title: Functional role for mouse cerebellar NO/cGMP/KATP pathway in ethanol-induced ataxia.
abstract: BACKGROUND
  We have previously shown that brain adenosine A1 receptors and nitric oxide (NO) play an important role in ethanol (EtOH)-induced cerebellar ataxia (EICA) through glutamate/NO/cGMP pathway. I now report possible modulation of EICA by the cerebellar NO/cGMP/K(ATP) pathway.
  
  
  METHODS
  EICA was evaluated by Rotorod in CD-1 male mice. All drugs (K(ATP) activators pinacidil, 0.05, 0.1, 0.5 nmol; minoxidil, 0.01, 0.1, 1.0 pmol; antagonists glipizide/glibenclamide, 0.01, 0.05, 0.1 nmol; NO donor l-arginine, 20 nmol; NOS inhibitors [iNOS] inhibitor L-NAME, 50 nmol; glutamate, 1.5 nmol; adenosine A1 receptor agonist N(6) -cyclohexyladenosine [CHA], 6, 12 pmol; antagonist DPCPX, 0.1 or 0.4 nmol) were given by direct intracerebellar microinfusion via stereotaxically implanted guide cannulas, except EtOH (2 g/kg, i.p.).
  
  
  RESULTS
  Pinacidil and minoxidil dose-dependently accentuated, whereas glipizide and glibenclamide markedly attenuated EICA, indicating tonic participation of K(ATP) channels. Glipizide abolished the pinacidil potentiation of EICA, which confirmed both drugs acted via K(ATP) channels. A possible link between K(ATP) channels and glutamate/NO pathway was suggested when (i) CHA (12 pmol) totally abolished l-arginine-induced attenuation of EICA; (ii) L-NAME abolished l-arginine-induced attenuation of EICA associated with further increase in EICA; and (iii) the combined l-arginine and glutamate infusion virtually abolished EICA. Also, whereas CHA abolished glibenclamide-induced attenuation and potentiated pinacidil/minoxidil-induced accentuation of EICA, the effects of DPCPX were just the opposite to those of CHA.
  
  
  CONCLUSIONS
  The results with CHA therefore suggest a functional link between K(ATP) and A1 receptors and between K(ATP) and glutamate/NO and as an extension may involve participation of NO/cGMP/K(ATP) pathway in EICA.
authors.affiliation: Department of Pharmacology, Brody School of Medicine, East Carolina University, Greenville, North Carolina.
authors.forename: M
authors.initials: M
authors.lastname: Saeed Dar
mesh_terms: D000818:Animals; D002524:Cerebellar Ataxia / Q000139:chemically induced* / Q000188:drug therapy / Q000503:physiopathology*; D006152:Cyclic GMP / Q000502:physiology*; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D051379:Mice; D008845:Microinjections; D008914:Minoxidil / Q000008:administration & dosage; D009569:Nitric Oxide / Q000502:physiology*; D020110:Pinacidil / Q000008:administration & dosage; D015221:Potassium Channels / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D009569:Nitric Oxide; D000431:Ethanol; D008914:Minoxidil; D020110:Pinacidil; D006152:Cyclic GMP
keywords: Cerebellar Ataxia; EtOH; K(ATP) channels; Microinfusion; Nitric Oxide; Rotorod