title: Neuronal nicotinic receptor agonists improve gait and balance in olivocerebellar ataxia.
abstract: Clinical studies have reported that the nicotinic receptor agonist varenicline improves balance and coordination in patients with several types of ataxia, but confirmation in an animal model has not been demonstrated. This study investigated whether varenicline and nicotine could attenuate the ataxia induced in rats following destruction of the olivocerebellar pathway by the neurotoxin 3-acetylpyridine (3-AP). The administration of 3-AP (70 mg/kg followed by 300 mg niacinamide/kg; i.p.) led to an 85% loss of inferior olivary neurons within one week without evidence of recovery, and was accompanied by a 72% decrease in rotorod activity, a 3-fold increase in the time to traverse a stationary beam, a 19% decrease in velocity and 31% decrease in distance moved in the open field, and alterations in gait parameters, with a 19% increase in hindpaw stride width. The daily administration of nicotine (0.33 mg free base/kg) for one week improved rotorod performance by 50% and normalized the increased hindpaw stride width, effects that were prevented by the daily preadministration of the nicotinic antagonist mecamylamine (0.8 mg free base/kg). Varenicline (1 and 3 mg free base/kg daily) also improved rotorod performance by approximately 50% following one week of administration, and although it did not alter the time to traverse the beam, it did improve the ability to maintain balance on the beam. Neither varenicline nor nicotine, at doses that improved balance, affected impaired locomotor activity in the open field. Results provide evidence that nicotinic agonists are of benefit for alleviating some of the behavioral deficits in olivocerebellar ataxia and warrant further studies to elucidate the specific mechanism(s) involved.
authors.affiliation: Laboratory of Neuropsychopharmacology, Department of Psychiatry and Behavioral Neurosciences, University of South Florida, Tampa, FL 33613-4706, USA. lwecker@health.usf.edu
authors.forename: L
authors.initials: L
authors.lastname: Wecker
authors.forename: M E
authors.initials: ME
authors.lastname: Engberg
authors.forename: R M
authors.initials: RM
authors.lastname: Philpot
authors.forename: C S
authors.initials: CS
authors.lastname: Lambert
authors.forename: C W
authors.initials: CW
authors.lastname: Kang
authors.forename: J C
authors.initials: JC
authors.lastname: Antilla
authors.forename: P C
authors.initials: PC
authors.lastname: Bickford
authors.forename: C E
authors.initials: CE
authors.lastname: Hudson
authors.forename: T A
authors.initials: TA
authors.lastname: Zesiewicz
authors.forename: Peter P
authors.initials: PP
authors.lastname: Rowell
mesh_terms: D000818:Animals; D001259:Ataxia / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D001552:Benzazepines / Q000494:pharmacology* / Q000627:therapeutic use; D002531:Cerebellum / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005684:Gait / Q000187:drug effects*; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology; D009434:Neural Pathways / Q000187:drug effects / Q000473:pathology; D009536:Niacinamide / Q000633:toxicity; D009538:Nicotine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D018733:Nicotinic Antagonists / Q000494:pharmacology; D009847:Olivary Nucleus / Q000187:drug effects / Q000473:pathology; D004856:Postural Balance / Q000187:drug effects*; D011725:Pyridines / Q000633:toxicity; D011810:Quinoxalines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D045442:Rotarod Performance Test; D000068580:Varenicline
chemical_list: D001552:Benzazepines; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011725:Pyridines; D011810:Quinoxalines; C010835:3-acetylpyridine; D009536:Niacinamide; D008464:Mecamylamine; D009538:Nicotine; D000068580:Varenicline
keywords: 3-AP; 3-acetylpyridine; ANOVA; Ataxia; Neuronal nicotinic receptors; Nicotine; Olivocerebellar degeneration; SCA3; Varenicline; analysis of variance; spinocerebellar ataxia type 3