Reciprocal modulation of glutamate and GABA release may underlie the anticonvulsant effect of phenytoin
Section snippets
Slice preparation
Experiments were performed on slices containing EC and hippocampus prepared from male Wistar rats (n=47, 120–150 g). All experiments were performed in accordance with the U.K. Animals (Scientific Procedures) Act 1986, European Communities Council Directive 1986 (86/609/EEC) and the University of Bristol ethical review document. All efforts were made to minimise the number of animals utilized in these experiments and to eliminate any suffering. Animals were decapitated under anaesthesia induced
Results
The current studies have all been conducted on neurons in the rat EC. We have previously suggested21 that the deeper layers IV/V may be more susceptible to epileptogenesis than the superficial layer (II), and provided information as to why this may be so.2., 18., 50. In the present study, we studied neurons in both deep and superficial layers but could detect no difference in the effects of phenytoin in the different layers.
Glutamate transmission
A number of studies have suggested that low-frequency responses at glutamate synapses, or responses to exogenous activation of AMPA and NMDA receptors, may be reduced by phenytoin.3., 14., 23., 48. In agreement with the data of others24., 25., 26., 30., 32. we found little effect of phenytoin on either AMPA or NMDA-mediated responses evoked at low frequency, indicating that phenytoin is unlikely to interact directly with the postsynaptic receptors in the EC. However, the frequency-dependent
Conclusion
The present results show that phenytoin effectively increases synaptic inhibition and at the same time decreases synaptic excitation. These reciprocal effects on both background and evoked inhibition and excitation are highly desirable actions required in an effective anticonvulsant.
Acknowledgements
We thank the Wellcome Trust, the MRC and the Taberner Trust for financial support, Dr John Dempster for the Strathclyde Software, and Novartis for the gift of CGP55845A.
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2012, NeuropharmacologyCitation Excerpt :The combined observations demonstrate that increased GABA release at the cellular level is reflected by an elevation of global background inhibition, and a shift in balance of network bias to reduce excitability. We have previously examined the effects of other anticonvulsants on spontaneous background synaptic activity using the same approaches (Cunningham et al., 2000, 2003, 2004; Cunningham and Jones, 2000; Yang et al., 2007; Greenhill and Jones, 2010) and the profile of effects varied. Phenytoin, lamotrigine and carbamazepine decreased background excitation and concurrently increased inhibition (Cunningham et al., 2000; Cunningham and Jones, 2000; Greenhill and Jones, 2010), all three drugs increasing I:E ratio.
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2012, NeuropharmacologyCitation Excerpt :Although the mode of antiepileptic action of phenytoin is generally agreed to be its suppression of sodium conductance (e.g., Tunnicliff, 1996), it would be of substantial interest to determine whether this mechanism is also how it mediates its anxiolytic action. An alternate possibility is that the anxiolytic-like effects of phenytoin are related to its ability to increase or decrease the relative efficacy of GABAergic, glutamatergic, and monoaminergic neurotransmission (e.g., Ahmad et al., 2005; Cunningham et al., 2000; Sitges et al., 2007), each of which have been implicated in anxiety modulation (e.g., Degroot and Treit, 2003; Menard and Treit, 2000; Shah et al., 2004). However, it should be noted that these latter effects of phenytoin are found at dosages higher than those used here (e.g., 100 mg/kg; Okada et al., 1997), and are difficult to separate from the primary action of sodium current inhibition (Sitges et al., 2007), and other toxic effects of phenytoin at these dosages.
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2011, NeuropharmacologyCitation Excerpt :For example, CRS reduces glutamatergic transmission in piriform cortex LIa fibers without acting on LII-III fibers (Whalley et al., 2009). In addition, both phenytoin and valproic acid reduce glutamatergic transmission and increase GABAergic transmission (Cunningham et al., 2000, 2003). These intriguing properties shared by most antiepileptic drugs may be attributed to the diversity of individual synapses in different brain regions (Craig and Boudin, 2001).
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2010, NeuroscienceCitation Excerpt :These effects are in good agreement with our previous patch clamp experiments in EC neurones. In these we showed that phenytoin, at the same concentration employed here, acted presynaptically to increase the spontaneous release of GABA, but to decrease the release of glutamate (Cunningham et al., 2000; Yang et al., 2007). Concurrent with the increase in I:E ratio induced by phenytoin, the drug also significantly altered neuronal excitability.