Abstracts

RATIONALE: The aim of this study was to examine if the novel anticonvulsant,Gabapentin, is active at native GABAB receptors in hippocampal pyramidal cells. METHODS: Using whole cell patch clamp recordings, membrane currents generated by bath application of gabapentin were monitored in CA1 pyramidal cells of rat hippocampal slices. In addition, monosynaptic GABAA inhibitory postsynaptic currents (IPSCs) were evoked by stimulation of stratum radiatum in the presence of blockers of NMDA (AP5, 50?M) and non-NMDA (CNQX, 20?M) glutamate synaptic transmission. RESULTS: Bath application of gabapentin activated outward currents in the pyramidal cells near resting membrane potential. Gabapentin currents reversed near the K+ equilibrium potential and were dose dependent (0.01-1mM). Baclofen (2-20?M) elicited similar K+ currents. These responses generated by both gabapentin and baclofen were coupled to GABAB receptors since they were blocked by the GABAB antagonist CGP55845 (1-4?M). Fast outward IPSCs evoked by stratum radiatum stimulations were reversibly depressed by 72% by baclofen (20?M). This presynaptic inhibition was dose dependent and was blocked by CGP55845. In contrast, Gabapentin (0.01-1mM) did not significantly affect GABAA IPSCs and thus lacked presynaptic GABAB actions. CONCLUSIONS: This study provides evidence that gabapentin is a selective agonist at postsynaptic GABAB receptors in hippocampus, likely composed of gb1a-gb2 heterodimers. The lack of presynaptic effects of gabapentin indicates that hippocampal pre- and postsynaptic GABAB receptor subtypes may be pharmacologically distinct. The selective agonist action of gabapentin at postsynaptic but not presynaptic GABAB receptors may underlie its anticonvulsant properties.