Modulation of K+-evoked [H-3]-noradrenaline release from rat and human brain slices by gabapentin: involvement of K-ATP channels

To elucidate the mechanism of action of the anticonvulsant gabapentin (GBP) , we compared its effects on K+-evoked [H-3]-noradrenaline ([H-3]-NA) relea se from rat hippocampal and human neocortical slices with those of the K-AT P channel opener pinacidil and the Na+ channel blockers phenytoin, carbamaz epine and lamotrigine. Rat hippocampal and human neocortical slices were lo aded with [H-3]-NA and superfused. [H-3]-NA release was evoked by increasin g the extracellular [K+] from 3 to 15 mM. GBP decreased [H-3]-NA release fr om rat hippocampal with a pIC(50) of 5.59 and a maximum inhibition of 44%. Concentration-dependent inhibition was also seen in human neocortical slice s (39% inhibition with 100 muM GBP). These inhibitory effects were antagoni zed by the K, channel antagonist glibenclamide, yielding a pA(2) of 7.50 in the rat. The K-ATP channel opener pinacidil (10 muM), like GBP, decreased [H-3]-NA release from rat hippocampal slices by 27% and this effect was als o antagonized by glibenclamide. In human neocortical slices the inhibition by pinacidil (10 muM) was 31%. Although phenytoin (10 muM), carbamazepine ( 100 muM) and lamotrigine (10 muM) also decreased [H-3]-NA release (by 25%, 57% and 22%, respectively), gribenclamide did not antagonize the effects of these classical Na+ channel blockers. These findings suggest that GBP inhi bits K+-evoked [H-3]-NA release through activation of K-ATP channels. To es tablish whether the K-ATP channels under investigation were located on nora drenegic nerve terminals or on other neuronal elements, the effects of GBP were compared in the absence and in the presence of tetrodotoxin (TTX 0.32 muM) throughout superfusion. Since the functional elimination of the perika rya of interneurons by TTX reduced the inhibitory effect of GBP, the K-ATP channels mediating the effect of GBP may be located on nerve terminals, pro bably on both noradrenergic and glutamatergic nerve endings.