Molecular mechanisms of tolerance to and withdrawal of GABAA receptor modulators

@article{Biggio2003MolecularMO,
  title={Molecular mechanisms of tolerance to and withdrawal of GABAA receptor modulators},
  author={Giovanni Biggio and Laura Dazzi and Francesca Biggio and Luisa Mancuso and Giuseppe Talani and Fabio Busonero and Maria C. Mostallino and Enrico Sanna and Paolo Follesa},
  journal={European Neuropsychopharmacology},
  year={2003},
  volume={13},
  pages={411-423}
}
Here, we summarize recent data pertaining to the effects of GABA(A) receptor modulators on the receptor gene expression in order to elucidate the molecular mechanisms behind tolerance and dependence induced by these drugs. Drug selectivity and intrinsic activity seems to be important to evidence at the molecular level the GABA(A) receptor tolerance. On the contrary, we suggested that all drug tested are equally potentially prone to induce dependence. Our results demonstrate that long-lasting… Expand
Neurosteroids, GABAA receptors, and ethanol dependence
TLDR
Chronic ethanol exposure elicits changes in the subunit composition of GABAARs, which, in turn, likely contribute to changes in receptor function associated with the altered pharmacological and behavioral sensitivity characteristic of ethanol tolerance and dependence. Expand
Regulation of GABAA receptors by prolonged exposure to endogenous and exogenous ligands
  • M. Gravielle
  • Chemistry, Medicine
  • Neurochemistry International
  • 2018
TLDR
This review is focused on the effect of long‐term treatment with GABA, and the positive allosteric modulators benzodiazepines, neurosteroids and ethanol on GABAA receptors. Expand
Zolpidem withdrawal induced uncoupling of GABA(A) receptors in vitro associated with altered GABA(A) receptor subunit mRNA expression.
TLDR
An insight is provided into molecular and cellular mechanisms probably underlying adaptive changes of GABAA receptor function in response to chronic usage and withdrawal of zolpidem and perhaps the observed molecular changes could be linked to the tolerance and dependence produced upon prolonged treatment with other GABAergic drugs. Expand
Stress, ethanol, and neuroactive steroids.
TLDR
Data is shown showing that the interaction among stress, ethanol, and neuroactive steroids may result in plastic molecular and functional changes of GABAergic inhibitory neurotransmission, which may shed new light on the physiopathology of diseases, such as anxiety, in which GABAergic transmission plays a pivotal role. Expand
Genetic manipulations of GABAA receptor in mice make inhibition exciting.
TLDR
Findings are reviewed and speculation on the new directions that the use of mice with altered expression of GABA(A) receptor subunits may provide are speculated. Expand
Flumazenil selectively prevents the increase in α4‐subunit gene expression and an associated change in GABAA receptor function induced by ethanol withdrawal
TLDR
Observations are the first molecular and functional evidence that show a selective inhibition by flumazenil of the up‐regulation of α4‐subunit expression elicited by ethanol withdrawal. Expand
The role of transcriptional and translational mechanisms in flumazenil-induced up-regulation of recombinant GABAA receptors
TLDR
The results suggest that the up-regulation of GABA(A) receptors, observed after prolonged flumazenil treatment is at least partly due to increased de novo synthesis of receptor proteins at both transcriptional and translational level. Expand
Role of brain neuroactive steroids in the functional interplay between the GABAA and the NPY-Y1 receptor mediated signals in the amygdala
TLDR
Extensive pharmacologically or physiologically induced changes in the cerebrocortical concentrations of the neuroactive steroids increases Y(1)R/LacZ transgene expression in the central and medial amygdala, an effect similar to that induced by long-term treatment with positive modulators of the GABA(A) receptor complex. Expand
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. Expand
Tolerance to the rate-increasing and not rate-decreasing effects of pregnanolone in rats
TLDR
The development of tolerance to the rate-increasing effects of pregnanolone indicates that neuro Adaptations occur during chronic treatment; the fact that tolerance develops to only some effects suggests that the behavioral consequences of these neuroadaptations are limited. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 86 REFERENCES
The role of GABAA receptors in the acute and chronic effects of ethanol
TLDR
It is proposed that alterations in native GABAA receptor subunit assembly could alter the functional properties of these receptors, and post-translational modifications or other post-synaptic mechanisms may also explain changes in GAB AA receptor function. Expand
The role of GABAergic neuroactive steroids in ethanol action, tolerance and dependence
TLDR
It is suggested that 3alpha,5alpha-TH PROG and 3 alpha,5 alpha-TH DOC contribute to ethanol action and this interaction may represent a new mechanism of ethanol action. Expand
GABA(A) receptor subtypes: dissecting their pharmacological functions.
TLDR
Evidence that the various actions of allosteric modulators of GABA(A) receptors, in particular the benzodiazepines, can be attributed to specific GABA( A) receptor subtypes will be discussed and could open up new avenues for drug development. Expand
Neurosteroids and GABAA receptor function.
TLDR
Recent advances in this field are reviewed and the therapeutic potential of this novel, non-genomic effect of steroids is discussed and whether they may influence behaviour under physiological, or pathophysiological, conditions is investigated. Expand
Molecular and neuronal substrate for the selective attenuation of anxiety.
TLDR
The findings indicate that the anxiolytic effect of benzodiazepine drugs is mediated by alpha2 GABAA receptors, which are largely expressed in the limbic system, but not by alpha3 GAB AA receptors,Which predominate in the reticular activating system. Expand
γ-Aminobutyric acidA receptor regulation: heterologous uncoupling of modulatory site interactions induced by chronic steroid, barbiturate, benzodiazepine, or GABA treatment in culture
TLDR
There are at least two distinct ways in which GABAAR modulatory site interactions can be regulated by chronic drug treatment, and heterologous uncoupling by pregnanolone is resistant to SR-95531. Expand
Changes in GABAA receptor gene expression induced by withdrawal of, but not by long-term exposure to, zaleplon or zolpidem
TLDR
The effects of zaleplon and zolpidem on GABA(A) receptor gene expression are consistent with the reduced tolerance liability of these drugs, compared with that of diazepam, as well as with their ability to induce both physical dependence and withdrawal syndrome. Expand
Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology
TLDR
The isolation of a cloned cDNA encoding a new GABAA receptor subunit, termed γ2, which shares approximately 40% sequence identity with α-and β-subunits and whose messenger RNA is prominently localized in neuronal subpopulations throughout the CNS. Expand
Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAA receptor α1 subtype
TLDR
This work created genetically modified mice with a diazepam-insensitive α1 subtype and a selective BZ site ligand to explore GABAA receptor subtypes mediating specific physiological effects and revealed that the α1Subtype mediated the sedative, but not the anxiolytic effects of benzodiazepines. Expand
An update on GABAA receptors
TLDR
The subunit requirement of various drugs such as anxiolytics, anticonvulsants, general anesthetics, barbiturates, ethanol and neurosteroids, which are known to elicit at least some of their pharmacological effects via the GABAA receptors, have been investigated during the last few years so as to understand their exact mechanism of action. Expand
...
1
2
3
4
5
...