Chronic treatment with caffeine blunts the hyperlocomotor but not cognitive effects of the N-methyl-D-aspartate receptor antagonist MK-801 in mice.
BACKGROUND
Administration of N-methyl- d-aspartate (NMDA) receptor antagonists produce hyperlocomotion and cognitive deficits in rodents. Activation of NMDA receptors promotes adenosine release, and adenosine agonists prevent central effects of NMDA receptor antagonists. We hypothesized that if NMDA receptor antagonists require adenosine to produce behavioral effects, mice tolerant to the adenosine receptor antagonist caffeine would have a diminished response to NMDA receptor antagonists.


OBJECTIVE
To evaluate MK-801-induced hyperlocomotion and cognitive deficits after chronic caffeine treatment in mice.


METHODS
Locomotor activity was analyzed in a computerized system, spontaneous alternation was assessed in the Y-maze and long-term memory was assessed with the inhibitory avoidance task in mice.


RESULTS
Mice chronically treated with caffeine in drinking solution (1 mg/ml for 7 days) presented normal habituation and substantial tolerance to acute caffeine (30 mg/kg, i.p.) locomotor effects. MK-801 (0.25 mg/kg, i.p.) produced pronounced hyperlocomotion in water-treated mice, but this effect was abolished in caffeine-drinking mice. Chronic caffeine treatment had no influence on either normal or MK-801-induced deficits in spontaneous alternation and inhibitory avoidance tasks.


CONCLUSIONS
Hyperlocomotion induced by MK-801 may be mediated by reduced adenosinergic activity. These results also suggest that locomotor and cognitive effects of MK-801 can be dissociated and are distinctly modulated. Finally, these findings agree with the adenosine hypofunction model of schizophrenia, since NMDA receptor antagonists are a pharmacological model for this disorder.
Dall'Igna
Oscar P
OP
Departamento de Bioquímica, ICBS, UFRGS, Porto Alegre, Brazil.
Da Silva
Adriana L
AL
Dietrich
Marcelo O
MO
Hoffmann
Anselmo
A
de Oliveira
Ricardo V
RV
Souza
Diogo O
DO
Lara
Diogo R
DR
D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D002110:Caffeine / Q000008:administration & dosage / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D004856:Postural Balance / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
D000697:Central Nervous System Stimulants; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D002110:Caffeine; D016291:Dizocilpine Maleate; D000241:Adenosine