Combined treatment of ascorbic acid or alpha-tocopherol with dopamine receptor antagonist or nitric oxide synthase inhibitor potentiates cataleptic effect in mice.
BACKGROUND
Drugs like haloperidol (Hal) that decrease dopamine (DA) neurotransmission in the striatum induce catalepsy in rodents and Parkinson disease-like symptoms in humans. Nitric oxide synthase (NOS) inhibitors interfere with motor activity, disrupting rodent exploratory behavior and inducing catalepsy. Catalepsy induced by NOS inhibitors probably involves striatal DA-mediated neurotransmission. Antioxidants such as ascorbic acid (vitamin C) and alpha-tocopherol (vitamin E) have also been shown to interfere with movement modulation and the DA system.


OBJECTIVE
The objective of the study is to investigate if the antioxidants vitamins C and E would influence the catalepsy produced by Hal and NOS inhibitors.


METHODS
The effects of the following treatments on catalepsy were examined using the hanging-bar test on male Swiss mice (25-30 g): (1) vitamin C (30-1,000 mg/kg)xHal (1 mg/kg); (2) vitamin C (90-1,000 mg/kg)xN (G)-nitro-L: -arginine (LNOARG, 10 and 40 mg/kg); (3) vitamin C (300 mg/kg)xN (G)-nitro-L: -arginine methylester (LNAME, 20-80 mg/kg); (4) vitamin C (300 mg/kg) x 7-nitroindazole (7NI, 3-50 mg/kg); (5) vitamin C (90 mg/kg i.p.) x LNOARG [40 mg/kg twice a day during 4 days (subchronic treatment)]; (7) vitamin E (3-100 mg/kg) x Hal (1 mg/kg); and (6) vitamin E (3-100 mg/kg) x LNOARG (40 mg/kg).


RESULTS
Vitamin C enhanced the catalepsy produced by NOS inhibitors and Hal. Treatment with vitamin C did not affect tolerance to LNOARG cataleptic effect induced by subchronic treatment. Vitamin E potentiated the catalepsy induced by LNOARG at all doses tested; in contrast, catalepsy induced by Hal was enhanced only by the dose of 100 mg/kg.


CONCLUSIONS
Results support an involvement of dopaminergic and nitrergic systems in motor behavior control and provide compelling evidence that combined administration of the antioxidants vitamins C and E with either Hal or NOS inhibitors exacerbates extrapyramidal effects. Further studies are needed to assess possible clinical implications of these findings.
Lazzarini
M
M
Department of Neurology, Psychiatry and Medical Psychology, School of Medicine, Campus USP, Av Bandeirantes 13400, 14049-900 Ribeirão Preto, SP, Brazil.
Salum
C
C
Del Bel
E A
EA
D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology*; D002375:Catalepsy / Q000139:chemically induced* / Q000473:pathology; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004361:Drug Tolerance; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology*; D013997:Time Factors; D014815:Vitamins / Q000494:pharmacology; D024502:alpha-Tocopherol / Q000494:pharmacology*
D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D007191:Indazoles; D014815:Vitamins; D019335:Nitroarginine; D019001:Nitric Oxide Synthase; D024502:alpha-Tocopherol; D006220:Haloperidol; D001205:Ascorbic Acid; C080122:7-nitroindazole; D019331:NG-Nitroarginine Methyl Ester