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Memantine Inhibits ATP-Dependent K+ Conductances in Dopamine Neurons of the Rat Substantia Nigra Pars Compacta
Michela Giustizieri,
Maria Letizia Cucchiaroni, Ezia Guatteo, Giorgio Bernardi,
Nicola B. Mercuri, and Nicola Berretta
J Pharmacol
Exp Ther. 2007 Aug;322(2):721-9. Epub 2007 May 11.
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 muM) 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 muM), 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 muM) 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 muM). 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.
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