Diazepam antagonizes GABA- and muscimol-induced changes of acetylcholine release in slices of guinea-pig cerebral cortex.
The acetylcholine (ACh) release was studied in superfused, electrically-stimulated slices of guinea-pig cerebral cortex. Muscimol and 4,5,6,7-tetrahydroisoxazolo (5-4-c)-pyridin-3-ol (THIP), as well as exogenous GABA, reduced the electrically-evoked ACh release and enhanced its spontaneous outflow. Picrotoxin antagonized these effects. In addition, picrotoxin and ethanolamine-O-sulphate (EOS) caused opposite changes in transmitter outflow, suggesting the existence of an exogenous GABAergic control on the cholinergic nerve endings. Neither flurazepam 6.6 X 10(-6)--3.3 X10(-5) mol/l nor diazepam 3.3 X 10(-6)--3.3 X 10(-5) mol/l by themselves affected ACh release. Diazepam prevented GABA-, muscimol- and EOS-induced changes in spontaneous and 1 Hz-evoked outflow. Ro 15-1788 3.3 X 10(*-6) mol/l abolished diazepam antagonism vs exogenous GABA. The ineffectiveness of flurazepam and diazepam on normal release (i.e. the lack of potentiation vs the endogenous GABAergic control) supports the view that "synaptic" GABA receptors acting upon the cholinergic nerve endings are not coupled with Benzodiazepine receptors. The unexpected diazepam antagonism vs exogenous GABA and GABA-like compounds can be explained with an unusual Diazepam negative cooperation with "extrasynaptic" GABA receptors, possibly present on the cholinergic terminals. Thus, the rule of benzodiazepine-GABA synergism does not seem always tenable, at least at certain pre-synaptic sites.
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D003975:Diazepam / Q000494:pharmacology*; D005442:Flumazenil; D018756:GABA Antagonists; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009118:Muscimol / Q000037:antagonists & inhibitors*; D010080:Oxazoles / Q000037:antagonists & inhibitors*
D001570:Benzodiazepinones; D018756:GABA Antagonists; D010080:Oxazoles; D009118:Muscimol; D005442:Flumazenil; D000109:Acetylcholine; D003975:Diazepam