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DNA damage in brain cells and behavioral deficits in mice after treatment with high doses of amantadine
Author(s) -
Kaefer Vanessa,
Semedo Juliane Garcia,
Silva Kahl Vivian Francília,
Von Borowsky Rafael Gomes,
Gianesini Janaína,
Ledur Kist Tarso Benigno,
Pereira Patrícia,
Picada Jaqueline Nascimento
Publication year - 2010
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.1550
Subject(s) - pharmacology , stereotypy , toxicity , dopaminergic , amantadine , neurotoxicity , open field , hypoactivity , dna damage , behavioural despair test , medicine , catalepsy , neuroscience , biology , hippocampus , antidepressant , dopamine , haloperidol , dna , genetics , amphetamine
Abstract Amantadine (AMA) is an uncompetitive antagonist of the N‐ methyl‐ d ‐aspartate receptor, with clinical application, acting on treatment of influenza A virus and Parkinson's disease. It has been proposed that AMA can indirectly modulate dopaminergic transmission. In high doses, the central nervous system is its primary site of toxicity. To examine deleterious effects on CNS induced by AMA, this study evaluated possible neurobehavioral alterations induced by AMA such as stereotyped behavior, the effects on locomotion and memory and its possible genotoxic/mutagenic activities. Adult male CF‐1 mice were treated with a systemic injection of AMA (15, 30 or 60 mg kg −1 ) 20 min before behavioral tasks on open field and inhibitory avoidance. Higher AMA doses increased the latency to step‐down inhibitory avoidance test in the training session in the inhibitory avoidance task. At 60 mg kg −1 AMA induced impairing effects on locomotion and exploration and hence impaired habituation to a novel environment. Stereotyped behavior after each administration in a 3‐day trial was observed, suggesting effects on dopaminergic system. Amantadine was not able to induce chromosomal mutagenesis or toxicity on bone marrow, as evaluated by the micronucleus assay. At the lowest dose tested, AMA did not induce DNA damage and it was unable to impair memory, locomotion, exploration or motivation in mice. However, higher AMA doses increased DNA damage in brain tissue, produced locomotor disturbances severe enough to preclude testing for learning and memory effects, and induced stereotypy, suggesting neurotoxicity.