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Combined treatment of ascorbic acid or alpha-tocopherol with dopamine receptor antagonist or nitric oxide synthase inhibitor potentiates cataleptic effect in mice

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Abstract

Rationale

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)×Hal (1 mg/kg); (2) vitamin C (90–1,000 mg/kg)×N G-nitro-l-arginine (LNOARG, 10 and 40 mg/kg); (3) vitamin C (300 mg/kg)×N G-nitro-l-arginine methylester (LNAME, 20–80 mg/kg); (4) vitamin C (300 mg/kg) × 7-nitroindazole (7NI, 3–50 mg/kg); (5) vitamin C (90 mg/kg i.p.) × LNOARG [40 mg/kg twice a day during 4 days (subchronic treatment)]; (7) vitamin E (3–100 mg/kg) × Hal (1 mg/kg); and (6) vitamin E (3–100 mg/kg) × 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.

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Acknowledgements

We acknowledge the helpful technical support provided by C.A da-Silva, L.P. Nucci-da-Silva, A. Schiaveto-de-Souza and M. Bermúdez-Echeverry who contributed with the development of this study in several ways. The authors would like to thank Dr. F.S. Guimarães (FMRP-USP) for his helpful comments in preparing the manuscript and for his expert statistical advice. The authors were recipients of CNPq, FAPESP and CAPES fellowships.

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  1. Department of Neurology, Psychiatry and Medical Psychology, School of Medicine, Campus USP, Av Bandeirantes 13400, 14049-900, Ribeirão Preto, SP, Brazil

    M. Lazzarini

  2. Department of MEF-Physiology, School of Odontology, FORP, Campus USP, Av Café S/N, 14040-904, Ribeirão Preto, SP, Brazil

    M. Lazzarini, C. Salum & E. A. Del Bel

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  1. M. Lazzarini
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  2. C. Salum
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Lazzarini, M., Salum, C. & Del Bel, E.A. Combined treatment of ascorbic acid or alpha-tocopherol with dopamine receptor antagonist or nitric oxide synthase inhibitor potentiates cataleptic effect in mice. Psychopharmacology 181, 71–79 (2005). https://doi.org/10.1007/s00213-005-2222-6

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