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

Linopirdine is a compound being assessed for value in reversing the de mentia associated with Alzheimer's disease. The drug improves learning and memory performance in several rodent behavioral paradigms. Its pr oposed mechanism of action is the enhancement of neurotransmitter rele ase, but the molecular site which mediates this action is unknown. The present study examines the possible involvement of channels which med iate the movement of K+, Cl- and Na+, which are important to the polar ization state of excitable membranes, in the release-enhancing effects of linopirdine. Linopirdine causes a shift in the K+ dose response fo r the release of tritium from cerebral cortical slices preloaded with [H-3]choline {[H-3]acetylcholine (ACh) released} to the left, consiste nt with the blockade of a site, such as a K+ channel, involved in damp ening the response of neuronal terminals to depolarizing stimuli. Lino pirdine does not appear to act at aminopyridine-sensitive K+ channels, inasmuch as the aminopyridines and linopirdine have different pattern s of effects regarding [H-3]ACh release. Tetraethylamonium (TEA), on t he other hand, does share common effects with linopirdine. TEA enhance s K+-evoked [H-3]ACh release to as much as 620% of control without aff ecting basal efflux of the neurotransmitter. Experiments using the mus carinic agonist carbachol indicate that linopirdine does not affect th e cholinergic autoreceptor influence on [H-3]ACh release. Linopirdine also does not appear to act at tetrodotoxin-sensitive Na+ channels. Th e anion channel blocker cetamido-4'-isothiocyanatostilbene-2,2'-disulf onic acid and Cl--deficient media do not affect the level of linopirdi ne 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 prese nted is most consistent with linopirdine-induced [H-3]ACh release enha ncement being mediated through the blockade of a TEA-sensitive K+ chan nel.