Clonidine prevents the short-term down regulation of muscarinic receptors in mouse brain induced by the acetylcholinesterase inhibitor soman.
The influence of clonidine on the down regulation of muscarinic acetylcholine receptors induced by the irreversible acetylcholinesterase inhibitor soman was studied in mouse brain (cortex and brainstem). Muscarinic receptor binding was measured using [N-methyl-3H]scopolamine ([3H]MS) as the probe in a filtration assay. Thirty min after subcutaneous injection of soman at a dose which killed 80-90% of the mice, the concentration of [3H]MS binding sites was reduced by 25-28% in surviving mice. [3H]MS binding affinity (Kd = 0.36-0.42 nM), agonist binding state, and receptor coupling to guanine nucleotide-dependent transducer proteins (G proteins) were not affected by soman. Administration of clonidine (1 mg/kg, s.c.) 5 min prior to soman prevented the decrease in receptor number and decreased the extent of acetylcholinesterase inhibition caused by the soman. It is possible that a reversible inhibition of acetylcholinesterase by clonidine protects the enzyme from irreversible inactivation by soman, thereby decreasing the extent of chronic cholinergic overstimulation with its attendant down regulation of muscarinic receptors.