title: Chronic Nicotine Exposure Attenuates Methamphetamine-Induced Dopaminergic Deficits.
abstract: Repeated methamphetamine (METH) administrations cause persistent dopaminergic deficits resembling aspects of Parkinson's disease. Many METH abusers smoke cigarettes and thus self-administer nicotine; yet few studies have investigated the effects of nicotine on METH-induced dopaminergic deficits. This interaction is of interest because preclinical studies demonstrate that nicotine can be neuroprotective, perhaps owing to effects involving α4β2 and α6β2 nicotinic acetylcholine receptors (nAChRs). This study revealed that oral nicotine exposure beginning in adolescence [postnatal day (PND) 40] through adulthood [PND 96] attenuated METH-induced striatal dopaminergic deficits when METH was administered at PND 89. This protection did not appear to be due to nicotine-induced alterations in METH pharmacokinetics. Short-term (i.e., 21-day) high-dose nicotine exposure also protected when administered from PND 40 to PND 61 (with METH at PND 54), but this protective effect did not persist. Short-term (i.e., 21-day) high-dose nicotine exposure did not protect when administered postadolescence (i.e., beginning at PND 61, with METH at PND 75). However, protection was engendered if the duration of nicotine exposure was extended to 39 days (with METH at PND 93). Autoradiographic analysis revealed that nicotine increased striatal α4β2 expression, as assessed using [(125)I]epibatidine. Both METH and nicotine decreased striatal α6β2 expression, as assessed using [(125)I]α-conotoxin MII. These findings indicate that nicotine protects against METH-induced striatal dopaminergic deficits, perhaps by affecting α4β2 and/or α6β2 expression, and that both age of onset and duration of nicotine exposure affect this protection.
authors.affiliation: Departments of Pharmacology and Toxicology (P.V.-B., L.M.M., S.M.N., J.D.E., E.T.W., K.A.S., G.R.H.), Psychiatry and Biology (J.M.M.), and Pathology (D.G.W.), School of Dentistry (G.R.H., A.E.F.), University of Utah, Salt Lake City, Utah; and George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, Utah (J.M.M.).
authors.forename: Paula L
authors.initials: PL
authors.lastname: Vieira-Brock
authors.affiliation: Departments of Pharmacology and Toxicology (P.V.-B., L.M.M., S.M.N., J.D.E., E.T.W., K.A.S., G.R.H.), Psychiatry and Biology (J.M.M.), and Pathology (D.G.W.), School of Dentistry (G.R.H., A.E.F.), University of Utah, Salt Lake City, Utah; and George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, Utah (J.M.M.).
authors.forename: Lisa M
authors.initials: LM
authors.lastname: McFadden
authors.affiliation: Departments of Pharmacology and Toxicology (P.V.-B., L.M.M., S.M.N., J.D.E., E.T.W., K.A.S., G.R.H.), Psychiatry and Biology (J.M.M.), and Pathology (D.G.W.), School of Dentistry (G.R.H., A.E.F.), University of Utah, Salt Lake City, Utah; and George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, Utah (J.M.M.).
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Nielsen
authors.affiliation: Departments of Pharmacology and Toxicology (P.V.-B., L.M.M., S.M.N., J.D.E., E.T.W., K.A.S., G.R.H.), Psychiatry and Biology (J.M.M.), and Pathology (D.G.W.), School of Dentistry (G.R.H., A.E.F.), University of Utah, Salt Lake City, Utah; and George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, Utah (J.M.M.).
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Ellis
authors.affiliation: Departments of Pharmacology and Toxicology (P.V.-B., L.M.M., S.M.N., J.D.E., E.T.W., K.A.S., G.R.H.), Psychiatry and Biology (J.M.M.), and Pathology (D.G.W.), School of Dentistry (G.R.H., A.E.F.), University of Utah, Salt Lake City, Utah; and George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, Utah (J.M.M.).
authors.forename: Elliot T
authors.initials: ET
authors.lastname: Walters
authors.affiliation: Departments of Pharmacology and Toxicology (P.V.-B., L.M.M., S.M.N., J.D.E., E.T.W., K.A.S., G.R.H.), Psychiatry and Biology (J.M.M.), and Pathology (D.G.W.), School of Dentistry (G.R.H., A.E.F.), University of Utah, Salt Lake City, Utah; and George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, Utah (J.M.M.).
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Stout
authors.affiliation: Departments of Pharmacology and Toxicology (P.V.-B., L.M.M., S.M.N., J.D.E., E.T.W., K.A.S., G.R.H.), Psychiatry and Biology (J.M.M.), and Pathology (D.G.W.), School of Dentistry (G.R.H., A.E.F.), University of Utah, Salt Lake City, Utah; and George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, Utah (J.M.M.).
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.affiliation: Departments of Pharmacology and Toxicology (P.V.-B., L.M.M., S.M.N., J.D.E., E.T.W., K.A.S., G.R.H.), Psychiatry and Biology (J.M.M.), and Pathology (D.G.W.), School of Dentistry (G.R.H., A.E.F.), University of Utah, Salt Lake City, Utah; and George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, Utah (J.M.M.).
authors.forename: Diana G
authors.initials: DG
authors.lastname: Wilkins
authors.affiliation: Departments of Pharmacology and Toxicology (P.V.-B., L.M.M., S.M.N., J.D.E., E.T.W., K.A.S., G.R.H.), Psychiatry and Biology (J.M.M.), and Pathology (D.G.W.), School of Dentistry (G.R.H., A.E.F.), University of Utah, Salt Lake City, Utah; and George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, Utah (J.M.M.).
authors.forename: Glen R
authors.initials: GR
authors.lastname: Hanson
authors.affiliation: Departments of Pharmacology and Toxicology (P.V.-B., L.M.M., S.M.N., J.D.E., E.T.W., K.A.S., G.R.H.), Psychiatry and Biology (J.M.M.), and Pathology (D.G.W.), School of Dentistry (G.R.H., A.E.F.), University of Utah, Salt Lake City, Utah; and George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, Utah (J.M.M.) fleckenstein@hsc.utah.edu.
authors.forename: Annette E
authors.initials: AE
authors.lastname: Fleckenstein
mesh_terms: D017668:Age of Onset; D000375:Aging / Q000187:drug effects; D000818:Animals; D001345:Autoradiography; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000172:deficiency*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D004347:Drug Interactions; D008297:Male; D008694:Methamphetamine / Q000493:pharmacokinetics / Q000494:pharmacology*; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C559463:alpha6beta2 nicotinic acetylcholine receptor; C403531:nicotinic receptor alpha4beta2; D008694:Methamphetamine; D009538:Nicotine; C082748:epibatidine; D004298:Dopamine