Brain allopregnanolone regulates the potency of the GABAA receptor agonist muscimol

@article{Pinna2000BrainAR,
  title={Brain allopregnanolone regulates the potency of the GABAA receptor agonist muscimol},
  author={Graziano Pinna and Veska Uzunova and Kinzo Matsumoto and Giulia Puia and Alessandro Guidotti},
  journal={Neuropharmacology},
  year={2000},
  volume={39},
  pages={440-448}
}
Allopregnanolone (ALLO), a potent positive-allosteric modulator of the action of GABA at GABA(A) receptors, is synthesized in the brain from progesterone by the sequential action of two enzymes: 5alpha-reductase and 3alpha-hydroxysteroidoxidoreductase. The concentration of ALLO in various parts of the mouse brain varies substantially, from 15 pmol/g in the olfactory bulb, to approximately 6 pmol/g in the frontoparietal cortex, and 2.7 pmol/g in the cerebellum. The systemic administration of 48… 
Brain 5α-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation
TLDR
Protracted social isolation in mice may provide a model to investigate whether 5α-DHP by a genomic action, and ALLO by a nongenomic mechanism down-regulate the action of drugs acting as agonist, partial agonists, or positive allosteric modulators of the benzodiazepine recognition sites expressed by GABAA receptors.
On the putative physiological role of allopregnanolone on GABAA receptor function
TLDR
The data demonstrate that endogenous ALLO physiologically regulates spontaneously induced Cl(-) current by acting on a specific recognition site, which is probably located on GABA(A) receptors (a receptor on a receptor), thereby prolonging inhibitory currents by facilitating conformational transition of the GABA-gated Cl(+) channel to an open state.
GABAB receptor-mediated increase of neurosteroids by γ-hydroxybutyric acid
Among the pharmacological actions of gamma-hydroxybutyric acid (GHB), some may involve GABA(A) receptor-mediated mechanisms. GHB, however, fails to directly interact with sites for agonists and
The socially-isolated mouse: a model to study the putative role of allopregnanolone and 5α-dihydroprogesterone in psychiatric disorders
TLDR
Using socially-isolated mice that have a downregulation of 3alpha,5alpha-TH PROG and of 5alpha-DH PROG expression to establish a model to study the behavioral consequences of this deficiency may enable us to design drugs that specifically affect neurosteroidogenic enzymatic activities and may provide an efficacious treatment for the psychopathologies associated with psychiatric disorders.
Region-specific dysregulation of allopregnanolone brain content in the olfactory bulbectomized rat model of depression
TLDR
Data indicates a strong region-specific dysregulation of ALLO homeostasis in brains of OB rats which may contribute to the formation of the bulbectomy syndrome via a sustained reduction in physiological GABA-ergic tone in amygdala and frontal cortex.
Allopregnanolone: From molecular pathophysiology to therapeutics. A historical perspective
TLDR
The discovery that allopregnanolone at low (nanomolar) concentrations elicits marked anxiolytic, anti-stress and antidepressant effects by facilitating allosterically the action of GABA at extrasynaptic GABAA receptors has provided new perspectives for the discovery of novel drugs useful for the treatment of mood disorders.
The influence of subunit composition on the interaction of neurosteroids with GABAA receptors
TLDR
Evidence is provided that 5alpha,3alpha discriminates amongst recombinant receptors of varied subunit composition and this selectivity may contribute to their neuronal specificity and behavioural profile.
Multifunctional aspects of allopregnanolone in stress and related disorders
  • Anjana Bali, A. Jaggi
  • Psychology, Medicine
    Progress in Neuro-Psychopharmacology and Biological Psychiatry
  • 2014
TLDR
The present review discusses the various aspects of allopregnanolone in stress and stress-related disorders including anxiety, depression and panic.
Clozapine, but not Haloperidol, Increases Brain Concentrations of Neuroactive Steroids in the Rat
TLDR
The results suggest that the clozapine-induced increases in neuroactive steroid concentrations in the brain may contribute to the atypical pharmacological profile of this antipsychotic drug.
Neurosteroid modulation of GABAA receptors
TLDR
Emerging evidence is reviewed that the GABA-modulatory actions of the pregnane steroids are highly selective, with their actions being brain region and indeed neuron dependent, and the sensitivity of GABA(A) receptors is not static but can dynamically change.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 29 REFERENCES
Permissive role of brain allopregnanolone content in the regulation of pentobarbital-induced righting reflex loss
TLDR
Evidence is provided suggesting that the endogenous cortical stores of ALLO physiologically upregulate GABAergic tone and by such a mechanism play a permissive or facilitatory role on the PTB-induced loss of the righting reflex.
Does neurosteroid modulatory efficacy depend on GABAA receptor subunit composition?
TLDR
A direct activation of Cl- current by 3 alpha-OH-DHP was observed in native and recombinant receptors but its efficacy on the various molecular forms of GABAA receptor tested was always smaller than that of identical concentrations (10 microM) of GABA.
Stress-induced elevations of gamma-aminobutyric acid type A receptor-active steroids in the rat brain.
TLDR
The presence of allopregnanolone and allotetrahydroDOC in brain is demonstrated and acute stress results in a rapid increase of these neuroactive steroids to levels known to modulate GABAA receptor function.
Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor.
TLDR
Two metabolites of the steroid hormones progesterone and deoxycorticosterone are potent barbiturate-like ligands of the gamma-aminobutyric acid (GABA) receptor-chloride ion channel complex and potentiated the inhibitory actions of GABA in cultured rat hippocampal and spinal cord neurons, which may explain the ability of certain steroid hormones to rapidly alter neuronal excitability.
Pharmacology of Neurosteroid Biosynthesis. Role of the Mitochondrial DBI Receptor (MDR) Complex
DBI is the acronym for diazepam binding inhibitor and refers to a 9-kd endogenous polypeptide first purified from rat brain by monitoring this peptide's ability to displace [3H]-diazepam specifically
Modulation of the GABA receptor complex by a steroid anaesthetic
TLDR
It is suggested that alphaxalone and pentobarbitone share a common mode of action on the GABA system, which may be relevant to the mechanisms by which these drugs produce anaesthesia.
Modulation of the GABAA receptor by progesterone metabolites
TLDR
The results suggest that certain naturally occurring steroids potentiate the actions of GABA and, additionally, directly activate the GABAA receptor.
A putative receptor for neurosteroids on the GABAA receptor complex: the pharmacological properties and therapeutic potential of epalons.
TLDR
Based upon some of the unique characteristics of the epalons relative to barbiturates and the BZs, it is plausible that the epAlons can be developed into a novel class of therapeutic agents for the treatment of anxiety, epilepsy, and insomnia.
Role of brain allopregnanolone in the plasticity of gamma-aminobutyric acid type A receptor in rat brain during pregnancy and after delivery.
TLDR
The results indicate that the plasticity of GABAA receptors during pregnancy and after delivery is functionally related to fluctuations in endogenous brain concentrations of AP whose rate of synthesis/metabolism appears to differ in the brain, compared with plasma, in pregnant rats.
Anticonvulsant activity of neurosteroids: correlation with gamma-aminobutyric acid-evoked chloride current potentiation.
TLDR
Although the anticonvulsant steroids had greater in vitro potencies than clonazepam, they were less potent in vivo, and they had lower protective indices.
...
1
2
3
...