Different actions of Gabapentin and baclofen in hippocampus from weaver mice

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Abstract
The pre‐ and postsynaptic effects of baclofen, a broad‐spectrum γ‐aminobutyric acid (GABA)B receptor agonist, and gabapentin, a selective agonist at GABAB receptors composed of GABAB(1a,2) heterodimers, were examined in CA1 pyramidal cells using whole‐cell patch‐clamp recordings in hippocampal slices from different strains of mice. In slices from C57BL/6 mice, by means of GABAB receptors, gabapentin and baclofen activated outward K+ currents at resting membrane potential. In weaver mice with a Kir3.2 channel mutation, baclofen and gabapentin failed to activate postsynaptic K+ currents. However, in littermate controls of weaver mice, gabapentin failed to evoke K+ currents, whereas baclofen activated currents in the same cells. Thus, postsynaptic actions of gabapentin and baclofen on K+ currents are different in this mouse strain. Via presynaptic GABAB receptors, baclofen significantly reduced GABAA inhibitory postsynaptic currents (IPSCs) in slices from C57BL/6 mice, as well as weaver and control mice. In contrast, gabapentin did not affect IPSCs significantly in any group of mice. These results indicate that although baclofen and gabapentin are agonists at postsynaptic GABAB receptors positively coupled to K+ channels, their mechanism of action differs in certain strains of mice, including the weaver wild‐type mice, suggesting a dissociation in their signaling mechanism and coupling to K+ channels. Hippocampus 2003;13:525–528.