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In recent years misuse of methylphenidate (MPH) has been reported. The main pharmacological target of methylphenidate is the dopaminergic system. Adenosine is a neuromodulator that influences the dopaminergic neurotransmission, but studies on MPH and adenosine are still lacking. In this study, adult mice were acutely treated with MPH (5 mg/kg, i.p.) and to model misuse, they received an acute overdosage (50 mg/kg, i.p). The involvement of adenosine A1 receptors in anxiety-related behavior and locomotor and exploratory activity was examined. The administration of methylphenidate (5 and 50 mg/kg) 30 min before the exposure to open field arena did not modify locomotor activity. The anxiolytic-like behavior was observed with both doses of MPH as revealed by the increase on the number of entries and the time spent in the open arms in the elevated plus-maze. Pre treatment with selective adenosine A1 receptor antagonist (DPCPX 1 mg/kg, i.p.) did not prevent anxiolytic effect caused by MPH 50 mg/kg. Immunoblotting of frontal cortex and hippocampal extracts revealed that MPH 50 mg/kg increased 88% adenosine A1 receptor density in the frontal cortex. Extracts from hippocampus did not reveal any differences in the adenosine A1 receptor density. Our findings ruled out the participation of adenosine A1 receptors on the MPH-triggered anxiolytic effects. However, the density of adenosine A1 receptors increased in a brain area strictly involved in the MPH-mediated effects. Thus, the adenosinergic system may play a role in the methylphenidate actions in the central nervous system.