Role of mouse cerebellar nicotinic acetylcholine receptor (nAChR) α(4)β(2)- and α(7) subtypes in the behavioral cross-tolerance between nicotine and ethanol-induced ataxia.
We have demonstrated that nicotine attenuated ethanol-induced ataxia via nicotinic-acetylcholine-receptor (nAChR) subtypes α(4)β(2) and α(7). In the present study, ethanol (2g/kg; i.p.)-induced ataxia was assessed by Rotorod performance following repeated intracerebellar infusion of α(4)β(2)- and α(7)-selective agonists. Localization of α(4)β(2) and α(7) nAChRs was confirmed immunohistochemically. Cerebellar NO(x) (nitrite+nitrate) was determined flurometrically. Repeated intracerebellar microinfusion of the α(4)β(2)-selective agonist, RJR-2403 (for 1, 2, 3, 5 or 7 days) or the α(7)-selective agonist, PNU-282987 (1, 2, 3 or 5 days), dose-dependently attenuated ethanol-induced ataxia. These results suggest the development of cross-tolerance between ethanol-induced ataxia and α(4)β(2) and α(7) nAChR agonists. With RJR-2403, the cross-tolerance was maximal after a 5-day treatment and lasted 48h. Cross-tolerance was maximal after a 1-day treatment with PNU-282987 and lasted 72h. Pretreatment with α(4)β(2)- and α(7)-selective antagonists, dihydro-β-erythroidine and methyllycaconitine, respectively, prevented the development of cross-tolerance confirming α(4)β(2) and α(7) involvement. Repeated agonist infusions elevated cerebellar NO(x) 16h after the last treatment while acute ethanol exposure decreased it. Pretreatment with repeated RJR-2403 or PNU-282987 reversed ethanol-induced decrease in NOx. The NO(x) data suggests the involvement of the nitric oxide (NO)-cGMP signaling pathway in the cross-tolerance that develops between α(4)β(2)- and α(7)-selective agonists and ethanol ataxia. Both α(4)β(2) and α(7) subtypes exhibited high immunoreactivity in Purkinje but sparse expression in molecular and granular cell layers. Our results support a role for α(4)β(2) and α(7) nAChR subtypes in the development of cross-tolerance between nicotine and ethanol with the NO signaling pathway as a potential mechanism.
Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
Najla
N
Taslim
Ken
K
Soderstrom
M Saeed
MS
Dar
D000818:Animals; D001522:Behavior, Animal; D001549:Benzamides / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D002524:Cerebellar Ataxia / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004361:Drug Tolerance; D000431:Ethanol / Q000633:toxicity*; D007276:Injections, Intraventricular / Q000379:methods; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009538:Nicotine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D018722:Nicotinic Agonists / Q000494:pharmacology; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013997:Time Factors; D064569:alpha7 Nicotinic Acetylcholine Receptor
D001549:Benzamides; D001643:Bridged Bicyclo Compounds; C579166:Chrna7 protein, mouse; D018722:Nicotinic Agonists; D009566:Nitrates; D009573:Nitrites; C498513:PNU-282987; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2; D000431:Ethanol; C012419:metanicotine; D009538:Nicotine