Ketamine impairs the performance of male mice in novel recognition object test and reduces the immunoreactivity of GAD67 in the hippocampus: Role of pioglitazone.

Abstract

Schizophrenia is a mental disorder characterized by positive, negative, and cognitive symptoms which is treated with antipsychotics. However, these drugs present several side effects and, some schizophrenia symptoms, like cognitive, are difficult to treat. The peroxisome proliferator-activated receptors-gamma (PPAR-γ) are expressed in dopaminergic neurons of the midbrain participating in the modulation of dopamine-mediated behavior . We investigated the effects of pioglitazone, an agonist of PPAR-γ, on the behavioral alterations induced by ketamine and, whether alterations in monoamine oxidase (MAO) activity, glutamic acid decarboxylase (GAD₆₇), PPAR-γ or tyrosine hydroxylase (TH) immunoreactivity in brain tissues are involved in these effects. Male mice received ketamine (30 mg/kg), intraperitoneally, for 14 consecutive days, and pioglitazone (3 or 9 mg/kg), by gavage (day 8 up to day 14). Ketamine decreased nail-biting increasing the time exploring the center of the open field on day 8 and the number of rearing evaluated 30 min after its administration on day 14. Furthermore, ketamine decreased the percentage of investigation in the NOR test and the immunoreactivity of GAD₆₇ in the hippocampus. No significant changes were found in other behavioral and biochemical tests. Pioglitazone attenuated the effects of ketamine on rearing and GAD₆₇ immunoreactivity in the hippocampus, recovering the ketamine effects on NOR test. At a dose of 9 mg/kg, pioglitazone alone reduced the immunoreactivity of GAD₆₇ in the hippocampus. Pioglitazone at both doses recovered the cognitive symptoms induced by ketamine an effect that seems to involve the modulation of GAD₆₇ immunoreactivity in the hippocampus. In conclusion, pioglitazone improved the effects of ketamine on the NOR test which was, at least in part, associated with the modulation of GAD₆₇ immunoreactivity in the hippocampus suggesting its beneficial role in cognitive symptoms.