Ketamine reduces cholinergic modulated GABA release from rat striatal slices

Striatal GABA release has been shown to be enhanced under pathological conditions of cholinergic overstimulation, e.g. inhibition of acetylcholine esterase. This increase in striatal GABA release during cholinergic overstimulation is mediated by M-cholinoceptors and is associated with clinical symptoms, e.g. the occurrence of seizures. Little is known about the effects of drugs on cholinergic modulated GABA release in the striatum. To investigate the effects of the N-methyl-d-aspartate (NMDA) antagonist MK-801 and the intravenous anaesthetic ketamine on cholinergic modulated depolarisation-induced GABA release, both drugs were coadministered with the M-cholinoceptor agonist pilocarpine in a superfusion model of rat striatal slices. The concentration of GABA was determined in the superfusate by use of high performance liquid chromatography. Evoked GABA release was increased by pilocarpine with a half-effective concentration of 53.8 μM. This increase could be attenuated by the M1-cholinoceptor antagonist pirenzepine (10 μM). MK-801 and ketamine reduced evoked GABA release enhanced by pilocarpine dose dependently with half-effective concentrations of 6.7 μM (MK-801) and 6.9 μM (ketamine), a concentration that is clinically relevant for ketamine anaesthesia. This reduction of striatal GABA release may therefore contribute to the beneficial effect of both drugs in pathological situations of cholinergic overstimulation, e.g. during intoxication with acetylcholine esterase inhibitors.