GABAA receptors and alcohol

Lobo, Ingrid A.; Harris, R. Adron

doi:10.1016/j.pbb.2008.03.006

Cited by 162 publications

(130 citation statements)

References 62 publications

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“…addiction | reward | self-administration | tonic inhibition G ABA A receptors (GABA A Rs) have long been considered a primary target for alcohol actions, including the voluntary consumption of alcohol (1)(2)(3)(4)(5). For example, treatment with the GABA A agonist 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)(8)(9).…”

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confidence: 99%

“…δ mRNA and protein would be decreased at this time because our previous studies indicated that effects induced by this adenovirus on other genes [α 4 -subunit (32); BDNF (37)] are transient, with an effective time window of <2 wk, beginning around day 10 for both mRNA and behavioral changes. Notably, in our prior studies, peak behavioral changes have occurred ∼17-18 d after virus infusion (32,37).…”

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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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confidence: 99%

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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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“…During the last decades it became clear that ethanol directly acts on proteins such as receptors and ion channels located in the plasma membrane or at intracellular signalling molecules. Experimental evidence revealed that some effects of ethanol are due to specific actions including most ligand-gated ion channels, such as glutamate-, -aminobutyric acid-(GABA) (Lobo & Harris 2008), dopamine-(Di Chiara & Imperato 1986), 5-hydroxytryptamine-, or acetylcholine-, opioid-, (Di Chiara et al 1996;Herz 1997;Gianoulakis 2009), adenosine-, ATP-(Asatryan et al, 2011Ostrovskaya et al, 2011), or TRP receptors (Benedikt et al, 2007, as well as voltage-gated ion channels, such as K + , Na + , and in particular Ca 2+ channels (Gonzales & Hoffman 1991;Crews et al, 1996b;Dopico et al 1996;Jakab et al 1997;Horishita & Harris 2008;Dopico & Lovinger 2009;Kerschbaum & Hermann 1997). Ethanol was also found to interact with signal-transduction mechanisms including Gproteins and protein kinases (Messing et al 1991;Lahnsteiner & Hermann 1995;Newton & Ron 2007;Martin 2010;Kelm et al 2011).…”

Section: Bk Channels -And Ethanol/acetaldehydementioning

confidence: 99%

BK Channels – Focus on Polyamines, Ethanol/Acetaldehyde and Hydrogen Sulfide (H2S)

Hermann¹,

Ситдикова²,

Weiger³

2012

Patch Clamp Technique

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“…Many of these subunit combinations have been examined for function and pharmacology in heterologous expression systems. To briefly summarize a large body of data, there is evidence that EtOH potentiates the function of α/β/γ-subunit-containing receptors, as well as those containing α4 or α6 along with β and δ subunits Lobo and Harris 2008;Mihic and Harris 1995;McCool et al 2003). However, none of these findings has been uniformly replicated in all laboratories that have examined EtOH effects in heterologous systems (reviewed in Lovinger and Homanics 2007;Aguayo et al 2002).…”

Section: Ligand-gated Ion Channels and Postsynaptic Ethanol Effectsmentioning

confidence: 99%

Synaptic Effects Induced by Alcohol

Lovinger

Roberto

2010

Current Topics in Behavioral Neurosciences

114

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Ethanol (EtOH) has effects on numerous cellular molecular targets, and alterations in synaptic function are prominent among these effects. Acute exposure to EtOH activates or inhibits the function of proteins involved in synaptic transmission, while chronic exposure often produces opposing and/or compensatory/homeostatic effects on the expression, localization, and function of these proteins. Interactions between different neurotransmitters (e.g., neuropeptide effects on release of small molecule transmitters) can also influence both acute and chronic EtOH actions. Studies in intact animals indicate that the proteins affected by EtOH also play roles in the neural actions of the drug, including acute intoxication, tolerance, dependence, and the seeking and drinking of EtOH. This chapter reviews the literature describing these acute and chronic synaptic effects of EtOH and their relevance for synaptic transmission, plasticity, and behavior. KeywordsGABA; Glutamate; Monoamine; Neuropeptide; Neurotransmitter receptor; Presynaptic; Postsynaptic; Protein phosphorylation; Synaptic plasticity; Intoxication; Tolerance; Dependence Acute Ethanol ActionsEthanol (EtOH) produces intoxication through actions on the central nervous system (CNS) at concentrations ranging from low to ~100 mM (at least in non-tolerant humans and experimental animals). A number of proteins involved in synaptic transmission are altered by EtOH effects within this concentration range. The target proteins include, but are not limited to, ion channels, neurotransmitter receptors, and intracellular signaling proteins. The first section of this article will review the literature describing the most prominent acute EtOH effects on synaptic transmission in the CNS. This review is not meant to be comprehensive, but rather to cover those effects that have been observed most consistently and are thought to contribute to intoxication.

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GABAA receptors and alcohol

Cited by 162 publications

References 62 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

BK Channels – Focus on Polyamines, Ethanol/Acetaldehyde and Hydrogen Sulfide (H2S)

Synaptic Effects Induced by Alcohol

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GABAA receptors and alcohol

Cited by 162 publications

References 62 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

BK Channels – Focus on Polyamines, Ethanol/Acetaldehyde and Hydrogen Sulfide (H2S)

Synaptic Effects Induced by Alcohol

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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