Ethanol Modulates Synaptic and Extrasynaptic GABA<sub>A</sub> Receptors in the Thalamus

Fan, Jia; Chandra, Dev; Homanics, Gregg E.; Harrison, Neil L.

doi:10.1124/jpet.108.139303

Cited by 78 publications

(77 citation statements)

References 65 publications

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“…It thus seems likely that striatal neurons within the NAc shell also express a δ-subunit-dependent GABAergic tonic current. Although the alcohol sensitivity of tonic inhibition in the striatum has not been reported, the GABAergic tonic currents mediated by δ-containing GABA A Rs in the hippocampus (23,24), thalamus (54), and cerebellum (20) are alcohol-sensitive, although those of the thalamus require higher alcohol concentrations (54). Together, these findings lead us to hypothesize that moderate levels of alcohol produce reinforcing/rewarding effects by enhancing GABAergic tonic inhibition in the medial shell, in agreement with proposals that reductions in the excitability of NAc shell neurons may provide a reinforcement signal (55).…”

Section: Discussionmentioning

confidence: 99%

Extrasynaptic δ-containing GABA _A receptors in the nucleus accumbens dorsomedial shell contribute to alcohol intake

Nie

Rewal²,

Gill³

et al. 2011

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

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Recent findings suggest that extrasynaptic δ-subunit-containing GABA A receptors are sensitive to low-to-moderate concentrations of alcohol, raising the possibility that these receptors mediate the reinforcing effects of alcohol after consumption of one or a few drinks. We used the technique of viral-mediated RNAi to reduce expression of the GABA A receptor δ-subunit in adult rats in localized regions of the nucleus accumbens (NAc) to test the hypothesis that δ-subunit-containing GABA A receptors in the NAc are necessary for oral alcohol consumption. We found that knockdown of the δ-subunit in the medial shell region of the NAc, but not in the ventral or lateral shell or in the core, reduced alcohol intake. In contrast, δ-subunit knockdown in the medial shell did not affect intake of a 2% sucrose solution, suggesting that the effects of GABA A receptor δ-subunit reduction are specific to alcohol. These results provide strong evidence that extrasynaptic δ-subunitcontaining GABA A receptors in the medial shell of the NAc are critical for the reinforcing effects of oral ethanol. 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) enhances the acquisition of alcohol consumption in laboratory rats (6), whereas the opposite effect, a reduction of alcohol self-administration, is observed after administration of the GABA A R antagonists Ro15-4513 or picrotoxin (7-9).GABA A Rs are pentamers assembled from a variety of subunits to form multiple isoforms that are likely to differ in their alcohol sensitivity (10). Although many GABA A R subunit combinations can be activated by high (anesthetic) alcohol concentrations (11), only specific GABA A R subunit combinations, specifically those containing a δ-subunit, appear to be sensitive to alcohol concentrations in the lower range of blood alcohol levels associated with mild to moderate intoxication in humans (12-15). For example, recombinant α 4 βδ and α 6 βδ GABA A Rs are reported to be sensitive to 3-30 mM concentrations of alcohol (12,14,16). Interestingly, δ-subunit-containing GABA A Rs are exclusively located at extrasynaptic locations (17-19), where they give rise to a tonic form of inhibition that potently suppresses neuronal excitability. A number of studies have shown that alcohol at low concentrations acts through extrasynaptic δ-containing GABA A Rs to increase tonic inhibition (20-24).The above findings suggest that actions at extrasynaptic δ-containing GABA A Rs could be critical for a variety of cognitive and behavioral effects of consumed alcohol, including anxiolysis, behavioral tolerance, and rewarding and reinforcing effects. However, δ-subunit knockout mice, and the related α 4 -subunit knockout mice, demonstrate relatively few alterations in the effects of alcohol in vivo. For example, the effects of acute alcohol administration on measures of anxiety, hypothermia, and sedation are not altered in these mice (25,26). In contrast, δ-subunit knockout mice drink less than their wild-type counterparts (25).Thus, δ-containing receptors may be involved in rewar...

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Section: Discussionmentioning

confidence: 99%

Extrasynaptic δ-containing GABA _A receptors in the nucleus accumbens dorsomedial shell contribute to alcohol intake

Nie

Rewal²,

Gill³

et al. 2011

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

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“…Reports of EtOH affecting current-induced spike firing of neurons in other brain areas are mixed with some studies showing effects similar to the present study and others showing no effect. For example, in mouse thalamic slices, 50 mM EtOH reduced currentevoked neuronal firing but had no effect at 20 mM; a concentration just above the legal limit for intoxication in the US (Jia et al, 2008). Conversely, current-evoked spiking of deep layer neurons in brain slice cocultures of the medial PFC was unaffected by 100 mM EtOH (Tu et al, 2007).…”

Section: Etoh Decreases Intrinsic Excitability Of Ofc Neuronsmentioning

confidence: 99%

“…For example, in the (Jia et al, 2008) study mentioned above, EtOH's effect on spike firing was prevented by a selective GABA A antagonist that also blocked the EtOH-induced increase in tonic current. In thalamus, these tonic currents are likely mediated by a4bd receptors as they are potentiated by the d-selective agonist THIP and are lost in mice devoid of a4 GABA A subunits.…”

Section: Etoh Decreases Intrinsic Excitability Of Ofc Neuronsmentioning

confidence: 99%

Ethanol Reduces Neuronal Excitability of Lateral Orbitofrontal Cortex Neurons Via a Glycine Receptor Dependent Mechanism

Badanich

Mulholland

Beckley

et al. 2013

Neuropsychopharmacol

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Trauma-induced damage to the orbitofrontal cortex (OFC) often results in behavioral inflexibility and impaired judgment. Human alcoholics exhibit similar cognitive deficits suggesting that OFC neurons are susceptible to alcohol-induced dysfunction. A previous study from this laboratory examined OFC mediated cognitive behaviors in mice and showed that behavioral flexibility during a reversal learning discrimination task was reduced in alcohol-dependent mice. Despite these intriguing findings, the actions of alcohol on OFC neuron function are unknown. To address this issue, slices containing the lateral OFC (lOFC) were prepared from adult C57BL/6J mice and whole-cell patch clamp electrophysiology was used to characterize the effects of ethanol (EtOH) on neuronal function. EtOH (66 mM) had no effect on AMPA-mediated EPSCs but decreased those mediated by NMDA receptors. EtOH (11-66 mM) also decreased current-evoked spike firing and this was accompanied by a decrease in input resistance and a modest hyperpolarization. EtOH inhibition of spike firing was prevented by the GABA A antagonist picrotoxin, but EtOH had no effect on evoked or spontaneous GABA IPSCs. EtOH increased the holding current of voltage-clamped neurons and this action was blocked by picrotoxin but not the more selective GABA A antagonist biccuculine. The glycine receptor antagonist strychnine also prevented EtOH's effect on holding current and spike firing, and western blotting revealed the presence of glycine receptors in lOFC. Overall, these results suggest that acutely, EtOH may reduce lOFC function via a glycine receptor dependent process and this may trigger neuroadaptive mechanisms that contribute to the impairment of OFC-dependent behaviors in alcohol-dependent subjects.

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“…It is well known that hyperpolarization, generated by NMDA receptor block, is sufficient to deinactivate T-type Ca 2+ channels, resulting in rhythmic thalamic bursting (20). By contrast, ethanol, known to elicit thalamic extrasynaptic GABA A -mediated tonic inhibition, also results in their burst firing via membrane hyperpolarization (21). From the above, it follows that in Ca V 3.1 KO mice, the reduced delta band activation during unconsciousness, elicited either through a blockage of NMDA receptors (by ketamine administration) or augmentation of GABA A receptor inhibition (by ethanol administration), can be ascribed to the absence of Ca V 3.1 channels and the resulting dynamic consequences-namely, lack of LTS that is consistent with the established role of Ca V 3.1 channels in lowfrequency thalamocortical oscillations.…”

Section: Discussionmentioning

confidence: 99%

Altered thalamocortical rhythmicity and connectivity in mice lacking Ca _V 3.1 T-type Ca ²⁺ channels in unconsciousness

Choi

Lee

et al. 2015

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

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In unconscious status (e.g., deep sleep and anesthetic unconsciousness) where cognitive functions are not generated there is still a significant level of brain activity present. Indeed, the electrophysiology of the unconscious brain is characterized by well-defined thalamocortical rhythmicity. Here we address the ionic basis for such thalamocortical rhythms during unconsciousness. In particular, we address the role of Ca V 3.1 T-type Ca 2+ channels, which are richly expressed in thalamic neurons. Toward this aim, we examined the electrophysiological and behavioral phenotypes of mice lacking Ca V 3.1 channels (Ca V 3.1 knockout) during unconsciousness induced by ketamine or ethanol administration. Our findings indicate that Ca V 3.1 KO mice displayed attenuated low-frequency oscillations in thalamocortical loops, especially in the 1-to 4-Hz delta band, compared with control mice (Ca V 3.1 WT). Intriguingly, we also found that Ca V 3.1 KO mice exhibited augmented highfrequency oscillations during unconsciousness. In a behavioral measure of unconsciousness dynamics, Ca V 3.1 KO mice took longer to fall into the unconscious state than controls. In addition, such unconscious events had a shorter duration than those of control mice. The thalamocortical interaction level between mediodorsal thalamus and frontal cortex in Ca V 3.1 KO mice was significantly lower, especially for delta band oscillations, compared with that of Ca V 3.1 WT mice, during unconsciousness. These results suggest that the Ca V 3.1 channel is required for the generation of a given set of thalamocortical rhythms during unconsciousness. Further, that thalamocortical resonant neuronal activity supported by this channel is important for the control of vigilance states.electroencephalogram | local field potential | mediodorsal thalamus | coherence T halamocortical interactive rhythmic activities are well-defined physiological correlates of both conscious and unconscious conditions (1, 2). From a functional perspective, abnormal slow cortical rhythms and their synchronized network dynamics are omnipresent correlates of unconscious states, such as coma and general anesthesia (3, 4). Moreover, a dynamic alteration of coherence as well as coupling/uncoupling in thalamocortical circuits also can be characterized as likely correlates of unconsciousness (3-5).Since the discovery of low threshold, T-type Ca 2+ channels (6, 7) and the subsequent studies of intrinsic electrophysiological properties in the thalamic neurons (8, 9), T-type Ca 2+ channels have been implicated in many physiological and pathological brain states (for a review, see ref. 10). The ionic conductances they support have been shown to generate synchronized oscillatory activity in thalamocortical circuits through calcium-dependent low-threshold spikes (LTSs). Indeed, these LTSs, generated by "deinactivation" of T-type Ca 2+ channels, underlie thalamic burst firing. This activity is reflected as high-amplitude low-frequency oscillations in electroencephalography, and its presence is recognized...

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Ethanol Modulates Synaptic and Extrasynaptic GABA_A Receptors in the Thalamus

Cited by 78 publications

References 65 publications

Extrasynaptic δ-containing GABA _A receptors in the nucleus accumbens dorsomedial shell contribute to alcohol intake

Extrasynaptic δ-containing GABA _A receptors in the nucleus accumbens dorsomedial shell contribute to alcohol intake

Ethanol Reduces Neuronal Excitability of Lateral Orbitofrontal Cortex Neurons Via a Glycine Receptor Dependent Mechanism

Altered thalamocortical rhythmicity and connectivity in mice lacking Ca _V 3.1 T-type Ca ²⁺ channels in unconsciousness

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Ethanol Modulates Synaptic and Extrasynaptic GABAA Receptors in the Thalamus

Cited by 78 publications

References 65 publications

Extrasynaptic δ-containing GABA A receptors in the nucleus accumbens dorsomedial shell contribute to alcohol intake

Extrasynaptic δ-containing GABA A receptors in the nucleus accumbens dorsomedial shell contribute to alcohol intake

Ethanol Reduces Neuronal Excitability of Lateral Orbitofrontal Cortex Neurons Via a Glycine Receptor Dependent Mechanism

Altered thalamocortical rhythmicity and connectivity in mice lacking Ca V 3.1 T-type Ca 2+ channels in unconsciousness

Contact Info

Product

Resources

About

Ethanol Modulates Synaptic and Extrasynaptic GABA_A Receptors in the Thalamus

Extrasynaptic δ-containing GABA _A receptors in the nucleus accumbens dorsomedial shell contribute to alcohol intake

Extrasynaptic δ-containing GABA _A receptors in the nucleus accumbens dorsomedial shell contribute to alcohol intake

Altered thalamocortical rhythmicity and connectivity in mice lacking Ca _V 3.1 T-type Ca ²⁺ channels in unconsciousness