GABAPENTIN POTENTIATES THE CONDUCTANCE INCREASE INDUCED BY NIPECOTIC ACID IN CA1 PYRAMIDAL NEURONS IN-VITRO

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 opti c nerve suggests that gabapentin may enhance promoted release of GABA, which is thought to be due to reverse operation of the GABA transport er. 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 cond itions, 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 bicuc ulline. The response to NPA was also present after blockade of synapti c transmission in the presence of calcium-free solution. These results are consistent with NPA promoting nonvesicular release of GABA from n eighboring neurons or glia via reverse operation of the GABA uptake sy stem, which then activated GABA, 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 GABA, rece ptor 'rundown'. However, in the presence of gabapentin there was a slo w 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 thr ee-fold. The potentiation of the NPA response may be due to gabapentin increasing cytosolic GABA in neighboring cells via a delayed metaboli c effect, and would have the functional effect of increasing neuronal inhibition during periods of hyperexcitability.