Mouse cerebellar adenosine-glutamate interactions and modulation of ethanol-induced motor incoordination.

BACKGROUND: It was demonstrated previously that cerebellar adenosine modulates ethanol-induced motor incoordination via A(1) subtype of adenosine receptors. Several reports suggest the involvement of brain glutamate mechanisms, in particular N-methyl-d-aspartate (NMDA) receptor sites, in the central nervous system (CNS) actions of ethanol. Mutually antagonistic functional responses as a result of glutamate and adenosine within the brain regions have also been well documented.
METHODS: With the use of rotorod performance as the test response, this study was conducted to evaluate possible functional interactions between cerebellar adenosine and glutamate and its consequence on ethanol-induced motor incoordination. Except for ethanol, which was injected intraperitoneally, all drugs used were microinfused directly into the cerebellum.
RESULTS: Direct intracerebellar microinfusion of glutamate (125, 250, and 500 ng) and the antagonist l-glutamic acid diethyl-ester (125, 250, and 500 ng) markedly and dose-dependently attenuated and accentuated, respectively, ethanol-induced motor incoordination, suggesting an involvement of glutamate. Subsequently, intracerebellar microinfusions of NMDA (125, 250, and 500 ng) and its antagonists AP-5 [(+)-2-amino-5-phosphoropentanoic acid; 125, 250, and 500 ng] and (+)-MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclo-hepten-5,10-imine hydrogen maleate; 25, 50, and 100 ng] significantly attenuated and accentuated, respectively, ethanol-induced motor incoordination in a dose-related manner, indicating participation of NMDA receptor. The attenuation of ethanol-induced motor incoordination by glutamate and NMDA was receptor mediated as it was antagonized by their receptor antagonists. Adenosine A(1) -selective agonist N(6) -cyclohexyladenosine and antagonist 8-cyclopentyl-1,3-dipropylxanthine functionally opposed the attenuation by glutamate and NMDA and the accentuation by L-glutamic acid diethyl-ester, AP-5, and (+)-MK-801, respectively, of ethanol-induced motor incoordination.
CONCLUSIONS: These results suggest a functional antagonism between glutamate NMDA and adenosine A(1) receptors exhibiting a co-modulation of ethanol-induced motor incoordination within the cerebellum.