An Inverse Agonist Selective for α5 Subunit-Containing GABAA Receptors Enhances Cognition

@article{Dawson2006AnIA,
  title={An Inverse Agonist Selective for $\alpha$5 Subunit-Containing GABAA Receptors Enhances Cognition},
  author={G. R. Dawson and Karen A. Maubach and Neil Collinson and Matthew R D Cobain and Barry J. Everitt and Angus Murray Macleod and Hedaythul I Choudhury and Louise M. McDonald and Goplan V Pillai and W. Stanley Rycroft and A. J. Smith and Francine Sternfeld and F. David Tattersall and Keith A. Wafford and David S. Reynolds and Guy R. Seabrook and J. R. Atack},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2006},
  volume={316},
  pages={1335 - 1345}
}
  • G. Dawson, K. Maubach, J. Atack
  • Published 1 March 2006
  • Biology, Psychology
  • Journal of Pharmacology and Experimental Therapeutics
α5IA is a compound that binds with equivalent subnanomolar affinity to the benzodiazepine (BZ) site of GABAA receptors containing an α1, α2, α3, or α5 subunit but has inverse agonist efficacy selective for the α5 subtype. As a consequence, the in vitro and in vivo effects of this compound are mediated primarily via GABAA receptors containing an α5 subunit. In a mouse hippocampal slice model, α5IA significantly enhanced the θ burst-induced long-term potentiation of the excitatory postsynaptic… 
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References

SHOWING 1-10 OF 65 REFERENCES
Trace fear conditioning involves hippocampal α5 GABAA receptors
  • F. Crestani, R. Keist, U. Rudolph
  • Biology, Psychology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2002
TLDR
The largely extrasynaptic α5GABAA receptors in hippocampal pyramidal cells are implicated as control elements of the temporal association of threat cues in trace fear conditioning, which altered the drug-independent behavior of mutant mice.
Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes
GABAA (γ-aminobutyric acidA) receptors are molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity and memory functions, which is evident from the…
Effects of Hippocampal Injections of a Novel Ligand Selective for the α5β2γ2 Subunits of the GABA/Benzodiazepine Receptor on Pavlovian Conditioning
TLDR
RY024 independently produced fear-related behavior prior to training and, at the highest concentration, decreased the strength of conditioning observed 24 h after training, providing further evidence for the involvement of hippocampal GABAA/benzodiazepine receptors in learning and anxiety.
Modulation of Long-term Potentiation in CA1 Region of Mouse Hippocampal Brain Slices by GABAA Receptor Benzodiazepine Site Ligands
Anxiogenic properties of an inverse agonist selective for α3 subunit‐containing GABAA receptors
TLDR
The data demonstrate that an inverse agonist selective for GABAA receptors containing an α3 subunit is anxiogenic, and suggest that since α3‐containing GAB AA receptors play a role in anxiety, then agonists selective for this subtype should be anxiolytic.
Enhanced Learning and Memory and Altered GABAergic Synaptic Transmission in Mice Lacking the α5 Subunit of the GABAAReceptor
TLDR
Data suggest that α5-containing GABAA receptors play a key role in cognitive processes by controlling a component of synaptic transmission in the CA1 region of the hippocampus.
Anxiogenic-like activity of L-655,708, a selective ligand for the benzodiazepine site of GABAA receptors which contain the alpha-5 subunit, in the elevated-plus maze test
Regional Differences in the Inhibition of Mouse In Vivo [3H]Ro 15-1788 Binding Reflect Selectivity for α1 versus α2 and α3 Subunit-Containing GABAA Receptors
Analysis of GABAA receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics.
TLDR
The point-mutated knockin mice in which specific GABAA receptor sub types are insensitive to diazepam or some general anesthetics have revealed the specific contribution of individual receptor subtypes to the pharmacological spectrum of diazepAM and general anESThetics.
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.
...
1
2
3
4
5
...