Mefloquine Enhances Nigral γ-Aminobutyric Acid Release via Inhibition of Cholinesterase

Zhou, Chunyi; Xia, Cheng; McArdle, Joseph J.; Ye, Jiang Hong

doi:10.1124/jpet.106.101923

Cited by 30 publications

(46 citation statements)

References 31 publications

(48 reference statements)

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“…2) demonstrates that perhaps all of the MFQ increase in Cx36 KO mouse VTA DA neuron sIPSCs was due to an increase in mIPSCs, while only half of the MFQ increase in WT sIPSCs was due to an increase in mIPSCs. From this data, and the finding by Zhou et al (2006) showing a significant portion of the MFQ increase of sIPSCs was due to a nonspecific calcium effect, we theorized that the MFQ increase of mIPSCs in both WT and Cx36 KO mice was due to an increase of intracellular calcium (Caridha et al, 2008;Dow et al, 2003;Zhou et al, 2006), while the increase in sIPSCs in WT mice was due to the blockade of Cx36 GJs. To test this idea, we examined the effects of CBX (100 μM, a GJ blocker with no calcium effects) on WT mouse VTA DA neuron mIPSCs.…”

Section: Mefloquine Effects On Vta Dopamine Neuron Mipsc Frequency Amentioning

confidence: 92%

“…Because MFQ has effects other than being a selective Cx36 GJ blocker, such as increasing intracellular Ca 21 (Caridha et al, 2008;Dow et al, 2003;Zhou et al, 2006), we compared its effects to carbenoxolone (CBX) in WT and KO mice. We reasoned that if MFQ's GJ blocking properties played a role in increasing sIPSC frequency, a less selective GJ blocker such as CBX, which has no reported effects on intracellular calcium, would increase sIPSC frequency similar to MFQ in WT mice, but not in Cx36 KO mice.…”

Section: Mefloquine Effects On Vta Dopamine Neuron Sipsc Frequency Amentioning

confidence: 99%

“…Recent studies demonstrated MFQ acts as a 5HT 3 receptor antagonist (Thompson and Lummis, 2008), and Zhou et al (2006) hypothesized MFQ's increases sIPSC frequency via its calcium-mediated effects by inhibition of cholinesterase , thereby increasing GABA release via excess acetylcholine activation of presynaptic nicotinic acetylcholine receptors (nAChRs). To this end, we also examined the effects of the specific 5HT 3 receptor antagonist odansetron (ODS) on baseline DA neuron sIPSC frequency and the non-α7nAChR antagonist mecamylamine (MEC) on MFQ's increase in sIPSC frequency.…”

Section: Mefloquine Effects On Vta Dopamine Neuron Sipsc Frequency Amentioning

confidence: 99%

“…Others have shown that the Connexin-36 (Cx36) gap junction (GJ) blocker mefloquine (MFQ) increases sIPSCs in substantia nigra pars compacta (SNc) DA neurons (EC 50 ≈ 3 μM; (Zhou et al, 2006)). However, the application time of MFQ in that study correlated with MFQ's ability to disrupt intracellular calcium (Dow et al, 2003), rather than its ability to selectively block Cx36 GJs (Cruikshank et al, 2004).…”

Section: Time Course Of Mefloquine Effects On Vta Dopamine Neuron Sipmentioning

confidence: 99%

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Mefloquine effects on ventral tegmental area dopamine and GABA neuron inhibition: A physiologic role for Connexin-36 gap junctions

Allison

Wilcox

Ellefsen

et al. 2011

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Connexin-36 (Cx36) gap junctions (GJs) appear to be involved in the synchronization of GABA interneurons in many brain areas. We have previously identified a population of Cx36-connected ventral tegmental area (VTA) GABA neurons that may regulate mesolimbic dopamine (DA) neurotransmission, a system implicated in reward from both natural behaviors and drugs of abuse. The aim of this study was to determine the effect mefloquine (MFQ) has on midbrain DA and GABA neuron inhibition, and the role Cx36 GJs play in regulating midbrain VTA DA neuron activity in mice. In brain slices from adolescent wild-type (WT) mice the Cx36-selective GJ blocker mefloquine (MFQ, 25 μM) increased VTA DA neuron sIPSC frequency sixfold, and mIPSC frequency threefold. However, in Cx36 KO mice, MFQ only increased sIPSC and mIPSC frequency threefold. The nonselective GJ blocker carbenoxolone (CBX, 100 μM) increased DA neuron sIPSC frequency twofold in WT mice, did not affect Cx36 KO mouse sIPSCs, and did not affect mIPSCs in WT or Cx36 KO mice. Interestingly, MFQ had no effect on VTA GABA neuron sIPSC frequency. We also examined MFQ effects on VTA DA neuron firing rate and currentevoked spiking in WT and Cx36 KO mice, and found that MFQ decreased WT DA neuron firing rate and current-evoked spiking, but did not alter these measures in Cx36 KO mice. Taken together these findings suggest that blocking Cx36 GJs increases VTA DA neuron inhibition, and that GJs play in key role in regulating inhibition of VTA DA neurons.

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Section: Mefloquine Effects On Vta Dopamine Neuron Mipsc Frequency Amentioning

confidence: 92%

Section: Mefloquine Effects On Vta Dopamine Neuron Sipsc Frequency Amentioning

confidence: 99%

Section: Mefloquine Effects On Vta Dopamine Neuron Sipsc Frequency Amentioning

confidence: 99%

Section: Time Course Of Mefloquine Effects On Vta Dopamine Neuron Sipmentioning

confidence: 99%

See 2 more Smart Citations

Mefloquine effects on ventral tegmental area dopamine and GABA neuron inhibition: A physiologic role for Connexin-36 gap junctions

Allison

Wilcox

Ellefsen

et al. 2011

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“…Mefloquine is the most promising [for review [73]]. Besides being used clinically as an antimalarial drug, MFQ disrupts intracellular calcium [74][75][76], acts as an antagonist at serotonin 5HT3 receptors [77] and also as an acetylcholinesterase inhibitor [78]. Thus, MFQ has multiple effects that need to be considered with any interpretation regarding its effects.…”

Section: Discussionmentioning

confidence: 99%

Connexin-36 Knock-Out Mice have Increased Threshold for Kindled Seizures: Role of GABA Inhibition

Shin¹

2013

Biochem & Pharmacol

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Blockade of gap junctions (GJs) has been shown to reduce seizures in different epilepsy models. Gap junctionmediated, electrically-coupled neuronal networks have been implicated in neuronal synchronization, which is the hallmark of seizure activity. To further understand the role of GJs in seizures, in particular hippocampal seizures, we evaluated electrophysiological responses in the dentate gyrus subfield of the hippocampus, including GABA-mediated recurrent inhibition, seizuregenic stimulation, and seizure activity in response to perforant path kindling in Cx36 knockout (KO) mice compared to wild-type (WT) controls. In anesthetized mice, Cx36 KO mice were characterized by enhanced GABA-mediated recurrent inhibition. Stimulation of the perforant path at 10 Hz for 10 sec (i.e., 100 pulses) markedly enhanced population spike (PS) amplitudes and reduced paired-pulse GABA-mediated inhibition during the stimulation, induced an after discharge for approximately 10 sec at 7-10 sec into the stimulation, and suppressed PS amplitudes postictally for 5-10 min in both KO and WT mice. Repeated epochs of 10 Hz for 10 sec stimulation of the perforant path at 20 min intervals resulted in progressive and persistent disinhibition of paired-pulse responses in WT, but not KO mice. In freely-behaving seizure studies, stimulation of the perforant path (10 Hz for 10 sec) once/day resulted in progressive Stage I-IV seizures in both WT and KO mice. Once Stage IV was achieved, another Stage IV seizure could be elicited each day with the same behavioral response (i.e., Stage V). The threshold for kindled seizures was significantly greater in KO mice compared to WT controls for most stages of seizures. The Cx36 antagonist mefloquine (MFQ) and the typical anticonvulsant pentobarbital reduced Stage IV seizures in both WT and KO mice. Knock-out mice were more sensitive to the anti-epileptic effects of the typical anti-convulsant pentobarbital (20 mg/ kg). Taken together, these findings support the emerging view that reduction in GJ-mediated GABA electrical coupling reduces seizures, perhaps through enhancement of GABAergic feedback inhibition, which results from the uncoupling of the GABA recurrent interneurons from the resistive load that is inherent in their electrical connectivity.

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

Steffensen

Bradley

Hansen

et al. 2010

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Ventral tegmental area (VTA) GABA neurons appear to be critical substrates underlying the acute and chronic effects of ethanol on dopamine (DA) neurotransmission in the mesocorticolimbic system implicated in alcohol reward. The aim of this study was to examine the role of midbrain connexin-36 (Cx36) gap junctions (GJs) in ethanol’s rewarding effects. Using behavioral, molecular and electrophysiological methods we compared the effects of ethanol in mature Cx36 knockout (KO) mice and age-matched wild-type (WT) controls. Cx36 KO mice exhibited significantly more ethanol-induced ataxia in the open field test, but less disruption in motor coordination than their WT controls in the rotarod paradigm. Cx36 KO mice and WT mice treated with the Cx36 antagonist mefloquine (MFQ) consumed significantly less ethanol than their vehicle-treated WT controls in the drink-in-the-dark procedure. The firing rate of VTA GABA neurons in WT mice was inhibited by ethanol with an IC50 of 0.25 g/kg, while VTA GABA neurons in KO mice were significantly less sensitive to ethanol. Dopamine neuron sIPSC frequency was reduced by ethanol (30 mM) in WT mice, but not affected in KO mice. Cx36 KO mice evinced a significant up-regulation in DAT and D2 receptors in the VTA, as assessed by quantitative RT-PCR. These findings demonstrate the behavioral relevance of Cx36 GJ-mediated electrical coupling between GABA neurons in mature animals, and suggest that loss of coupling between VTA GABA neurons results in disinhibition of DA neurons, a hyper-DAergic state and lowered hedonic valence for ethanol consumption.

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Mefloquine Enhances Nigral γ-Aminobutyric Acid Release via Inhibition of Cholinesterase

Cited by 30 publications

References 31 publications

Mefloquine effects on ventral tegmental area dopamine and GABA neuron inhibition: A physiologic role for Connexin-36 gap junctions

Mefloquine effects on ventral tegmental area dopamine and GABA neuron inhibition: A physiologic role for Connexin-36 gap junctions

Connexin-36 Knock-Out Mice have Increased Threshold for Kindled Seizures: Role of GABA Inhibition

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

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