Vc. Hinz et al., EFFECTS OF SUBCHRONIC ADMINISTRATION OF METRIFONATE ON CHOLINERGIC NEUROTRANSMISSION IN RATS, Neurochemical research, 23(7), 1998, pp. 931-938
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.