Rationale: N-Methyl-D-aspartate (NMDA) receptor antagonists is well known to cause both hyperlocomotion as cognitive deficits in rodents. However, mice chronically treated with caffeine show diminished locomotor response to the effects of NMDA receptor antagonists.
Objectives: The aim of this study was to evaluate the effect of subchronic caffeine treatment on MK-801-induced hyperlocomotion, ataxia and cognitive deficits, as well as amphetamine-induced hyperlocomotion in mice.
Methodology: Mice were treated subchronically with caffeine (0, 0.1, 0.3 and 1 mg/mL and 1, 3 and 7 days) and evaluated for locomotor activity, receiving MK-801 (0.25 mg/kg and 0.5 mg/kg), amphetamine (5 mg/kg) or saline, i.p., after one hour habituation; ataxia, which was evaluated at 30 and 60 min after MK-801 (0.5 mg/kg) i.p. administration (ataxia scores were adapted from Hönack and Löscher, 1995); long-term memory (the inhibitory avoidance task): it was examined using the step-down type of inhibitory avoidance, with 0.01 mg/kg i.p. MK-801; working memory (the delayed alternation test), assessed in the T-maze protocol, with MK-801 (0.4 mg/kg), i.p.
Results: Hyperlocomotion induced by MK-801 (0.25 mg/kg i.p.) was diminished after 3 days and almost abolished after 7 days of caffeine treatment at the 1 mg/ml dose, and this effect was also dose-dependent. Ataxia was not affected by caffeine treatment, but a short-lived hyperlocomotor effect was observed. Performance deficit in the inhibitory avoidance task was prevented in mice treated with caffeine for 7 days at 1 mg/ml, and perseverative errors in the T-maze were attenuated. The locomotor effect of amphetamine was unaffected by subchronic caffeine treatment.
Conclusions: In agreement with Dall'Igna et al. (2003), subchronic treatment with caffeine reduced MK-801 induced hyperlocomotion. In this study, we observed that the full expression of this effect requires one week of treatment with 1 mg/mL of caffeine. In our previous study, there was no effect of subchronic treatment with caffeine on inhibitory avoidance deficit induced by 0.25 mg/kg of MK-801, but with the minimum dose to produce impairment (0.01 mg/kg), this impairment was fully prevented. We also evaluated this drug interaction in a model of working memory, which revealed a partial reversal in the number of total errors induced by MK-801. Therefore, the adjustment of MK-801 doses for cognitive impairments allowed the detection of cross-tolerance with caffeine, suggesting that this pharmacological interaction in both locomotor and cognitive effects may involve common pathways. Then, we concluded that hyperlocomotion and cognitive effects induced by MK-801 can be influenced by reduced adenosinergic activity. These findings agree with a model of adenosine hypofunction in schizophrenia, since NMDA receptor antagonists are pharmacological models for this disorder.