Not Another Gabapentin Mechanism!

Abstract

In electrically stimulated rat neocortical brain slices preloaded with [ 3 H]γ-aminobutyric acid (GABA) or [ 3 H]glutamic acid, the pharmacologic actions of 1-(aminomethyl)-cyclohexaneacetic acid (gabapentin, GBP) were compared with those of the GABA B-receptor ago-nists baclofen (Bac) and [3-amino-2-(S)-hydroxypropyl]-methylphosphinic acid (CGP 44532). GBP, baclofen, and CGP 44532 all reduced the electrically stimulated release of [ 3 H]glutamic acid [median inhibitory concentration (IC 50), 20 µM, 0.8 µM, and 2 µM, respectively). These effects were sensitive to the GABA B receptor antagonists (+)-(S)-5,5 dimethylmorpholinyl-2-acetic acid (Sch 50911) or N-3-{[1-(S)-(3,4-dichlorophenyl)ethyl]amino}-2-(S)-hydroxypropyl-P-(cyclo-hexylmethyl)-phosphinic acid (CGP 54626). By contrast, GBP was without effect on the release of [ 3 H]GABA, whereas baclofen (IC 50 , 8 µM) and CGP 44532 (IC 50 , 1 µM) inhibited [ 3 H]GABA release. It is concluded that GBP selectively activates presynap-tic GABA B heteroreceptors, but not GABA B autoreceptors, and may be a useful ligand to discriminate between presy-naptic GABA B-receptor subtypes. COMMENTARY