Gabapentin (GBP, Neurontin) has been used for several years to treat neurologic diseases. It has been demonstrated to be useful in the treatment of focal epilepsies, essential tremor, chronic neuropathic pain syndromes, and migraine (1–4). Although its clinical relevance in treating partial seizures has been proven, the molecular mechanisms underlying its efficacy are still unclear. GBP exerts effects on the extrinsic properties of neurons (i.e., on different neurotransmitter systems at the presynaptic and the postsynaptic site), as well as on the intrinsic properties (e.g., on voltage-dependent ionic channels) (for review, see (5,6). GBP binds to the α2δ subunit of voltage-gated calcium channels and may thereby induce an inhibition of calcium currents (7–12, but see 13). Recently GBP also was suggested to act as a KATP channel agonist (14).
Epilepsy is one of the most common neurologic diseases. Among the different types of epilepsy, temporal lobe epilepsy (TLE) is the most frequent. There is increasing evidence that the genesis of epileptiform activity within the hippocampus is due to alterations in extrinsic as well as intrinsic properties of neurons (15–17). The hyperpolarization-activated cation current (Ih) contributes substantially to the intrinsic membrane properties of hippocampal neurons (18,19). The Ih is a slowly developing inward current, carried by K+ and Na+, which shows no inactivation and is modulated by internal cyclic adenosine-3′-5′-monophospate (cAMP; 20,21) as well as by external K+(22). Because the Ih has been found in a variety of neuronal tissues, it is thought to be an ubiquitous component of the nervous system (21,23). Several recent findings pointed out that Ih is essentially involved in pathophysiologic processes such as epilepsy (24–26). Therefore we tested the effect of the GBP on the biophysical properties of Ih in CA1 pyramidal cells with the help of the whole-cell patch-clamp technique in hippocampal slices. We demonstrate here that GBP increases Ih in a concentration-dependent manner. At clinically relevant concentrations, GBP mainly increases the conductance of Ih without significant changes in the activation properties or in the time course of Ih. This effect may contribute to the anticonvulsant action of GBP in partial seizures and may represent a new concept of how this anticonvulsant drug (ACD), and perhaps also others, work.