title: Carbamazepine and oxcarbazepine, but not eslicarbazepine, enhance excitatory synaptic transmission onto hippocampal CA1 pyramidal cells through an antagonist action at adenosine A1 receptors.
abstract: This study assessed the anticonvulsant and seizure generation effects of carbamazepine (CBZ), oxcarbazepine (OXC) and eslicarbazepine (S-Lic) in wild-type mice. Electrophysiological recordings were made to discriminate potential cellular and synaptic mechanisms underlying anti- and pro-epileptic actions. The anticonvulsant and pro-convulsant effects were evaluated in the MES, the 6-Hz and the Irwin tests. Whole-cell patch-clamp recordings were used to investigate the effects on fast excitatory and inhibitory synaptic transmission in hippocampal area CA1. The safety window for CBZ, OXC and eslicarbazepine (ED50 value against the MES test and the dose that produces grade 5 convulsions in all mice), was 6.3, 6.0 and 12.5, respectively. At high concentrations the three drugs reduced synaptic transmission. CBZ and OXC enhanced excitatory postsynaptic currents (EPSCs) at low, therapeutically-relevant concentrations. These effects were associated with no change in inhibitory postsynaptic currents (IPSCs) resulting in altered balance between excitation and inhibition. S-Lic had no effect on EPSC or IPSC amplitudes over the same concentration range. The CBZ mediated enhancement of EPSCs was blocked by DPCPX, a selective antagonist, and occluded by CCPA, a selective agonist of the adenosine A1 receptor. Furthermore, reduction of endogenous adenosine by application of the enzyme adenosine deaminase also abolished the CBZ- and OXC-induced increase of EPSCs, indicating that the two drugs act as antagonists at native adenosine receptors. In conclusion, CBZ and OXC possess pro-epileptic actions at clinically-relevant concentrations through the enhancement of excitatory synaptic transmission. S-Lic by comparison has no such effect on synaptic transmission, explaining its lack of seizure exacerbation.
authors: School of Life Sciences, College of Medical, Veterinary and Life Sciences, University Avenue, University of Glasgow, Glasgow, G12 8QQ, UK.
authors: Sam A
authors: SA
authors: Booker
authors: Department of Research and Development, BIAL-Portela & Cª, S.A., S. Mamede do Coronado, Portugal.
authors: Nuno
authors: N
authors: Pires
authors: Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University Avenue, University of Glasgow, Glasgow, G12 8QQ, UK.
authors: Stuart
authors: S
authors: Cobb
authors: Department of Research and Development, BIAL-Portela & Cª, S.A., S. Mamede do Coronado, Portugal; Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal; MedInUP - Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal. Electronic address: psoares.silva@bial.com.
authors: Patrício
authors: P
authors: Soares-da-Silva
authors: School of Life Sciences, College of Medical, Veterinary and Life Sciences, University Avenue, University of Glasgow, Glasgow, G12 8QQ, UK. Electronic address: Imre.vida@charite.de.
authors: Imre
authors: I
authors: Vida
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D056547:CA1 Region, Hippocampal / Q000166:cytology*; D016466:CHO Cells; D002220:Carbamazepine / Q000031:analogs & derivatives / Q000494:pharmacology; D003412:Cricetulus; D003984:Dibenzazepines / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D000078330:Oxcarbazepine; D018408:Patch-Clamp Techniques; D011485:Protein Binding / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D058905:Purinergic Agents / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects*; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000378:metabolism*; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D000927:Anticonvulsants; D003984:Dibenzazepines; D058905:Purinergic Agents; D043682:Receptor, Adenosine A1; D014316:Tritium; D002220:Carbamazepine; C571001:eslicarbazepine; D000078330:Oxcarbazepine
keywords: A(1) adenosine receptor; Carbamazepine; Epilepsy; Eslicarbazepine; Oxcarbazepine; Synaptic transmission