EFFECTS OF SUBCHRONIC ADMINISTRATION OF METRIFONATE ON CHOLINERGIC NEUROTRANSMISSION IN RATS

The effects of subchronic oral administration of metrifonate, a long-a cting cholinesterase (ChE) inhibitor, on cholinergic neurotransmission were assessed in young adult male Wistar rats. Animals were treated t wice daily with metrifonate. In a pilot study testing a 100 mg/kg dose of metrifonate for up to 14 days, ChE activity was found to steadily decrease to reach maximum inhibition levels of about 55%, 80% and 35% in brain, erythrocytes and plasma. Steady-state inhibition levels were attained by the 10th day of treatment. When metrifonate-treatment was discontinued, ChE activity in plasma returned to control levels withi n another day, while erythrocyte and brain ChE activity took more than 2 weeks to recover. In subsequent dose-response studies, metrifonate treatment was given for 3 and 4.5 weeks at doses of 0, 12.5, 25, 50, a nd 100 mg/kg, to different groups of animals, respectively. Correlatio n analysis indicted that brain ChE inhibition was more accurately refl ected by erythrocyte than by plasma ChE inhibition, although all effec ts were highly correlated. The changes in ChE activity were not parall eled by changes in other parameters of the cholinergic neurotransmissi on, such as acetylcholine synthesis rate or acetylcholine receptor bin ding. It is therefore concluded that repeated administration of metrif onate to rats induces a long-lasting inhibition of ChE activity in a d ose-related and predictable manner, which is neither subject to desens itization nor paralleled by counterregulatory downregulation of muscar inic or nicotinic receptor binding sites in brain.