Withdrawal from chronic intermittent ethanol treatment changes subunit composition, reduces synaptic function, and decreases behavioral responses to positive allosteric modulators of GABAA receptors.

@article{Cagetti2003WithdrawalFC,
  title={Withdrawal from chronic intermittent ethanol treatment changes subunit composition, reduces synaptic function, and decreases behavioral responses to positive allosteric modulators of GABAA receptors.},
  author={Elisabetta Cagetti and Jing Liang and Igor Spigelman and Richard W. Olsen},
  journal={Molecular pharmacology},
  year={2003},
  volume={63 1},
  pages={
          53-64
        }
}
One of the pharmacological targets of ethanol is the GABAA receptor (GABAR), whose function and expression are altered after chronic administration of ethanol. The details of the changes differ between experimental models. In the chronic intermittent ethanol (CIE) model for alcohol dependence, rats are exposed to intermittent episodes of intoxicating ethanol and withdrawal, leading to a kindling-like state of behavioral excitability. This is accompanied by presumably causal changes in GABAR… 

Figures and Tables from this paper

Plasticity of GABAA Receptors in Brains of Rats Treated with Chronic Intermittent Ethanol
TLDR
Evidence is presented that changes in GABAA receptor subunit levels, in receptor localization, and in physiology and pharmacology are leading to alterations in behavior that contribute to the hyperexcitable alcohol withdrawal state (anxiety, insomnia, seizure susceptibility) and alcohol dependence.
Role of GABAA receptors in alcohol use disorders suggested by chronic intermittent ethanol (CIE) rodent model
TLDR
It is suggested that the craving, drug-seeking, and increased consumption in the rat model are tied to ethanol-induced plastic changes in GABAA receptors, importantly the development of ethanol-sensitive synaptic GAB AA receptor-mediating inhibitory currents that participate in maintained positive reward actions of ethanol on critical neuronal circuits.
Changes in GABAA Receptor Gene Expression Associated with Selective Alterations in Receptor Function and Pharmacology after Ethanol Withdrawal
TLDR
Changes in GABAA receptor gene expression induced by prolonged exposure to and withdrawal of ethanol are associated with altered GAB AA receptor function and pharmacological sensitivity.
Chronic Intermittent Ethanol-Induced Switch of Ethanol Actions from Extrasynaptic to Synaptic Hippocampal GABAA Receptors
TLDR
The profound alterations in EtOH sensitivity and α4 subunit localization at hippocampal GABAARs of CIE rats suggest that such changes in these and other relevant brain circuits may contribute to the development of tolerance to the sleep-inducing effects and long-term dependence on alcohol.
Ethanol-Induced Plasticity of GABAA Receptors in the Basolateral Amygdala
TLDR
The results suggest that EtOH intoxication-induced GABAAR plasticity in the BLA might contribute to the diminished sedative/hypnotic and maintained anxiolytic effectiveness of EtOH.
Altered Pharmacology of Synaptic and Extrasynaptic GABAA Receptors on CA1 Hippocampal Neurons Is Consistent with Subunit Changes in a Model of Alcohol Withdrawal and Dependence
Previously, we reported (Cagetti, Liang, Spigelman, and Olsen, 2003) that chronic intermittent ethanol (CIE) treatment leads to signs of alcohol dependence, including anxiety and hyperactivity,
Differential effects of chronic ethanol administration and withdrawal on gamma-aminobutyric acid type A and NMDA receptor subunit proteins in male and female rat brain.
  • L. Devaud, P. Alele
  • Medicine, Biology
    Alcoholism, clinical and experimental research
  • 2004
TLDR
There was a strong association between increased GABAA receptor alpha4 subunit levels and previously determined withdrawal-induced changes in seizure susceptibility, highlighted by the sex differences in ethanol exposure length required to cause withdrawal signs.
Tolerance to sedative/hypnotic actions of GABAergic drugs correlates with tolerance to potentiation of extrasynaptic tonic currents of alcohol-dependent rats.
TLDR
A striking correlation between tolerance in the LORR assay and tolerance to enhancement of tonic currents, but not mIPSCs suggests that the sedative/anesthetic actions of GABAergic drugs may be mediated primarily via the potentiation of extrasynaptic GABAARs.
Plasticity of GABA(A) receptor-mediated neurotransmission in the nucleus accumbens of alcohol-dependent rats.
TLDR
The long-lasting alterations of γ-aminobutyric acid type A receptors of medium spiny neurons (MSNs) in the NAcc after chronic intermittent ethanol (CIE) treatment, a rat model of alcohol dependence, reveal CIE-induced long- lasting neuroadaptations in theNAcc GABAergic neurotransmission.
...
...

References

SHOWING 1-10 OF 61 REFERENCES
Chronic Intermittent Ethanol Treatment in Rats Increases GABAA Receptor α4‐Subunit Expression: Possible Relevance to Alcohol Dependence
TLDR
It is suggested that GABar subunit‐selective alterations occur after CIE treatment, possibly resulting in the alteration of the subunit composition of GABARs, with presumably altered physiological functions.
Bidirectional Alterations of GABAA Receptor Subunit Peptide Levels in Rat Cortex During Chronic Ethanol Consumption and Withdrawal
TLDR
Findings show that specific alterations in GABAA receptor subunit peptide levels are associated with ethanol dependence in rats, consistent with the suggestion that alterations in gabAA receptor gene expression underlie the functional properties of GAB AA receptors in ethanol‐dependent rats and those undergoing ethanol withdrawal.
Alteration in the sensitivity of GABA(A) receptors to allosteric modulatory drugs in rat hippocampus after chronic intermittent ethanol treatment.
TLDR
The results suggest that the sensitization of GABA(A)R to acute ethanol and benzodiazepine inverse agonists, and possibly neurosteroids, may underlie ethanol dependence after multiple ethanol withdrawal episodes.
Altered gabaa receptor subunit and splice variant expression in rats treated with chronic intermittent ethanol.
TLDR
The transient change in cerebellar alpha6 subunit-containing receptors is unlikely to account for the persistently hyperexcitable, kindled, seizure-susceptible state seen in CIE, but changes in GABAA receptors were found in rats given CIE.
Antibodies specific for GABAA receptor alpha subunits reveal that chronic alcohol treatment down-regulates alpha-subunit expression in rat brain regions.
TLDR
This study investigates the expression of alpha 1, alpha 2, and alpha 3 subunits of the GABAA receptor in the cerebral cortex and the alpha 1 subunit in the cerebellum by immunoblotting using polyclonal antibodies raised against alpha 1-, alpha 2-, andalpha 3-subunit polypeptides following chronic ethanol treatment to reveal an ethanol-induced reduction in content.
Antibodies Specific for GABAA Receptor α Subunits Reveal that Chronic Alcohol Treatment Down‐Regulates α‐Subunit Expression in Rat Brain Regions
TLDR
This ethanol‐induced reduction in content of the GABAA receptor α subunits may underlie alterations in the GabAA receptor function and could be related to cellular adaptation to the functional disturbance caused by ethanol.
Acute and chronic ethanol treatments alter GABA receptor-operated chloride channels
Sensitization of gamma-aminobutyric acidA receptors to neuroactive steroids in rats during ethanol withdrawal.
TLDR
Ethan withdrawal produces alterations in GABA(A) receptors that sensitize rats to the pharmacological effects of neuroactive steroids, which could have significant therapeutic potential.
...
...