Actions of the sodium channel inhibitor 202W92 on rat midbrain dopaminergic neurons.
Excessive glutamatergic activity is implicated in Parkinson's disease (PD) and sodium channel blockade, resulting in inhibition of glutamate release, is a potential therapeutic approach to PD therapy. Beneficial effects of riluzole and lamotrigine have been reported in animal models of PD, but these compounds have relatively low potency as sodium channel inhibitors and also inhibit N and P/Q-type calcium channels. 202W92, a structural analog of lamotrigine, is a potent sodium channel inhibitor, with no effect on N, P/Q-type channels. Here we present the effects of 202W92 on single patch-clamped dopaminergic neurons. 202W92 (> or =10 microM) inhibited spontaneous action potential firing and reduced amplitude and frequency of evoked action potentials. It also inhibited the frequency of 4-aminopyridine (4-AP)- and electrically evoked excitatory postsynaptic currents (EPSCs) and GABAergic inhibitory postsynaptic currents (IPSCs), with >80% inhibition at 10 microM (IC(50) 1.5 microM). EPSC and IPSC amplitudes were partially inhibited. 202W92 did not affect postsynaptic responses to locally applied glutamate and GABA, nor spontaneously occurring mini-IPSCs. These actions of 202W92 are compatible with sodium channel inhibition and depression of transmitter release.
Caputi
Luigi
L
IRCCS Fondazione Santa Lucia, Rome, Italy.
Hainsworth
Atticus
A
Guatteo
Ezia
E
Tozzi
Alessandro
A
Stefani
Alessandro
A
Spadoni
Francesca
F
Leach
Michael
M
Bernardi
Giorgio
G
Mercuri
Nicola B
NB
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects*
C443646:2,4-diamino-6-(fluromethyl)-5-(2,3,5-trichlorophenyl)pyrimidine; D011743:Pyrimidines; D026941:Sodium Channel Blockers; D004298:Dopamine