On the interaction of drugs with the cholinergic nervous system-V. Characterization of some effects induced by physostigmine in mice: in vivo and in vitro studies

Four systemic effects induced by s.c. injection of physosthmine and neostigmine to mice were investigated by the "quadro-test" procedure, a novel design in which salivation, tremor, hypothermia and the rotarod-effects are simultaneously and continuously recorded. The time profiles of these effects were used to construct dose-response curves, which were compared to those of brain acetylcholinesterase (AcChE) inhibition by the drug. A good relationship was found between the dose and time dependency of these pharmacological and biochemical parameters, as well as between the relative potencies of physostigmine and neostigmine and their affinity to the enzyme. Using scopolamine. Hbr and its quaternary analogue, as well as tertiary cholinergic agonists and other cholinesterase agents, it was found that the physostigmine-induced hypothermia is mostly a central-muscarinic response, while the tremor is most probably a non-muscarinic peripheral effect. The peripheral-muscarinic origin of the salivation was confirmed. The effects measured in the rotarod test were found to be muscarinic and mixed central-peripheral for physostigmine, and non-muscarinic for neostigmine. The lethality caused by physostigmine seems to be partially centrally mediated, while that of neostigmine is peripheral.