RT Journal Article
SR Electronic
T1 Memantine Inhibits ATP-Dependent K<sup>+</sup> Conductances in Dopamine Neurons of the Rat Substantia Nigra <em>Pars Compacta</em>
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 721
OP 729
DO 10.1124/jpet.107.122036
VO 322
IS 2
A1 Michela Giustizieri
A1 Maria Letizia Cucchiaroni
A1 Ezia Guatteo
A1 Giorgio Bernardi
A1 Nicola B. Mercuri
A1 Nicola Berretta
YR 2007
UL http://jpet.aspetjournals.org/content/322/2/721.abstract
AB 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 (KATP) channel antagonist tolbutamide (300 μM), and this increase occluded further effects of memantine. In addition, KATP 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 × 8 multielectrodes in conditions of hypoglycemia. These results highlight KATP channels as possible relevant targets of memantine effects in the brain. Moreover, in view of a proposed role of KATP conductances in dopamine neuron degeneration, they suggest another mechanism of action underlying the protective role of memantine in Parkinson's disease. The American Society for Pharmacology and Experimental Therapeutics