that combine to enhance fusion. Alternate hypotheses are also discussed. The inhibitory effect of ethanol on liposome-membrane fusion is large enough to provide a possible biophysical explanation of compromised neuronal behavior.

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“…Ethanol enhances the function of recombinant (Trudell et al, 2014) and native brain GlyRs (Badanich et al, 2013;Maguire et al, 2014). The work of Badanich et al (2013) emphasized a selective effect of GlyRs in ethanol action in lateral orbitofrontal cortex neurons.…”

Section: Introductionmentioning

confidence: 99%

Glycine Receptors Containingα2 orα3 Subunits Regulate Specific Ethanol-Mediated Behaviors

Blednov

Benavidez

Black

et al. 2015

J Pharmacol Exp Ther

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Glycine receptors (GlyRs) are broadly expressed in the central nervous system. Ethanol enhances the function of brain GlyRs, and the GlyRa1 subunit is associated with some of the behavioral actions of ethanol, such as loss of righting reflex. The in vivo role of GlyRa2 and a3 subunits in alcohol responses has not been characterized despite high expression levels in the nucleus accumbens and amygdala, areas that are important for the rewarding properties of drugs of abuse. We used an extensive panel of behavioral tests to examine ethanol actions in mice lacking Glra2 (the gene encoding the glycine receptor alpha 2 subunit) or Glra3 (the gene encoding the glycine receptor alpha 3 subunit). Deletion of Glra2 or Glra3 alters specific ethanol-induced behaviors. Glra2 knockout mice demonstrate reduced ethanol intake and preference in the 24-hour two-bottle choice test and increased initial aversive responses to ethanol and lithium chloride. In contrast, Glra3 knockout mice show increased ethanol intake and preference in the 24-hour intermittent access test and increased development of conditioned taste aversion to ethanol. Mutants and wild-type mice consumed similar amounts of ethanol in the limited access drinking in the dark test. Other ethanol effects, such as anxiolysis, motor incoordination, loss of righting reflex, and acoustic startle response, were not altered in the mutants. The behavioral changes in mice lacking GlyRa2 or a3 subunits were distinct from effects previously observed in mice with knock-in mutations in the a1 subunit. We provide evidence that GlyRa2 and a3 subunits may regulate ethanol consumption and the aversive response to ethanol.

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Extrasynaptic Glycine Receptors of Rodent Dorsal Raphe Serotonergic Neurons: A Sensitive Target for Ethanol

Cited by 36 publications

References 61 publications

Glycine receptor α3 and α2 subunits mediate tonic and exogenous agonist-induced currents in forebrain

Glycine receptor α3 and α2 subunits mediate tonic and exogenous agonist-induced currents in forebrain

Drunken Membranes: Short-Chain Alcohols Alter Fusion of Liposomes to Planar Lipid Bilayers

Glycine Receptors Containingα2 orα3 Subunits Regulate Specific Ethanol-Mediated Behaviors

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