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.

Abstract

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.

• Authors: Najla Taslim, Ken Soderstrom, M Saeed Dar
• Journal: Behavioural brain research (Behav Brain Res) Vol. 217 Issue 2 Pg. 282-92 (Mar 01 2011) ISSN: 1872-7549 [Electronic] Netherlands
• PMID: 20974182 (Publication Type: Journal Article)
• Copyright: Copyright © 2010 Elsevier B.V. All rights reserved.

Chemical References

• Benzamides
• Bridged Bicyclo Compounds
• Chrna7 protein, mouse
• Nicotinic Agonists
• Nitrates
• Nitrites
• PNU-282987
• Receptors, Nicotinic
• alpha7 Nicotinic Acetylcholine Receptor
• nicotinic receptor alpha4beta2
• Ethanol
• metanicotine
• Nicotine

Topics

• Animals
• Behavior, Animal
• Benzamides (pharmacology)
• Bridged Bicyclo Compounds (pharmacology)
• Cerebellar Ataxia (chemically induced, drug therapy, pathology)
• Cerebellum (drug effects, metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Interactions
• Drug Tolerance
• Ethanol (toxicity)
• Injections, Intraventricular (methods)
• Male
• Mice
• Motor Activity (drug effects)
• Nicotine (analogs & derivatives, pharmacology, therapeutic use)
• Nicotinic Agonists (pharmacology)
• Nitrates (metabolism)
• Nitrites (metabolism)
• Psychomotor Performance (drug effects)
• Receptors, Nicotinic (metabolism)
• Time Factors
• alpha7 Nicotinic Acetylcholine Receptor