KCNQ2/3 channel agonist flupirtine reduces cocaine place preference in rats

Mooney, James

doi:10.1097/fbp.0000000000000287

Cited by 13 publications

(6 citation statements)

References 11 publications

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“…Recent studies have indeed suggested a causal role for potassium channels in CUD. Specifically, Mooney & Rawls, (2017) reported that flupirtine, an agonist of the voltage-gated KCNQ2/3 channel, can reduce the development of cocaine place preference and locomotor activation [ 101 ]. Studies using knock-out mice models have reported that K cnj6 and K cnj9 knockout mice exhibited reduced cocaine seeking compared to WT mice [ 102 ].…”

Section: Potassium Channels and Cocaine Use Disordermentioning

confidence: 99%

Potassium Channels and Their Potential Roles in Substance Use Disorders

McCoy

Jayanthi

Cadet

2021

IJMS

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Substance use disorders (SUDs) are ubiquitous throughout the world. However, much remains to be done to develop pharmacotherapies that are very efficacious because the focus has been mostly on using dopaminergic agents or opioid agonists. Herein we discuss the potential of using potassium channel activators in SUD treatment because evidence has accumulated to support a role of these channels in the effects of rewarding drugs. Potassium channels regulate neuronal action potential via effects on threshold, burst firing, and firing frequency. They are located in brain regions identified as important for the behavioral responses to rewarding drugs. In addition, their expression profiles are influenced by administration of rewarding substances. Genetic studies have also implicated variants in genes that encode potassium channels. Importantly, administration of potassium agonists have been shown to reduce alcohol intake and to augment the behavioral effects of opioid drugs. Potassium channel expression is also increased in animals with reduced intake of methamphetamine. Together, these results support the idea of further investing in studies that focus on elucidating the role of potassium channels as targets for therapeutic interventions against SUDs.

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Section: Potassium Channels and Cocaine Use Disordermentioning

confidence: 99%

Potassium Channels and Their Potential Roles in Substance Use Disorders

McCoy

Jayanthi

Cadet

2021

IJMS

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“…After a minimum of a 4-h washout period, mice were injected with 0.9% saline and placed in the preferred compartment for 30 min. [29][30][31] This schedule persisted for 6 days.…”

Section: Conditioned Place Preferencementioning

confidence: 99%

Experimental Traumatic Brain Injury during Adolescence Enhances Cocaine Rewarding Efficacy and Dysregulates Dopamine and Neuroimmune Systems in Brain Reward Substrates

Cannella

Andrews

Tran

et al. 2020

Journal of Neurotrauma

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Although clinical studies identify traumatic brain injury (TBI) as a risk factor for the development of substance use disorder, much remains unknown about the possible underlying pathogenesis and age-specific effects. Thus, the aim of this study is to test the hypothesis that at an age of ongoing maturation, adolescent TBI alters elements of the reward pathway, resulting in increased sensitivity to the rewarding effects of a subthreshold dose of cocaine that does not induce significant behavioral changes in naı ¨ve, non-injured mice. Specifically, these results were derived from the combination of the controlled cortical impact model of TBI, performed on either adolescent (6 weeks) or young adult (8 weeks) mice, followed by the cocaine-induced conditioned place preference assay 2 weeks later. Using three-dimensional isosurface rendering and volumetric image analysis, TBI was found to induce neuromorphological changes such as decreased dendritic complexity and reduced spine density in brain regions essential for reward perception and processing of druginduced euphoria. Further, we demonstrated that these neuronal changes may affect the differential expression of dopamine-associated genes. Our analysis also provided evidence for age-related differences in immune response and the distinct involvement of augmented microglial phagocytic activity in the remodeling of neuronal structures in the adolescent TBI brain. Our studies suggest that TBI during adolescence, a period associated with ongoing maturation of dopaminergic systems, may subsequently enhance the abuse liability of cocaine in adulthood.

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“…These electrophysiological adaptations may be behaviorally significant since mice with more global deletion of the inward rectifying channel, Kir3/Girk3, were reported to exhibit decreased cocaine SA [35] whereas mice with Girk2 deletion in midbrain DA neurons showed increased cocaine intake in a SA paradigm [11]. Consistent with the latter findings, activation of the KCNQ2/3 channel by the agonist, flupirtine, significantly reduced cocaine conditioned place preference (CPP) in rats [36]. Moreover, acute [37] or repeated non-contingent injections of METH for 5 days [37,38] caused decreases in the size of GABAB-activated GIRK currents in rodent VTA DA neurons.…”

Section: Introductionmentioning

confidence: 67%

A Single Prior Injection of Methamphetamine Enhances Methamphetamine Self-Administration (SA) and Blocks SA-Induced Changes in DNA Methylation and mRNA Expression of Potassium Channels in the Rat Nucleus Accumbens

et al. 2019

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The transition from occasional to escalated psychostimulant use is accelerated by prior drug exposure. These behavioral observations may be related to long-lasting transcriptional and/or epigenetic changes induced by the drug pre-exposure. Herein, we investigated if a single methamphetamine (METH) injection would enhance METH self-administration (SA) and impact any METH SA-induced epigenetic or transcriptional alterations. We thus injected a single METH dose (10 mg/kg) or saline to rats before training them to self-administer METH or saline. There were three experimental groups in SA experiments: (1) a single saline injection followed by saline SA (SS); (2) a single saline injection followed by METH SA (SM); and (3) a single METH injection followed by METH SA (MM). METH-pretreated rats escalated METH SA earlier and took more METH than salinepretreated animals. Both groups showed similar incubation of cue-induced METH craving. Because compulsive METH takers and METH-abstinent rats show differences in potassium (K +) channel mRNA levels in their nucleus accumbens (NAc), we wondered if K + channel expression might also help to distinguish between SM and MM groups. We found increases in mRNA and protein expression of shaker-related voltage-gated K + channels (Kv1: Kcna1, Kcna3, and Kcna6) and calcium-activated K + channels (Kcnn1) in the SM compared to MM rats. SM rats also showed decreased DNA methylation at the CpG-rich sites near the promoter region of Kcna1, Kcna3 and Kcnn1 genes in comparison to MM rats. Together, these results provide additional evidence for potentially using K + channels as therapeutic targets against METH use disorder.

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KCNQ2/3 channel agonist flupirtine reduces cocaine place preference in rats

Cited by 13 publications

References 11 publications

Potassium Channels and Their Potential Roles in Substance Use Disorders

Potassium Channels and Their Potential Roles in Substance Use Disorders

Experimental Traumatic Brain Injury during Adolescence Enhances Cocaine Rewarding Efficacy and Dysregulates Dopamine and Neuroimmune Systems in Brain Reward Substrates

A Single Prior Injection of Methamphetamine Enhances Methamphetamine Self-Administration (SA) and Blocks SA-Induced Changes in DNA Methylation and mRNA Expression of Potassium Channels in the Rat Nucleus Accumbens

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