The
anticonvulsant gabapentin (1-(aminomethyl)
cyclohexane acetic acid) has been found to be effective for treatment of
partial seizures, but the mechanism of action is unknown. Recent evidence from the rat optic nerve suggests that
gabapentin may enhance promoted release of
GABA, which is thought to be due to reverse operation of the
GABA transporter. We have used whole-cell patch clamp recordings from CA1 pyramidal neurons in hippocampal slices to directly measure currents induced by
nipecotic acid (NPA) during exposure to
gabapentin. Under control conditions, pressure microejection of NPA increased whole-cell conductance with a reversal potential equal to the
chloride equilibrium potential. This response was mimicked by
GABA application, and blocked by
bicuculline. The response to NPA was also present after blockade of synaptic transmission in the presence of
calcium-free
solution. These results are consistent with NPA promoting nonvesicular release of
GABA from neighboring neurons or glia via reverse operation of the
GABA uptake system, which then activated GABAA receptors on the recorded neurons. In control
solution, the response to NPA slowly decreased over 45 min to approximately 50% of the initial response, consistent with GABAA receptor 'rundown'. However, in the presence of
gabapentin there was a slow increase in the response, reaching approximately 170% of the control level after 45 min of
gabapentin exposure. These results demonstrate that
gabapentin enhances the promoted release of
GABA by more than three-fold. The potentiation of the NPA response may be due to
gabapentin increasing cytosolic
GABA in neighboring cells via a delayed metabolic effect, and would have the functional effect of increasing neuronal inhibition during periods of hyperexcitability.