STUDIES ON THE ROLE OF K+, CL- AND NA+ ION PERMEABILITIES IN THE ACETYLCHOLINE-RELEASE ENHANCING EFFECTS OF LINOPIRDINE (DUP-996) IN RAT CEREBRAL CORTICAL SLICES

Linopirdine is a compound being assessed for value in reversing the dementia associated with Alzheimer's disease. The drug improves learning and memory performance in several rodent behavioral paradigms. Its proposed mechanism of action is the enhancement of neurotransmitter release, but the molecular site which mediates this action is unknown. The present study examines the possible involvement of channels which mediate the movement of K+, Cl- and Na+, which are important to the polarization state of excitable membranes, in the release-enhancing effects of linopirdine. Linopirdine causes a shift in the K+ dose response for the release of tritium from cerebral cortical slices preloaded with [H-3]choline {[H-3]acetylcholine (ACh) released} to the left, consistent with the blockade of a site, such as a K+ channel, involved in dampening the response of neuronal terminals to depolarizing stimuli. Linopirdine does not appear to act at aminopyridine-sensitive K+ channels, inasmuch as the aminopyridines and linopirdine have different patterns of effects regarding [H-3]ACh release. Tetraethylamonium (TEA), on the other hand, does share common effects with linopirdine. TEA enhances K+-evoked [H-3]ACh release to as much as 620% of control without affecting basal efflux of the neurotransmitter. Experiments using the muscarinic agonist carbachol indicate that linopirdine does not affect the cholinergic autoreceptor influence on [H-3]ACh release. Linopirdine also does not appear to act at tetrodotoxin-sensitive Na+ channels. The anion channel blocker 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid and Cl--deficient media do not affect the level of linopirdine release enhancement. However, picrotoxin, the tau-aminobutyric acid-sensitive Cl- channel blocker, does enhance the K+-evoked release of [H-3]ACh, but not to the same magnitude as linopirdine. The data presented is most consistent with linopirdine-induced [H-3]ACh release enhancement being mediated through the blockade of a TEA-sensitive K+ channel.