On the interaction of drugs with the cholinergic nervous system - VI. Tolerance to physostigmine in mice

Tolerance to physostigmine salicylate was induced in mice using various schedules of s.c. injections. The rate and degree of tolerance development were assessed by comparing the ED₅₀ values (equipotent doses) and by comparing the peak effects induced by a constant dose. These were measured on four systemic responses induced by the drug - hypothermia, tremor, salivation, and the effects measured in the rotarod test. The degree of tolerance development was found to be dose-dependent with a maximal achievable tolerance for every dose. The tolerance development to the four systemic effects differed in time course: tolerance to the hypothermia was induced even with daily injections, while tolerance to the salivation and rotarod effects could be detected only when the drug was given every 4 h. No tolerance developed to the tremor with any of the schedules and doses used. The maximal achievable tolerance degree and the pattern of changes of the duration were different for each systemic effect. The tolerance was found to be reversible, with different rates of recovery, for the different effects. The tolerance state could not be correlated with changes in the pattern of brain acetylcholinesterase (AcChE) inhibition by physostigmine in vivo or with changes in the rate of the enzyme's spontaneous reactivation. Scopolamine. HBr given 10 min before physostigmine prevented tolerance development. In addition, cross-tolerance to various muscarinic agonists and cholinesterase inhibitors was found in the physostigmine-tolerant mice. The correlation between these results and our previous findings concerning possible biochemical adaptations is presented and discussed.