RAT STRIATAL ADENOSINERGIC MODULATION OF ETHANOL-INDUCED MOTOR IMPAIRMENT - POSSIBLE ROLE OF STRIATAL CYCLIC-AMP

We have previously reported the involvement of the striatum in acute e thanol-induced motor incoordination and the striatal adenosinergic mod ulation of ethanol-induced motor incoordination through A(1) receptor- mediated mechanism(s). The present study, a continuation of our previo us work, was carried out to investigate the possible functional correl ation between striatal cyclic AMP and ethanol-induced motor incoordina tion, and its modulation by striatal adenosine in Sprague-Dawley rats. Forskolin (0.1, 0.5 and 1.0 pmol), a known activator of adenylate cyc lase, significantly attenuated ethanol-induced motor incoordination in a dose-dependent manner following its direct intrastriatal microinfus ion. Forskolin also antagonized the accentuating effect of intrastriat al N-6-cyclohexyladenosine on ethanol-induced motor incoordination. Th ese results suggested that ethanol-induced motor incoordination might be functionally correlated to a decrease in the striatal cyclic AMP le vels and that the striatal adenosine A(1) receptors might modulate eth anol-induced motor incoordination through cyclic AMP signaling mechani sm(s). Further support to this hypothesis was obtained by the actual m easurement of the striatal cyclic AMP levels in the same experimental conditions as in motor coordination studies using high-performance liq uid chromatography with fluoroscence detection. Regardless of the meth od (focused microwave irradiation, cervical dislocation or decapitatio n into a dry ice-ethanol mixture) used to kill the animals, a signific ant decrease in the striatal cyclic AMP levels was observed due to eth anol. Intrastriatal adenosine A(1)-selective agonist, N-6-cyclohexylad enosine (24 ng), caused a further significant decrease in the striatal cyclic AMP levels in the ethanol-but not in the vehicle-treated anima ls. Thee further enhancement in the ethanol-induced decrease in the st riatal cyclic AMP levels by intrastriatal N-6-cyclohexyladenosine, the refore, functionally correlated with the observed potentiating effect of intrastriatal N-6-cyclohexyladenosine on ethanol-induced motor inco ordination. The effects of intrastriatal N-6-cyclohexyladenosine+ethan ol and of ethanol alone on the striatal cyclic AMP levels were blocked by intrastriatal pertussis toxin (500 ng) pretreatment, indicating th e involvement of pertussis toxin-sensitive G-proteins (G(i), G(o)) and possibly of the adenosine A(1) receptor coupled to the G-proteins in the striatum. Furthermore, ethanol alone significantly decreased the b asal as well as the cyclic AMP-stimulated catalytic activities of the striatal cyclic AMP protein kinase, which were further reduced by intr astriatal N-6-cyclohexyladenosine. The results of the present study th erefore support an involvement of a cyclic AMP signaling pathway in th e striatal adenosinergic modulation of ethanol-induced motor incoordin ation at the post-adenosine A(1) receptor level. (C) 1998 IBRO. Publis hed by Elsevier Science Ltd.