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Background-The rostral anterior cingulated cortex (rACC) and the amygdala consistently emerge from neuroimaging studies as brain regions crucially involved in normal and abnormal fear processing. The aim of this study is to investigate a possible top-down modulation of a specific rACC sub-region on the acquisition of auditory fear conditioning.

The antiepileptic drug (AED) oxcarbazepine (OCBZ) and its rapidly formed 10-monohydroxy metabolite (MHD) protect against electroshock-induced tonic hindlimb extension in rodents (ED50 14-21 mg/kg p.o.). Both stereoisomers of MHD also protect. As with carbamazepine (CBZ), these findings suggest clinical efficacy against generalized tonic-clonic and, to some extent, partial seizures. OCBZ (IC50 5 x 10(-8) M), MHD (IC50 2 x 10 (-8) M), and CBZ (IC50 6 x 10(-7) M) limit the frequency of firing of sodium-dependent action potentials by cultured mouse central neurons and reduce Vmax progressively in a use-dependent manner at concentrations below therapeutic plasma concentrations in OCBZ-treated patients. This suggests that blockade of voltage-sensitive sodium channels could contribute to the antiepileptic efficacy of OCBZ. Blockade of penicillin-induced epileptiform discharges in hippocampal slices by MHD and its stereoisomers was diminished when the potassium channel blocker 4-aminopyridine was added to the bath fluid. This indicates that additional mechanisms of action, e.g., an effect on potassium channels, might be clinically important. In addition, both stereoisomers are equally responsible for the antiepileptic activity of the racemate, i.e., MHD, and are therefore likely to play a therapeutic role. Such actions could confer broad clinical utility on OCBZ.

1 The pharmacological properties of CGP 37849 (DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid; 4-methyl-APPA) and its carboxyethylester, CGP 39551, novel unsaturated analogues of the Nmethyl-D-aspartate (NMDA) receptor antagonist, 2-amino-5-phosphonopentanoate (AP5), were evaluated in rodent brain in vitro and in vivo. 2 Radioligand binding experiments demonstrated that CGP 37849 potently (K1 220 nM) and competitively inhibited NMDA-sensitive L-[3H]-glutamate binding to postsynaptic density (PSD) fractions from rat brain. It inhibited the binding of the selective NMDA receptor antagonist, [3H]-( ±)-342-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP), with a Ki of 35 nm, and was 4, 5 and 7 fold more potent than the antagonists ((±)-cis-4-phosphonomethylpiperidine-2-carboxylic acid) (CGS 19755), CPP and D-AP5, respectively. Inhibitory activity was associated exclusively with the trans configuration of the APPA molecule and with the D-stereoisomer. CGP 39551 showed weaker activity at NMDA receptor recognition sites and both compounds were weak or inactive at 18 other receptor binding sites. 3 CGP 37849 and CGP 39551 were inactive as inhibitors of L-[3H]-glutamate uptake into rat brain synaptosomes and had no effect on the release of endogenous glutamate from rat hippocampal slices evoked by electrical field stimulation. 4 In the hippocampal slice in vitro, CGP 37849 selectively and reversibly antagonized NMDA-evoked increases in CAI pyramidal cell firing rate. In slices bathed in medium containing low Mg2+ levels, concentrations of CGP 37849 up to 10pM suppressed burst firing evoked in CAl neurones by stimulation of Schaffer collateral-commissural fibres without affecting the magnitude of the initial population spike; CGP 39551 exerted the same effect but was weaker. In vivo, oral administration to rats of either CGP 37849 or CGP 39551 selectively blocked firing in hippocampal neurones induced by ionophoreticallyapplied NMDA, without affecting the responses to quisqualate or kainate. al., 1988). Many studies have demonstrated that activation of the NMDA receptor is involved in the generation of epileptiform activity and in hypoxic-ischaemic neuronal damage, and conversely that NMDA receptor antagonists are anticonvulsant and cerebroprotective in animal models of epilepsy and stroke (see reviews by Meldrum, 1985;Rothman & Olney, 1986;Choi, 1988;Patel et al., 1988;Iversen et al., 1989;Albers et al., 1989 (Meldrum, 1985;Rothman & Olney, 1986;Albers et al., 1989;.Antagonism of NMDA receptor mechanisms potentially may be achieved by a number of different approaches. In addition to the transmitter recognition site, the NMDA receptor complex comprises an allosteric regulatory site and a channel binding domain (Foster & Fagg, 1987b), and possibly also sites defined by the actions of Zn2", polyamines, tricyclic antidepressants, ifenprodil and CGP 31358 (see Lodge, 1989;Baud et al., 1989). At present, however, the two most well characterized sites are (1) the transmitter recognition site, at which substances such as ...