Actions of the Sodium Channel Inhibitor 202W92 on Rat Midbrain Dopaminergic Neurons LUIGI CAPUTI, 1,3 ATTICUS HAINSWORTH, 2 EZIA GUATTEO, 1 ALESSANDRO TOZZI, 1 ALESSANDRO STEFANI, 3 FRANCESCA SPADONI, 3 MICHAEL LEACH, 4 GIORGIO BERNARDI, 1,3 AND NICOLA B. MERCURI 1,3 * 1 IRCCS Fondazione Santa Lucia, Rome, Italy 2 Pharmacology Research group, School of Pharmacy, De Montfort University, Leicester, United Kingdom 3 Clinica Neurologica, Universita ` di Roma, Tor Vergata, Rome, Italy 4 University of Greenwich, London, United Kingdom KEY WORDS neuroprotection; sodium influx; firing discharge; synaptic transmis- sion; Parkinson’s disease ABSTRACT 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 lam- otrigine have been reported in animal models of PD, but these compounds have rela- tively 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 (10 M) inhibited spontane- ous 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 postsynap- tic currents (IPSCs), with 80% inhibition at 10 M (IC 50 1.5 M). 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. Synapse 48:123–130, 2003. © 2003 Wiley-Liss, Inc. INTRODUCTION Increased glutamatergic transmission, excessive membrane depolarization, mitochondrial dysfunction, and oxidative stress have all been put forward as fac- tors contributing to the pathology of neurodegenerative diseases such as Parkinson’s disease (PD) (Beal, 1992; Blandini and Greenamyre, 1998; Doble, 1999; Gotz et al., 1994; Greenamyre et al., 1999; Mereu et al., 1991). Thus, drugs that inhibit glutamatergic transmission might have protective potential in PD, possibly by in- hibiting overactive glutamatergic inputs, depressing postsynaptic sodium influx, or reducing energy con- sumption in metabolically stressed dopaminergic neu- rons (Beal, 1992; Blandini and Greenamyre, 1998; Doble, 1999). Agents shown to have a beneficial effect in PD models in vivo include glutamate receptor antago- nists such as amantadine and remacemide (Greenamyre et al., 1994; Kornhuber et al., 1991) and sodium channel inhibitors such as lamotrigine (Fredriksson et al., 1999; Jones-Humble et al., 1994; Kaur and Starr, 1996; Starr et al., 1997) and riluzole (Barneoud et al., 1996; Benaz- zouz et al., 1995; Bezard et al., 1998; Boireau et al., 2000; Hassani et al., 2001). Here we studied the effects of a structural analog of lamotrigine, 202W92 (R-(–)- 2,4-diamino-6-(fluoromethyl)-5-(2,3,5-trichlorophe- nyl)pyrimidine (Caputi et al., 2001; Pollard et al., 1998), which is one of the most potent sodium channel inhibitors currently available (Clare et al., 2000). We have previously shown that 202W92 inhibits native neuronal sodium channels (IC 50 3 M; Caputi et al., 2001) about 20-fold more potently than does lam- otrigine (Xie et al., 1995). While lamotrigine exhibits little selectivity for sodium channels over presynaptic Contract grant sponsor: the Italian Ministry of Health. *Correspondence to: Prof. Nicola B. Mercuri, IRCCS Fondazione Santa Lucia, Via Ardeatina 306, 00179 Rome, Italy. E-mail: mercurin@med.uniroma2.it Received 12 November 2002; Accepted 28 January 2003 DOI 10.1002/syn.10195 SYNAPSE 48:123–130 (2003) © 2003 WILEY-LISS, INC.