Changes induced by ovariectomy on the acute effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in a model of rat poor metabolizer of debrisoquine.
The female 'dark-adapted' rat, an animal model of poor metabolizer of debrisoquine, is more susceptible to neurotoxic effects of 1,2,3,6-tetrahydropyridine (MPTP) than other rat species (extensive metabolizers). Since ovariectomy improves the ability for the 4-hydroxylation of debrisoquine in female 'dark-adapted' rats, we studied the acute effects of MPTP (three doses of 10, 20, and 30 mg/kg s.c., respectively, at 12 hour intervals) in ovariectomized and laparotomized female 'dark-adapted' rats to test whether ovariectomy prevents MPTP-induced neurotoxicity. We measured regional brain monoamine levels. MPTP-induced depletion of dopamine (DA) and its metabolites was more prominent in the striatum. Ovariectomy, by itself, reduced dopamine and serotonin (5-HT) and their metabolites in striatum in both control and MPTP-treated animals. Factorial analysis of the effects of ovariectomy and MPTP treatment by two-way ANOVA revealed that both experimental procedures reduced DA and 5-HT neurotransmission in the striatum while the combined effect of both treatments did not produce any significant change. In spite of its induction of monoamine depletion in intact animals, ovariectomy partially prevented MPTP-induced depletion of monoamines in the surviving rats, suggesting that changes in metabolic rates of debrisoquine induced by ovariectomy produce resistance to MPTP in 'dark-adapted' rats.
Jiménez-Jiménez
F J
FJ
Hospital "Príncipe de Asturias"- Alcalá de Henares, Madrid, Spain.
Mena
M A
MA
García-Agúndez
J
J
Tabernero
C
C
Pardo
B
B
Carazo
A
A
Benítez
J
J
García-Ruiz
P J
PJ
Yébenes
J G
JG