DNA damage in brain cells and behavioral deficits in mice after treatment with high doses of amantadine.
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.
Kaefer
Vanessa
V
Laboratório de Genética Toxicológica, Programa de Pós-Graduação em Genética e Toxicologia Aplicada, Universidade Luterana do Brasil, ULBRA, Av. Farroupilha 8001, Bairro São José, Canoas, RS, CEP: 92425-900, Brazil.
Semedo
Juliane Garcia
JG
Silva Kahl
Vivian Francília
VF
Von Borowsky
Rafael Gomes
RG
Gianesini
Janaína
J
Ledur Kist
Tarso Benigno
TB
Pereira
Patrícia
P
Picada
Jaqueline Nascimento
JN
D000547:Amantadine / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects*; D020552:Comet Assay; D004249:DNA Damage; D015259:Dopamine Agents / Q000633:toxicity; D006185:Habituation, Psychophysiologic / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D015162:Micronucleus Tests; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013239:Stereotyped Behavior / Q000187:drug effects
D015259:Dopamine Agents; D016194:Receptors, N-Methyl-D-Aspartate; D000547:Amantadine