Dexmedetomidine improves excessive extracellular glutamate-induced synaptic depression (BRAINRES-D-21-00941)

We investigated the effects of dexmedetomidine, a selective α2-adrenergic agonist and a sedative, on excessive glutamate-induced depressions of central excitatory synaptic transmissions in vitro. From the CA1 in rat hippocampal slices, orthodromically elicited population spikes (PSs) and field excitatory postsynaptic potentials (fEPSPs) at 0.1 Hz were simultaneously recorded. ANOVA was used for statistics, and p < 0.05 was accepted as significant. Glutamate (10 mM for 10 min) completely depressed PSs and fEPSPs, which were partially recovered by the following washout for 40 min (57.4 ± 10.2% and 59.9 ± 9.8% of the control, respectively, p < 0.01, n = 6). The recoveries in PSs and fEPSPs were improved by pre-treatment and simultaneous treatment with dexmedetomidine (p < 0.01, n = 6) but were not altered by post-treatment. Dexmedetomidine alone did not alter PSs and fEPSPs. Simultaneous treatment with isoproterenol or dobutamine exacerbated the recoveries in PSs and fEPSPs (p < 0.01, n = 6), but simultaneous treatment with salbutamol, propranolol, phenylephrine or phentramine did not influence the recoveries. Simultaneous treatment with AP5 improved the recoveries in PSs and fEPSPs that were depressed by glutamate alone and by glutamate with dexmedetomidine, isoproterenol or dobutamine (p < 0.01, n = 6). Excessive glutamate depresses glutamatergic excitatory synaptic transmissions by mainly mediating NMDA receptors, and the depressed transmissions are improved by α2-adrenoceptor stimulation but are exacerbated by β1-adrenoceptor stimulation. Dexmedetomidine has a protective effect on neuronal dysfunctions induced by excessive glutamate, which is one of the main mechanisms of the secondary damage in the central nervous system.