Acute Cocaine Exposure Weakens GABA<sub>B</sub>Receptor-Dependent G-Protein-Gated Inwardly Rectifying K<sup>+</sup>Signaling in Dopamine Neurons of the Ventral Tegmental Area

Arora, Devinder; Hearing, Matthew; Haluk, Desirae M.; Mirkovic, Kelsey; Fajardo-Serrano, Ana; Wessendorf, Martin W.; Watanabe, Masahiko; Luján, Rafael; Wickman, Kevin

doi:10.1523/jneurosci.0494-11.2011

Cited by 56 publications

(88 citation statements)

References 35 publications

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“…Coronal and horizontal slices from wild-type and mutant mice (4 -10 weeks old) were prepared as described previously (Arora et al, 2011). VTA neurons found in the lateral aspect of the VTA, near the medial terminal nucleus of the accessory optic tract, were targeted for analysis.…”

Section: Methodsmentioning

confidence: 99%

“…For rheobase measurements, cells were held in currentclamp mode at 0 pA to obtain resting membrane potential, and then progressively increasing current pulses (1 s duration) were applied until the cell fired an action potential. Changes in somatodendritic holding current evoked by baclofen, DAMGO, or ML297 were measured at a holding potential of Ϫ60 mV, as described previously (Arora et al, 2011).…”

Section: Methodsmentioning

confidence: 99%

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GIRK Channels Modulate Opioid-Induced Motor Activity in a Cell Type- and Subunit-Dependent Manner

et al. 2015

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G-protein-gated inwardly rectifying Kϩ (GIRK/Kir3) channel activation underlies key physiological effects of opioids, including analgesia and dependence. GIRK channel activation has also been implicated in the opioid-induced inhibition of midbrain GABA neurons and consequent disinhibition of dopamine (DA) neurons in the ventral tegmental area (VTA). Drug-induced disinhibition of VTA DA neurons has been linked to reward-related behaviors and underlies opioid-induced motor activation. Here, we demonstrate that mouse VTA GABA neurons express a GIRK channel formed by GIRK1 and GIRK2 subunits. Nevertheless, neither constitutive genetic ablation of Girk1 or Girk2, nor the selective ablation of GIRK channels in GABA neurons, diminished morphine-induced motor activity in mice. Moreover, direct activation of GIRK channels in midbrain GABA neurons did not enhance motor activity. In contrast, genetic manipulations that selectively enhanced or suppressed GIRK channel function in midbrain DA neurons correlated with decreased and increased sensitivity, respectively, to the motor-stimulatory effect of systemic morphine. Collectively, these data support the contention that the unique GIRK channel subtype in VTA DA neurons, the GIRK2/GIRK3 heteromer, regulates the sensitivity of the mouse mesolimbic DA system to drugs with addictive potential.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

GIRK Channels Modulate Opioid-Induced Motor Activity in a Cell Type- and Subunit-Dependent Manner

et al. 2015

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“…The GIRK channel in VTA DA neurons undergoes activity-dependent bidirectional modulation; burst firing increases GIRK-dependent signaling in VTA DA neurons, whereas tonic firing suppresses channel activity (Lalive et al, 2014). The latter phenomenon is reminiscent of the cocaine-induced suppression of GIRKdependent signaling in VTA DA neurons, attributable to a subcellular redistribution of GIRK2-containing channels (Arora et al, 2011). The plasticity of GIRK channels provides a plausible explanation for how experience could impact the sensitivity of the mesocorticolimbic system to subsequent experiences, drug or otherwise.…”

Section: Girk-dependent Inhibitory Feedback and Cocaine Reinforcementmentioning

confidence: 99%

“…Pharmacological blockade or genetic suppression of G protein-dependent inhibitory feedback pathways in midbrain DA neurons alters behavioral effects of cocaine, including locomotor activation and self-administration (Steketee and Kalivas, 1991;Bello et al, 2011;Holroyd et al, 2015;de Jong et al, 2015). Moreover, inhibitory G protein signaling mediated by GABA B R and D 2 R is decreased following cocaine administration (Ackerman and White, 1990;Kushner and Unterwald, 2001;Arora et al, 2011), highlighting the reciprocal relationship between cocaine and inhibitory G protein signaling in DA neurons.…”

Section: Introductionmentioning

confidence: 99%

Selective Ablation of GIRK Channels in Dopamine Neurons Alters Behavioral Effects of Cocaine in Mice

McCall

Kotecki

Domínguez-López

et al. 2016

Neuropsychopharmacol

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The increase in dopamine (DA) neurotransmission stimulated by in vivo cocaine exposure is tempered by G protein-dependent inhibitory feedback mechanisms in DA neurons of the ventral tegmental area (VTA). G protein-gated inwardly rectifying K + (GIRK/Kir3) channels mediate the direct inhibitory effect of GABA B receptor (GABA B R) and D 2 DA receptor (D 2 R) activation in VTA DA neurons. Here we examined the effect of the DA neuron-specific loss of GIRK channels on D 2 R-dependent regulation of VTA DA neuron excitability and on cocaine-induced, reward-related behaviors. Selective ablation of Girk2 in DA neurons did not alter the baseline excitability of VTA DA neurons but significantly reduced the magnitude of D 2 R-dependent inhibitory somatodendritic currents and blunted the impact of D 2 R activation on spontaneous activity and neuronal excitability. Mice lacking GIRK channels in DA neurons exhibited increased locomotor activation in response to acute cocaine administration and an altered locomotor sensitization profile, as well as increased responding for and intake of cocaine in an intravenous self-administration test. These mice, however, showed unaltered cocaine-induced conditioned place preference. Collectively, our data suggest that feedback inhibition to VTA DA neurons, mediated by GIRK channel activation, tempers the locomotor stimulatory effect of cocaine while also modulating the reinforcing effect of cocaine in an operant-based self-administration task.

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“…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.…”

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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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Acute Cocaine Exposure Weakens GABA_BReceptor-Dependent G-Protein-Gated Inwardly Rectifying K⁺Signaling in Dopamine Neurons of the Ventral Tegmental Area

Cited by 56 publications

References 35 publications

GIRK Channels Modulate Opioid-Induced Motor Activity in a Cell Type- and Subunit-Dependent Manner

GIRK Channels Modulate Opioid-Induced Motor Activity in a Cell Type- and Subunit-Dependent Manner

Selective Ablation of GIRK Channels in Dopamine Neurons Alters Behavioral Effects of Cocaine in Mice

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

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Acute Cocaine Exposure Weakens GABABReceptor-Dependent G-Protein-Gated Inwardly Rectifying K+Signaling in Dopamine Neurons of the Ventral Tegmental Area

Cited by 56 publications

References 35 publications

GIRK Channels Modulate Opioid-Induced Motor Activity in a Cell Type- and Subunit-Dependent Manner

GIRK Channels Modulate Opioid-Induced Motor Activity in a Cell Type- and Subunit-Dependent Manner

Selective Ablation of GIRK Channels in Dopamine Neurons Alters Behavioral Effects of Cocaine in Mice

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

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Acute Cocaine Exposure Weakens GABA_BReceptor-Dependent G-Protein-Gated Inwardly Rectifying K⁺Signaling in Dopamine Neurons of the Ventral Tegmental Area