GEA 857 [2-(4-chlorophenyl)-1,1-dimethylethyl 2-amino-3-methylbutanoate], a structural analogue of the
5-HT uptake blocker
alaproclate, was tested for its ability to modify
tremor and salivation induced by
muscarinic agonists (
oxotremorine,
arecoline) and
acetylcholinesterase inhibitors (
physostigmine, THA) in the male rat. These agents were employed at submaximal doses.
GEA 857, similarly to
alaproclate (Ogren et al. 1985a & b), produced a dose-dependent, statistically significant (in the 5-20 mg/kg dose range) enhancement of the
tremor response induced by all four
cholinergic stimulants. However, unlike
alaproclate,
GEA 857 failed to enhance salivation in a consistent manner.
GEA 857 itself did not produce
tremor in the absence of the
muscarinic agonists or the
acetylcholinesterase inhibitors. The potentiation of
oxotremorine tremor by
GEA 857 could be fully blocked by
atropine (1 mg/kg intraperitoneally). Unlike
alaproclate,
GEA 857 failed to affect
5-HT uptake or
5-HT metabolism in the 10-20 mg/kg dose range. However, similarly to the action of
alaproclate, the potentiating effect of
GEA 857 on
muscarinic responses could be explained neither by actions on serotonergic mechanisms nor by actions on
muscarinic receptor mechanisms in the striatum. Evidence is presented suggesting that the ability of
GEA 857 to enhance responses evoked by
muscarinic agonists involves inhibitory properties of
GEA 857 at certain membranal Ca(2+)-dependent K+ channels, the blockade of which can potentiate or prolong
muscarinic cholinergic actions.