title: DNA damage in brain cells and behavioral deficits in mice after treatment with high doses of amantadine.
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.
authors.affiliation: 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.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Kaefer
authors.forename: Juliane Garcia
authors.initials: JG
authors.lastname: Semedo
authors.forename: Vivian Francília
authors.initials: VF
authors.lastname: Silva Kahl
authors.forename: Rafael Gomes
authors.initials: RG
authors.lastname: Von Borowsky
authors.forename: Janaína
authors.initials: J
authors.lastname: Gianesini
authors.forename: Tarso Benigno
authors.initials: TB
authors.lastname: Ledur Kist
authors.forename: Patrícia
authors.initials: P
authors.lastname: Pereira
authors.forename: Jaqueline Nascimento
authors.initials: JN
authors.lastname: Picada
mesh_terms: 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
chemical_list: D015259:Dopamine Agents; D016194:Receptors, N-Methyl-D-Aspartate; D000547:Amantadine