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NEUROPHARMACOLOGY

Memantine Inhibits ATP-Dependent K⁺ Conductances in Dopamine Neurons of the Rat Substantia Nigra Pars Compacta

Fondazione Santa Lucia Istituto di Ricovero e Cura a Carattere Scientifico, Laboratory of Experimental Neurology (M.G., M.L.C., E.G., G.B., N.B.M., N.B.) and Department of Neuroscience, University of Rome "Tor Vergata" (G.B., N.B.M.), Rome, Italy

1-Amino-3,5-dimethyl-adamantane (memantine) is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist used in clinical practice to treat neurodegenerative disorders that could be associated with excitotoxic cell death. Because memantine reduces the loss of dopamine neurons of the substantia nigra pars compacta (SNc) in animal models of Parkinson's disease, we examined the effects of this drug on dopamine cells of the SNc. Besides inhibition of NMDA receptor-mediated currents, memantine (30 and 100 µM) increased the spontaneous firing rate of whole-cell recorded dopamine neurons in a midbrain slice preparation. Occasionally, a bursting activity was observed. These effects were independent from the block of NMDA receptors and were prevented in neurons dialyzed with a high concentration of ATP (10 mM). An increase in firing rate was also induced by the ATP-sensitive potassium (K_ATP) channel antagonist tolbutamide (300 µM), and this increase occluded further effects of memantine. In addition, K_ATP channel-mediated outward currents, induced by hypoxia, were inhibited by memantine (30 and 100 µM) in the presence of the NMDA receptor antagonist (5S, 10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) (10 µM). An increase in the spontaneous firing rate by memantine was observed in dopamine neurons recorded with extracellular planar 8 x 8 multielectrodes in conditions of hypoglycemia. These results highlight K_ATP channels as possible relevant targets of memantine effects in the brain. Moreover, in view of a proposed role of K_ATP conductances in dopamine neuron degeneration, they suggest another mechanism of action underlying the protective role of memantine in Parkinson's disease.

Address correspondence to: Nicola Berretta, Fondazione Santa Lucia I.R.C.C.S., Via del Fosso di Fiorano, 64, 00143 Rome, Italy. E-mail: n.berretta{at}hsantalucia.it