We have previously reported the involvement of the striatum in acute
ethanol-induced motor
incoordination and the striatal adenosinergic modulation of
ethanol-induced motor
incoordination through A1 receptor-mediated mechanism(s). The present study, a continuation of our previous work, was carried out to investigate the possible functional correlation between striatal
cyclic AMP and
ethanol-induced motor
incoordination, and its modulation by striatal
adenosine in Sprague-Dawley rats.
Forskolin (0.1, 0.5 and 1.0 pmol), a known activator of
adenylate cyclase, significantly attenuated
ethanol-induced motor
incoordination in a dose-dependent manner following its direct intrastriatal microinfusion.
Forskolin also antagonized the accentuating effect of intrastriatal
N6-cyclohexyladenosine on
ethanol-induced motor
incoordination. These results suggested that
ethanol-induced motor
incoordination might be functionally correlated to a decrease in the striatal
cyclic AMP levels and that the striatal
adenosine A1 receptors might modulate
ethanol-induced motor
incoordination through
cyclic AMP signaling mechanism(s). Further support to this hypothesis was obtained by the actual measurement of the striatal
cyclic AMP levels in the same experimental conditions as in motor coordination studies using high-performance liquid chromatography with fluoroscence detection. Regardless of the method (focused microwave irradiation, cervical dislocation or
decapitation into a
dry ice-
ethanol mixture) used to kill the animals, a significant decrease in the striatal
cyclic AMP levels was observed due to
ethanol. Intrastriatal
adenosine A1-selective agonist,
N6-cyclohexyladenosine (24 ng), caused a further significant decrease in the striatal
cyclic AMP levels in the
ethanol- but not in the vehicle-treated animals. The further enhancement in the
ethanol-induced decrease in the striatal
cyclic AMP levels by intrastriatal
N6-cyclohexyladenosine, therefore, functionally correlated with the observed potentiating effect of intrastriatal
N6-cyclohexyladenosine on
ethanol-induced motor
incoordination. The effects of intrastriatal N6-cyclohexyladenosine+ethanol and of
ethanol alone on the striatal
cyclic AMP levels were blocked by intrastriatal
pertussis toxin (500 ng) pretreatment, indicating the involvement of
pertussis toxin-sensitive
G-proteins (Gi, Go) and possibly of the
adenosine A1 receptor coupled to the
G-proteins in the striatum. Furthermore,
ethanol alone significantly decreased the basal as well as the
cyclic AMP-stimulated catalytic activities of the striatal
cyclic AMP protein kinase, which were further reduced by intrastriatal
N6-cyclohexyladenosine. The results of the present study therefore support an involvement of a
cyclic AMP signaling pathway in the striatal adenosinergic modulation of
ethanol-induced motor
incoordination at the post-
adenosine A1 receptor level.