The overall objectives of this research are to determine the mechanism of the effects of the barbiturates on the cholinergic system in the brain and to determine the relationship of these effects to the effects of these drugs in the whole animal. Barbiturates in vivo cause an inhibition of high affinity choline uptake and acetylcholine turnover and release in some, but not all, regions of the brain. Since these effects on cholinergic neurons are probably related, we are using the effects on choline uptake as our assay system. Previous work in our laboratory and others indicates that the effects of the barbiturates on cholinergic processes are indirect and may be mediated by mimicing and/or enhancing GABAergic influences on certain cholinergic pathways including the septal-hippocampal projection. We are using lesions and injections of barbiturates via indwelling cannulae into selected brain sites to determine the site at which these drugs act to inhibit choline uptake in hippocampal cholinergic nerve terminals. When the site is identified the pharmacology of the drug action there will be investigated-including the relationship with the GABAergic system. In another approach the possible existence of specific barbiturate binding sites ('receptors') will be investigated by radioligand binding studies. Subsequently their relationship to the GABAergic and cholinergic connections will be examined. Our recent studies have lead to the suggestion that the inhibition of choline uptake by barbiturates is more closely related to their anticonvulsant effect than to their sedative/hypnotic/anesthetic effect. This relationship will be explored further using a variety of approaches.
