An evaluation of various antiparkinsonian agents as releasing agents and uptake inhibitors for 3H-dopamine in slices of rat neostriatum

Abstract

Various antiparkinsonian agents (trihexyphenidyl, diphenhydramine, benztropine, orphenadrine, diphenylpyraline and phenindamine) produced a dose dependent inhibition of accumulation of 3H-catecholamines in tissue slices of rat neostriatum and cerebral cortex. In the neostriatum, trihexyphenidyl, orphenadrine and phenindamine were almost equipotent in causing an inhibition of accumulation and in causing release of 3H-dopamine. Benztropine, diphenylpyraline and diphenhydramine were better inhibitors of accumulation than releasing agents. In the cortex, all of the compounds studied, except trihexyphenidyl, were better inhibitors of 3H-norepinephrine accumulation than releasing agents. Trihexyphenidyl was equally effective both as an inhibitor of accumulation and as a releasing agent. Inhibition of 3H-catecholamine accumulation as measured experimentally consists of two components: an inhibition of uptake and an apparent inhibition of uptake caused by release. When the observed inhibition of accumulation equals the observed release, we conclude that both phenomena are due to release and that there is not actual inhibition of uptake (see discussion). With this in mind, we conclude that three of the compounds (trihexyphenidyl, orphenadrine and phenindamine) are striatal releasing agents. The other three drugs are both uptake inhibitors and releasing agents for 3H-dopamine in the neostriatum. In the cortex, trihexyphenidyl appearstto be the sole releasing agent for 3H-norepinephrine. The remaining compounds appear to be considerably better cortical uptake inhibitors than releasing agents.