title: Prior nicotine self-administration attenuates subsequent dopaminergic deficits of methamphetamine in rats: role of nicotinic acetylcholine receptors.
abstract: Preclinical studies have demonstrated that oral nicotine exposure attenuates long-term dopaminergic damage induced by toxins, including repeated, high doses of methamphetamine. It is suggested that alterations in nicotinic acetylcholine receptor (nAChR) expression, including α4β2* and α6β2* subtypes, likely contribute to this protection. The current study extended these findings by investigating whether nicotine self-administration in male, Sprague-Dawley rats (a) attenuates short-term dopaminergic damage induced by methamphetamine and (b) causes alterations in levels of α4β2* and α6β2* nAChR subtypes. The findings indicate that nicotine self-administration (0.032 mg/kg/infusion for 14 days) per se did not alter α4β2* and α6β2* nAChR expression or dopamine transporter (DAT) expression and function. Interestingly, prior nicotine self-administration attenuated methamphetamine-induced decreases in DAT function when assessed 24 h, but not 1 h, after methamphetamine treatment (4×7.5 mg/kg/injection). The ability of nicotine to attenuate the effects of methamphetamine on DAT function corresponded with increases in α4β2*, but not α6β2*, nAChR binding density. Understanding the role of nAChRs in methamphetamine-induced damage has the potential to elucidate mechanisms underlying the etiology of disorders involving dopaminergic dysfunction, as well as to highlight potential new therapeutic strategies for prevention or reduction of dopaminergic neurodegeneration.
authors.affiliation: Departments of aPharmacology and Toxicology bPsychiatry cSchool of Dentistry dInterdepartmental Program in Neuroscience, University of Utah eBiology and George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, Utah, USA.
authors.forename: Michelle G
authors.initials: MG
authors.lastname: Baladi
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Nielsen
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.forename: Glen R
authors.initials: GR
authors.lastname: Hanson
authors.forename: Annette E
authors.initials: AE
authors.lastname: Fleckenstein
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000633:toxicity; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D009538:Nicotine / Q000008:administration & dosage* / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012646:Self Administration; D013997:Time Factors
chemical_list: D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C559463:alpha6beta2 nicotinic acetylcholine receptor; C403531:nicotinic receptor alpha4beta2; D008694:Methamphetamine; D009538:Nicotine; D004298:Dopamine