The striatal adenosinergic modulation of ethanol-induced motor incoordination in rats: possible role of chloride flux.
Previous studies from our laboratory have provided strong evidence that brain adenosine modulates acute ethanol (i.p.)-induced motor incoordination (MI) through receptor mediated mechanism(s). Recently, we have reported the involvement of the striatum in ethanol-induced MI as well as the striatal adenosinergic modulation of the ethanol-induced motor deficit. The present study was thus designed to further characterize the modulatory effect of striatal adenosine on ethanol-induced MI and to look for its functional correlation with chloride flux within the rat striatum. Intrastriatal microinfusion of adenosine A1 receptor agonist N6-cyclohexyladenosine (CHA) and antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), significantly accentuated and attenuated, respectively, the motor incoordinating effect of ethanol while having no effect on the normal motor coordination in saline-treated control animals. These data confirmed the role of striatal adenosine in ethanol-induced MI. The selectivity of interactions between adenosine A1 agonist and antagonist and ethanol was further confirmed by the study in which neither intrastriatal CHA nor DPCPX significantly altered the MI induced by sodium pentobarbital. Previously, we have shown that intrastriatal Ro15-4513 not only significantly attenuated ethanol-induced MI but also blocked its accentuation by intrastriatal CHA. It is well known that Ro15-4513 antagonizes many, but not all, CNS effects of ethanol by blocking the ethanol potentiation of GABA-stimulated uptake of chloride. Therefore, experiments using striatal microsac preparations were carried out to investigate the possible modulation of chloride conductance by CHA and its relationship to ethanol. High concentrations of CHA (10 and 100 nM) increased the total chloride uptake by the striatal microsacs. Corresponding to the ethanol-adenosine interaction observed behaviorally, a much lower concentration (1 nM) of CHA, being ineffective itself, significantly enhanced the stimulatory action of ethanol on chloride uptake. This effect was blocked by either Ro15-4513 (100 nM) or DPCPX (10 nM). The modulatory effect of GABA and/or ethanol on chloride influx was also evaluated, and the results supported the appropriateness to use striatal microsac preparations in the present study. Overall, the data suggested a functional interaction between ethanol and striatal adenosine and further supported the hypothesis that striatal adenosine might, in part, modulate ethanol-induced MI through its effect on chloride conductance through chloride channels coupled to GABA-benzodiazepine receptor complex.
Meng
Z H
ZH
Department of Pharmacology, School of Medicine, East Carolina University, Greenville, NC 27858, USA.
Anwer
J
J
Dar
M S
MS
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D000345:Affinity Labels / Q000494:pharmacology; D000818:Animals; D001386:Azides / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002555:Cerebrospinal Fluid; D002712:Chlorides / Q000493:pharmacokinetics / Q000502:physiology*; D003342:Corpus Striatum / Q000378:metabolism* / Q000503:physiopathology; D000431:Ethanol / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects*; D010424:Pentobarbital / Q000494:pharmacology; D011868:Radioisotopes; D051381:Rats; D017207:Rats, Sprague-Dawley; D014970:Xanthines / Q000494:pharmacology
D000345:Affinity Labels; D001386:Azides; D002492:Central Nervous System Depressants; D002712:Chlorides; D018757:GABA Modulators; D011868:Radioisotopes; D014970:Xanthines; D001569:Benzodiazepines; C027513:N(6)-cyclohexyladenosine; D000431:Ethanol; C042957:Ro 15-4513; C051360:1,3-dipropyl-8-cyclopentylxanthine; D010424:Pentobarbital; D000241:Adenosine