Reduced ethanol-induced conditioned taste aversion and conditioned place preference in GIRK2 null mutant mice

Hill, K.G.; Alva, H.; Blednov, Yuri A.; Cunningham, Christopher L.

doi:10.1007/s00213-003-1472-4

Cited by 60 publications

(67 citation statements)

References 38 publications

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“…Interestingly, GIRK2 knockout mice show reduced ethanol-induced conditioned taste aversion and conditioned place preference and are less sensitive than wild-type mice to some of the acute effects of ethanol, including anxiolysis, habituated locomotor stimulation, and acute handlinginduced convulsions (Hill et al, 2003). In the present study, atomoxetine inhibited ethanol-induced GIRK1/2 currents, suggesting that it may suppress some GIRK-related effects of ethanol.…”

Section: Discussionsupporting

confidence: 44%

Inhibition of G-Protein-Activated Inwardly Rectifying K+ Channels by the Selective Norepinephrine Reuptake Inhibitors Atomoxetine and Reboxetine

Kobayashi

Washiyama

Ikeda

2010

Neuropsychopharmacol

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Atomoxetine and reboxetine are commonly used as selective norepinephrine reuptake inhibitors (NRIs) for the treatment of attentiondeficit/hyperactivity disorder and depression, respectively. Furthermore, recent studies have suggested that NRIs may be useful for the treatment of several other psychiatric disorders. However, the molecular mechanisms underlying the various effects of NRIs have not yet been sufficiently clarified. G-protein-activated inwardly rectifying K + (GIRK or Kir3) channels have an important function in regulating neuronal excitability and heart rate, and GIRK channel modulation has been suggested to be a potential treatment for several neuropsychiatric disorders and cardiac arrhythmias. In this study, we investigated the effects of atomoxetine and reboxetine on GIRK channels using the Xenopus oocyte expression assay. In oocytes injected with mRNA for GIRK1/GIRK2, GIRK2, or GIRK1/GIRK4 subunits, extracellular application of atomoxetine or reboxetine reversibly reduced GIRK currents. The inhibitory effects were concentrationdependent, but voltage-independent, and time-independent during each voltage pulse. However, Kir1.1 and Kir2.1 channels were insensitive to atomoxetine and reboxetine. Atomoxetine and reboxetine also inhibited GIRK currents induced by activation of cloned A 1 adenosine receptors or by intracellularly applied GTPgS, a nonhydrolyzable GTP analogue. Furthermore, the GIRK currents induced by ethanol were concentration-dependently inhibited by extracellularly applied atomoxetine but not by intracellularly applied atomoxetine. The present results suggest that atomoxetine and reboxetine inhibit brain-and cardiac-type GIRK channels, revealing a novel characteristic of clinically used NRIs. GIRK channel inhibition may contribute to some of the therapeutic effects of NRIs and adverse side effects related to nervous system and heart function.

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Section: Discussionsupporting

confidence: 44%

Inhibition of G-Protein-Activated Inwardly Rectifying K+ Channels by the Selective Norepinephrine Reuptake Inhibitors Atomoxetine and Reboxetine

Kobayashi

Washiyama

Ikeda

2010

Neuropsychopharmacol

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“…The interaction between GIRK2 and neurobiological stress systems is suggestive of a mechanism by which the reinforcing effects of alcohol develop during periods of environmental stress. Indeed, Hill et al (2003) found that they were unable to establish a place preference for ethanol in GIRK2-null mice, which confirms the notion that GIRK2 is important for alcohol reward. In support of this, we find that genetic variation in GIRK2 is associated with the initiation of alcohol abuse in adolescents when psychosocial stress is present, and in addition, an association is also found with the maintenance of alcohol dependence in adults.…”

Section: Discussionsupporting

confidence: 62%

“…They found that they could not establish a place preference or conditioned taste aversion for 2-3 g/kg of ethanol in mice lacking GIRK2 channels (Hill et al, 2003), concluding that GIRK2 may be mediating the reinforcing and/or aversive motivational aspects of ethanol action. In human beings, only one study has examined GIRK2 and addictive phenotypes.…”

Section: Introductionmentioning

confidence: 99%

KCNJ6 is Associated with Adult Alcohol Dependence and Involved in Gene × Early Life Stress Interactions in Adolescent Alcohol Drinking

Clarke

Laucht

Wodarz

et al. 2011

Neuropsychopharmacol

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Alcohol abuse and dependence have proven to be complex genetic traits that are influenced by environmental factors. Primate and human studies have shown that early life stress increases the propensity for alcohol abuse in later life. The reinforcing properties of alcohol are mediated by dopaminergic signaling; however, there is little evidence to indicate how stress alters alcohol reinforcement. KCNJ6 (the gene encoding G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2)) is a brain expressed potassium channel with inhibitory effects on dopaminergic tone. The properties of GIRK2 have been shown to be enhanced by the stress peptide corticotrophin-releasing hormone. Therefore, we sought to examine the role of KCNJ6 polymorphisms in adult alcohol dependence and stress-related alcohol abuse in adolescents. We selected 11 SNPs in the promoter region of KCNJ6, which were genotyped in 1152 adult alcohol dependents and 1203 controls. One SNP, rs2836016, was found to be associated with alcohol dependence (p ¼ 0.01, false discovery rate). We then assessed rs2836016 in an adolescent sample of 261 subjects, which were characterized for early life stress and adolescent hazardous drinking, defined using the Alcohol Use Disorders Identification Test (AUDIT), to examine gene-environment interactions. In the adolescent sample, the risk genotype of rs2836016 was significantly associated with increased AUDIT scores, but only in those individuals exposed to high levels of psychosocial stress in early life (p ¼ 0.01). Our findings show that KCNJ6 is associated with alcohol dependence and may moderate the effect of early psychosocial stress on risky alcohol drinking in adolescents. We have identified a candidate gene for future studies investigating a possible functional link between the response to stress and alcohol reinforcement.

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“…Alcohol modulation of GIRK channels regulates neuronal excitability in the brain's reward circuit (11) and underlies forms of alcohol addiction (6,(8)(9)(10)36). Here, we uncovered previously undescribed principles governing alcohol modulation of GIRK channels.…”

Section: Discussionmentioning

confidence: 91%

“…G-proteingated inwardly rectifying K + (GIRK or Kir3) channels are activated by concentrations of ethanol relevant to human consumption (18 mM ethanol or 0.08% blood alcohol level) (3)(4)(5) and have been found to play a key role in alcohol-related disorders (6)(7)(8)(9). For example, mice lacking GIRK2 (or Kir3.2) channels self-administer more ethanol and fail to develop conditioned place preference for ethanol, compared with wild-type (WT) littermates (6,10). These results support a model in which ethanol may have lost its target in GIRK knockout mice, thus failing to elicit behaviors associated with ethanol consumption.…”

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confidence: 99%

Molecular mechanism underlying ethanol activation of G-protein–gated inwardly rectifying potassium channels

Bodhinathan

Slesinger

2013

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

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Alcohol (ethanol) produces a wide range of pharmacological effects on the nervous system through its actions on ion channels. The molecular mechanism underlying ethanol modulation of ion channels is poorly understood. Here we used a unique method of alcohol-tagging to demonstrate that alcohol activation of a G-protein-gated inwardly rectifying potassium (GIRK or Kir3) channel is mediated by a defined alcohol pocket through changes in affinity for the membrane phospholipid signaling molecule phosphatidylinositol 4,5-bisphosphate. Surprisingly, hydrophobicity and size, but not the canonical hydroxyl, were important determinants of alcohol-dependent activation. Altering levels of G protein Gβγ subunits, conversely, did not affect alcohol-dependent activation, suggesting a fundamental distinction between receptor and alcohol gating of GIRK channels. The chemical properties of the alcohol pocket revealed here might extend to other alcoholsensitive proteins, revealing a unique protein microdomain for targeting alcohol-selective therapeutics in the treatment of alcoholism and addiction.A lcohol (ethanol) produces a wide range of pharmacological effects on the nervous system, ranging from anxiolytic effects to intoxication and alcohol addiction in certain individuals. Although the neural circuits underlying such addictive disorders are becoming better understood (1, 2), little is known about the molecular mechanisms underlying ethanol's interaction with specific target proteins, such as ion channels. G-proteingated inwardly rectifying K + (GIRK or Kir3) channels are activated by concentrations of ethanol relevant to human consumption (18 mM ethanol or 0.08% blood alcohol level) (3-5) and have been found to play a key role in alcohol-related disorders (6-9). For example, mice lacking GIRK2 (or Kir3.2) channels self-administer more ethanol and fail to develop conditioned place preference for ethanol, compared with wild-type (WT) littermates (6, 10). These results support a model in which ethanol may have lost its target in GIRK knockout mice, thus failing to elicit behaviors associated with ethanol consumption. Receptor activation of GIRK channels generates an outward, slow inhibitory postsynaptic current, which reduces neuronal activity (11). In addition to directly activating GIRKs, ethanol potentiates the slow inhibitory postsynaptic potential in midbrain dopamine neurons of the ventral tegmental area (8), which is produced by GABA B receptor activation of GIRK channels (7,12,13). Together these observations implicate GIRK channels in the etiology of alcohol dependence and addiction; however, the molecular details underlying ethanol activation of GIRK channels remain unknown.A major challenge is to understand how ethanol, with its simple chemistry of only two carbons and a hydroxyl, can produce behavioral changes with rapidity and reproducibility. Ethanol has little volume or distinguishing stereochemistry. Although it was once thought to interact nonspecifically with membrane lipids, a preponderance of evidence sugg...

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Reduced ethanol-induced conditioned taste aversion and conditioned place preference in GIRK2 null mutant mice

Cited by 60 publications

References 38 publications

Inhibition of G-Protein-Activated Inwardly Rectifying K+ Channels by the Selective Norepinephrine Reuptake Inhibitors Atomoxetine and Reboxetine

Inhibition of G-Protein-Activated Inwardly Rectifying K+ Channels by the Selective Norepinephrine Reuptake Inhibitors Atomoxetine and Reboxetine

KCNJ6 is Associated with Adult Alcohol Dependence and Involved in Gene × Early Life Stress Interactions in Adolescent Alcohol Drinking

Molecular mechanism underlying ethanol activation of G-protein–gated inwardly rectifying potassium channels

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