title: Mouse cerebellar GABAB participation in the expression of acute ethanol-induced ataxia and in its modulation by the cerebellar adenosinergic A1 system.
abstract: The possible modulation and of co-modulation by the cerebellar GABAB and adenosine A1 receptors of ethanol-induced motor impairment were investigated in the mice using rotorod performance as the test response. Direct cerebellar microinfusion of GABAB agonist, baclofen, and antagonist, phaclofen, into the permanently cannulated mice, produced a dose-dependent accentuation and attenuation, respectively of ethanol-induced motor impairment. The baclofen and phaclofen exhibited accentuation and attenuation, respectively, via GABAB receptors linked to pertussis toxin-sensitive G protein. A comodulation by the cerebellar adenosine A1 receptors was also observed because intracerebellar microinfusion of adenosine agonists NB-cyclohexyladenosine (CHA), 5'-N-ethylcarbox-amidoadenosine (NECA), and 2-p-(2-carboxyethyl)-phenyl-ethylamino-5'-N-ethylacarbox- amidoadenosine (CGS-21680), and antagonist, 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX), also accentuated and attenuated, respectively, ethanol-induced motor impairment. The accentuation of ethanol-induced motor impairment by baclofen was further enhanced after the intracerebellar microinfusion of CHA, suggesting a co-modulation by the co-localized adenosine A1 receptors. A similar response was observed after the intracerebellar microinfusion of adenosine A1 = A2 agonist NECA and the several-fold higher dose of adenosine A2-selective agonist CGS-21680. Ethanol-induced motor impairment was markedly blocked by intracerebellar A1-selective antagonist, DPCPX, as well as by the intracerebellar pertussis toxin pretreatment suggesting again a co-modulation by the adenosine A1 receptors and the involvement of pertussis toxsin-sensitive G protein, respectively. The almost 25-fold higher dose of CGS-21680 to accentuate and DPCPX to attenuate, respectively, ethanol-induced motor impairment together with the reported cerebellar localization of adenosine A1 subtype only, suggested A1 receptor activation by NECA and CGS-21680. The functional similarity between GABAB and adenosine A1, receptors associated with their anatomical co-localization on the cerebellar granule cells, mainly axons and axonal terminals, may suggest a possible common adenylate cyclase catalytic unit as the basis of modulation of ethanol's motor impairment by these two receptor mechanisms.
authors.affiliation: Department of Pharmacology, School of Medicine, East Carolina University, Greenville, North Carolina 27858, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Dar
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D037361:Adenylate Cyclase Toxin; D000818:Animals; D001259:Ataxia / Q000139:chemically induced*; D001418:Baclofen / Q000031:analogs & derivatives / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D002531:Cerebellum / Q000737:chemistry* / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000633:toxicity*; D018755:GABA Agonists / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects; D009118:Muscimol / Q000494:pharmacology; D037342:Pertussis Toxin; D018080:Receptors, GABA-B / Q000187:drug effects*; D018047:Receptors, Purinergic P1 / Q000187:drug effects / Q000502:physiology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D037361:Adenylate Cyclase Toxin; D018755:GABA Agonists; D018080:Receptors, GABA-B; D018047:Receptors, Purinergic P1; D010566:Virulence Factors, Bordetella; C052329:phaclofen; D009118:Muscimol; C027513:N(6)-cyclohexyladenosine; D000431:Ethanol; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D001418:Baclofen; D000241:Adenosine