The role of connexin‐36 gap junctions in alcohol intoxication and consumption

Steffensen, Scott C.; Bradley, Katie D.; Hansen, David M.; Wilcox, Jeffrey D.; Wilcox, Rebecca S.; Allison, David W.; Merrill, Collin B.; Edwards, Jeffrey G.

doi:10.1002/syn.20885

Cited by 48 publications

(44 citation statements)

References 44 publications

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“…In anesthetized (Isoflurane) mice, the average firing rate VTA GABA neurons recorded in GAD-GFP mice in vivo was 31.5 ± 2.5 Hz (n=79), consistent with what we have reported previously in other studies in mice [28,35]. Intravenous administration of freebase NIC (0.2 mg/kg) markedly enhanced the firing rate of VTA GABA neurons recorded in GAD-GFP mice in vivo ( Figure 1A).…”

Section: Effects Of Systemic Administration Of Nicotine On Vta Gaba Nsupporting

confidence: 90%

“…The expression of Cx36, a marker for GABA neurons in the VTA [25,28], is also shown for comparison. The α7 subunit was expressed in only two of the twenty-four cells tested.…”

Section: Discussionmentioning

confidence: 99%

“…All neurons classified as VTA GABA neurons in vivo were located in the VTA, and met the criteria established in previous studies for spike waveform characteristics in rats [24][25][26], and in mice [27,28]. Presumed VTA GABA neurons were characterized by short-duration (<200 µsec; measured at half-peak amplitude of the spike), initially negative-going, relatively fast-firing (10-80 Hz), non-bursting spikes.…”

Section: Characterization Of Vta Gaba Neurons In Vivomentioning

confidence: 99%

“…Substantia nigra compacta (SNc) was then identified medial to SNr. GABA neurons in the VTA were studied by visualizing GAD+ neurons in an area medial to the glowing SNr, posterior to the fasciculus retroflexus and mammillothalamic tract, and anterior to the decussation of the superior cerebellar peduncle [27,28]. Neurons in the VTA of GAD-GFP mice that did not fluoresce but exhibited a non-cation specific inward rectifying current (I h ), in combination with relatively low input resistance and regular, slow spike activity were assumed to be DA neurons [25,27,28,30,31].…”

Section: Characterization Of Vta Gaba Neurons In Vitromentioning

confidence: 99%

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Nicotine Enhances the Excitability of Gaba Neurons in the Ventral Tegmental Area via Activation of Alpha 7 Nicotinic Receptors on Glutamate Terminals

Taylor¹,

Burman²,

Hansen³

et al. 2013

Biochem & Pharmacol

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Ventral tegmental area dopamine (DA) and GABA neurons express nicotinic acetylcholine receptor (nAChR) subtypes, whose net activation results in enhancement of DA release in the nucleus accumbens (NAc). This effect decreases after repeated nicotine (NIC) treatment via desensitization. We evaluated the effects of acute NIC on glutamate decarboxylase (GAD67)-positive GABA neurons in the VTA of green fluorescent protein (GFP) knockin (GAD-GFP) mice, and determined the expression of selected nAChR subunits in VTA GABA neurons. In vivo, tachylphylaxis accrued to repeated systemic, but not local administration of NIC. Microelectrophoretic application of NIC and the α7 nAChR partial agonist JN403 markedly enhanced the firing rate of VTA GABA neurons. This activation was suppressed by intraperitoneal administration of the α7 nAChR antagonist methyllycaconitine (MLA, 1 mg/kg), or the glutamate (GLU) NMDA receptor antagonist APV (1 mg/kg), but not by the non-selective non-competitive antagonist mecamylamine (MEC, 1 mg/kg). In patch clamp studies in the slice preparation, the α7 nAChR agonist choline (1-10 mM), in the presence of the muscarinic cholinergic antagonist atropine (50 µM), enhanced sEPSC and mini-EPSC frequency, but not amplitude, which was blocked by MLA (0.5 µM). JN403 (0.1-1 µM) enhanced evoked EPSCs, without affecting membrane currents of VTA GABA neurons. In patch clamp studies in dissociated VTA GABA neurons, choline+atropine failed to induce whole-cell current responses in most cells tested. Single cell RT-qPCR revealed that most GABA neurons did not express α7 nAChRs. Together, this indicates that NIC excites VTA GABA neurons via α7 nAChRs located on GLUergic terminals.

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Section: Effects Of Systemic Administration Of Nicotine On Vta Gaba Nsupporting

confidence: 90%

“…The expression of Cx36, a marker for GABA neurons in the VTA [25,28], is also shown for comparison. The α7 subunit was expressed in only two of the twenty-four cells tested.…”

Section: Discussionmentioning

confidence: 99%

Section: Characterization Of Vta Gaba Neurons In Vivomentioning

confidence: 99%

Section: Characterization Of Vta Gaba Neurons In Vitromentioning

confidence: 99%

See 2 more Smart Citations

Nicotine Enhances the Excitability of Gaba Neurons in the Ventral Tegmental Area via Activation of Alpha 7 Nicotinic Receptors on Glutamate Terminals

Taylor¹,

Burman²,

Hansen³

et al. 2013

Biochem & Pharmacol

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show abstract

“…But despite decades of investigation, the evidence is inconclusive for any specific molecular target for ethanol on any protein (for reviews see (6,7)). Many potential protein targets have been identified (4,8) including voltage-gated Na þ channels (9), adenylyl cyclase (10,11), guanine nucleotide binding protein G s (12), the GLT1 glutamate transporter (13), gap junctions (14), g-aminobutyric acid (GABA) A receptors (6), n-methyl-daspartate (NMDA) receptors (15), nicotinic acetylcholine receptor (nAChR) channels (16,17), and the cannabinoid receptor 1 (18). One system within the brain that appears to be sensitive to alcohol dependence is the endocannabinoid system (for review see (19)).…”

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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Inhibition of Connexin 36 attenuates HMGB1‐mediated depressive‐like behaviors induced by chronic unpredictable mild stress

Jiang

Zeng

et al. 2022

Brain and Behavior

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Background: High mobility group box 1 (HMGB1) released by neurons and microglia was demonstrated to be an important mediator in depressive-like behaviors induced by chronic unpredictable mild stress (CUMS), which could lead to the imbalance of two different metabolic approaches in kynurenine pathway (KP), thus enhancing glutamate transmission and exacerbating depressive-like behaviors. Evidence showed that HMGB1 signaling might be regulated by Connexin (Cx) 36 in inflammatory diseases of central nervous system (CNS). Our study aimed to further explore the role of Cx36 in depressive-like behaviors and its relationship with HMGB1.Methods: After 4-week chronic stress, behavioral tests were conducted to evaluate depressive-like behaviors, including sucrose preference test (SPT), tail suspension test (TST), forced swimming test (FST), and open field test (OFT). Western blot analysis and immunofluorescence staining were used to observe the expression and location of Cx36. Enzyme-linked immunosorbent assay (ELISA) was adopted to detect the concentrations of inflammatory cytokines. And the excitability and inward currents of hippocampal neurons were recorded by whole-cell patch clamping. Results:The expression of Cx36 was significantly increased in hippocampal neurons of mice exposed to CUMS, while treatment with glycyrrhizinic acid (GZA) or quinine could both down-regulate Cx36 and alleviate depressive-like behaviors. The proinflammatory cytokines like HMGB1, tumor necrosis factor alpha (TNF-α), and interleukin-1β (IL-1β) were all elevated by CUMS, and application of GZA and quinine could decrease them. In addition, the enhanced excitability and inward currents of hippocampal neurons induced by lipopolysaccharide (LPS) could be reduced by either GZA or quinine.Conclusions: Inhibition of Cx36 in hippocampal neurons might attenuates HMGB1mediated depressive-like behaviors induced by CUMS through down-regulation of the proinflammatory cytokines and reduction of the excitability and intracellular ion overload.

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The role of connexin‐36 gap junctions in alcohol intoxication and consumption

Cited by 48 publications

References 44 publications

Nicotine Enhances the Excitability of Gaba Neurons in the Ventral Tegmental Area via Activation of Alpha 7 Nicotinic Receptors on Glutamate Terminals

Nicotine Enhances the Excitability of Gaba Neurons in the Ventral Tegmental Area via Activation of Alpha 7 Nicotinic Receptors on Glutamate Terminals

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

Inhibition of Connexin 36 attenuates HMGB1‐mediated depressive‐like behaviors induced by chronic unpredictable mild stress

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