Summary:Purpose: To investigate the effects of lamotrigine (LTG), a new anticonvulsant, on neuronal excitability, synaptic transmission, and long-term potentiation (LTP) in guinea pig hippocampal slices.Methods: Electrically evoked field excitatory postsynaptic potentials (fEPSPs) and population spikes (PSs) were investigated in the CAI region of the hippocampus.Results: The concentration-response curves showed different actions of LTG in concentrations near therapeutic plasma levels (1 0 pM) on fEPSPs and PSs. The initial slopes of fEPSPs were not affected, whereas the amplitudes of PSs were significantly decreased. Higher concentrations of LTG decreased both fEPSP slopes and PS amplitudes; however, the effects on PSs were much stronger. Also, there were no differences in fEPSP slopes or PS amplitudes compared with controls when LTP was induced in the presence of LTG (10 pM).Conclusions: Our data are in contrast to previous findings that suggest LTG acts primarily on presynaptic sites by blocking the release of excitatory amino acids. The new antiepileptic drug lamotrigine [3,5-diamino-6-(2,3-dichlorophenyl)-1,2,3-trazine] (LTG) has been used in the treatment of focal epilepsies with or without secondary generalization (1,2). Also, several reports have indicated efficacy in the treatment of bipolar affective disorders (3-6). LTG is believed to block presynaptic voltage-sensitive sodium channels, inhibiting the release of excitatory amino acids (7,8). Further, antagonistic effects of LTG on calcium channels have been found in rat cortical neurons (9) and in the CAl/CA3 hippocampal area of guinea pigs (10). Recently, LTG has been shown to modulate the transient potassium outward current I , (1 l).Long-term potentiation (LTP) is a widely accepted model for synaptic plasticity, learning, and memory (12,13). Synaptic plasticity has been suggested to play an important role in epileptogenic mechanisms (14-16) as well as in the development and time course of affective disorders (6,17,18). LTG was found to have no influence on the induction of LTP in the dentate gyrus of urethaneAccepted May 11, 2000. Address correspondence and reprint requests to J. M. Langosch, Dept. of Psychiatry, University of Freiburg, Hauptstr. 5, Fr ei b u r g , Germ an y . E-mai 1 : j en s-1 a n g 0 s c h @ p s y a 1 I g . u kl .uni-freiburg.de anesthetized rats in vivo (1 9,20). In contrast, LTG inhibits tetraethylammonium-induced synaptic plasticity in rat amygdala (21). In the present study, we investigated the influence of LTG on field potentials and high frequency-induced synaptic plasticity in area CAI of guinea pig hippocampal slices. Parts of the results have been published in abstract form (22,23).
METHODSHippocampal slices were prepared as described previously (24). In brief, white female guinea pigs (Charles River, Sulzfeld, Germany; 280-350 g) were anesthetized with ether, brains were removed, and transverse hippocampal slices (400 bm thick) were prepared in ice-cold medium. After preparation, all slices were incubated in a holding c...