Effect of subchronic caffeine treatment on MK-801-induced changes in locomotion, cognition and ataxia in mice.

N-Methyl-D-aspartate (NMDA) receptor antagonists cause hyperlocomotion and cognitive deficits in rodents, and caffeine-tolerant mice show diminished locomotor response to NMDA receptor antagonists. 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. 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, working memory (delayed alternation test), long-term memory (inhibitory avoidance task) and ataxia. 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 induced by 0.5 mg/kg MK-801 was not affected by caffeine treatment, but a short-lived hyperlocomotor effect was observed. Performance deficit in the inhibitory avoidance task induced by MK-801 (0.01 mg/kg) was prevented in mice treated with caffeine for 7 days at 1 mg/ml, and perseverative errors in the T-maze by MK-801 (0.4 mg/kg) were attenuated. The locomotor effect of amphetamine (5 mg/kg) was unaffected by subchronic caffeine treatment. The findings that hyperlocomotion and cognitive effects induced by MK-801 can be specifically influenced by reduced adenosinergic activity agree with a model of adenosine hypofunction in schizophrenia, since NMDA receptor antagonists are pharmacological models for this disorder.

Catalepsy and hypolocomotion induced by a nitric oxide donor: attenuation by theophylline.

Nitric oxide (NO) promotes adenosine release in the striatum and hippocampus. Behavioral effects of the nitric oxide donor sodium nitroprusside were studied in mice and included an examination of spontaneous locomotion and catalepsy, which are behaviors modulated by adenosine. Sodium nitroprusside caused a dose-dependent (2, 4 and 6 mg/kg) decrease in locomotor activity and catalepsy at the dose of 6 mg/kg. These effects were substantially attenuated by pretreatment with the non-selective adenosine receptors antagonist theophylline (10 and 30 mg/kg). Moreover, combined treatment with theophylline (30 mg/kg) and sodium nitroprusside (6 mg/kg) induced limbic seizures in 23% of animals. The pretreatment with the selective adenosine A(1) receptor antagonist 8-cyclopentyl-1, 3-dimethylxanthine (CPT) (1.2 mg/kg) caused no effect on the spontaneous or sodium nitroprusside-induced behavior. These data suggest that these behavioral effects of sodium nitroprusside are at least partially mediated by adenosine in the striatum and hippocampus, probably via adenosine A(2A) receptors.