1.Inhibition of α5 γ-Aminobutyric acid type A receptors restores recognition memory after general anesthesia.
Zurek AA;Bridgwater EM;Orser BA Anesth Analg. 2012 Apr;114(4):845-55. doi: 10.1213/ANE.0b013e31824720da. Epub 2012 Mar 1.
BACKGROUND: ;General anesthetics cause cognitive deficits that persist much longer than would be expected on the basis of their pharmacokinetics. The cellular mechanisms underlying these postanesthetic cognitive deficits remain unknown. γ-Aminobutyric acid type A (GABA(A)) receptors are principal targets for most anesthetics. In particular, the α5GABA(A) receptor subtype has been implicated in acute memory blockade during anesthesia and memory deficits in the early postoperative period. We first sought to determine whether working memory and short-term recognition memory are impaired after isoflurane anesthesia. The second aim of the study was to determine whether memory deficits after isoflurane can be reversed by inhibiting α5GABA(A) receptors. We also sought to determine whether the expression of α5GABA(A) receptors is necessary for the development of memory dysfunction after isoflurane. Lastly, the effect of sevoflurane on memory was studied.;METHODS: ;Wild-type and α5GABA(A) receptor null-mutant (Gabra5-/-) mice were treated with isoflurane (1.3%; 1 minimum alveolar concentration [MAC]) or sevoflurane (2.3%; 1 MAC) or vehicle gas for 1 hour. Memory performance was assessed with a novel object recognition task.
2.Rapid Antidepressant Action and Restoration of Excitatory Synaptic Strength After Chronic Stress by Negative Modulators of Alpha5-Containing GABAA Receptors.
Fischell J;Van Dyke AM;Kvarta MD;LeGates TA;Thompson SM Neuropsychopharmacology. 2015 Oct;40(11):2499-509. doi: 10.1038/npp.2015.112. Epub 2015 Apr 22.
Selective serotonin reuptake inhibitors (SSRIs) are the primary pharmacological treatment for depression, but SSRIs are effective in only half of the patients and typically take several weeks to relieve symptoms. The NMDA receptor antagonist ketamine exerts a rapid antidepressant action, but has troubling side effects. We hypothesized that negative allosteric modulators of GABAA receptors would exert similar effects on brain activity as ketamine, but would not exert as many side effects if targeted only to GABAA receptors containing α5 subunits, which are enriched in the hippocampus and prefrontal cortex. Here, we show that the α5-selective negative modulator L-655,708 reversed the alterations in hedonic behavior in the sucrose preference and social interaction tests produced by two different chronic stress paradigms in rats within 24 h of systemic administration. Similar effects were observed with another α5-selective negative modulator, MRK-016. L-655,708 had no effect on hedonic or open-field behavior in unstressed animals. Within 24 h, L-655,708 injection also restored the strength of pathologically weakened excitatory synaptic transmission at the stress-sensitive temporoammonic-CA1 synapse, measured electrophysiologically, and increased levels of the GluA1 subunit of the AMPA receptor, measured with western blotting.
3.Evaluation of native GABA(A) receptors containing an alpha 5 subunit.
Li M;Szabo A;Rosenberg HC Eur J Pharmacol. 2001 Feb 9;413(1):63-72.
The type A receptor for gamma-aminobutyric acid (GABA), or GABA(A) receptor, is a pentamer of highly variable quaternary structure. It includes two alpha subunits, drawn from a pool of six genes, which largely determine benzodiazepine pharmacology of the receptor. In brain sections, both [(3)H]RY-80 (ethyl-8-acetylene-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a][1,4]benzodiazepine-3-carboxylate) and [(3)H]L-655,708 (ethyl (S)-11,12,13,13a-tetrahydro-7-methoxy-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate), which are selective for the benzodiazepine site of alpha 5 subunit-containing receptors, showed high-affinity, specific binding, but to fewer regions than did the nonselective benzodiazepine, [(3)H]flunitrazepam. The pattern mirrored alpha 5 mRNA distribution, and was similar to that previously reported for [(3)H]L-655,708 binding. Displacement of [(3)H]RY-80 bound to hippocampal homogenates, and of [(3)H]flunitrazepam bound to cerebellar and hippocampal homogenates showed comparable displacement by flumazenil (K(i)'s 5--7 nM). However, the K(i)'s for diazepam and for clobazam to displace [(3)H]RY-80 binding in hippocampus were about fourfold higher than for [(3)H]flunitrazepam, and the K(i) for clonazepam was sixfold larger, suggesting that these benzodiazepine receptor agonists bind with relatively lower affinity at hippocampal alpha 5-containing receptors.