Gabapentin increases the hyperpolarization-activated cation current Ih in rat CA1 pyramidal cells.
OBJECTIVE
Gabapentin (GBP) is a commonly used drug in the treatment of partial seizures, but its mode of action is still unclear. The genesis of seizures in temporal lobe epilepsy is thought to be crucially influenced by intrinsic membrane properties. Because the Ih substantially contributes to the intrinsic membrane properties of neurons, the effects of GBP on the Ih were investigated in CA1 pyramidal cells of rat hippocampus.


METHODS
CA1 pyramidal cells in hippocampal slices were examined by using the whole-cell patch-clamp technique.


RESULTS
GBP increased the Ih amplitude in a concentration-dependent manner mainly by increasing the conductance, without significant changes in the activation properties or in the time course of Ih. The effects ranged from approximately 20% at 50 microM, approximately 25% at 75 microM, to approximately 35% at 100 microM GBP (at -110 mV). In the presence of intracellular cyclic adenosine monophosphate (cAMP), the effects of GBP on Ih were similar to those obtained in the absence of cAMP.


CONCLUSIONS
These results suggest that GBP increases the Ih through a cAMP-independent mechanism. Because the applied GBP concentrations were in a clinically relevant range, the observed effect may contribute to the anticonvulsant action of GBP in partial seizures and may represent a new concept of how this anticonvulsant drug works.
Surges
Rainer
R
Department of Neurology, Section of Clinical Neuropharmacology, Neurozentrum, University of Freiburg, Germany. surges@nz.ukl.uni-freiburg.de
Freiman
Thomas M
TM
Feuerstein
Thomas J
TJ
D000085:Acetates / Q000494:pharmacology*; D000588:Amines; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002412:Cations / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids; D004305:Dose-Response Relationship, Drug; D004828:Epilepsies, Partial / Q000503:physiopathology; D004833:Epilepsy, Temporal Lobe / Q000503:physiopathology; D005260:Female; D000077206:Gabapentin; D006624:Hippocampus / Q000187:drug effects*; D007473:Ion Channels / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000588:Amines; D000927:Anticonvulsants; D002412:Cations; D003509:Cyclohexanecarboxylic Acids; D007473:Ion Channels; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D000242:Cyclic AMP