Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Journal of Pharmacology and Experimental Therapeutics
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Journal of Pharmacology and Experimental Therapeutics

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Visit jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleNeuropharmacology

Chronic Nicotine Exposure Attenuates Methamphetamine-Induced Dopaminergic Deficits

Paula L. Vieira-Brock, Lisa M. McFadden, Shannon M. Nielsen, Jonathan D. Ellis, Elliot T. Walters, Kristen A. Stout, J. Michael McIntosh, Diana G. Wilkins, Glen R. Hanson and Annette E. Fleckenstein
Journal of Pharmacology and Experimental Therapeutics December 2015, 355 (3) 463-472; DOI: https://doi.org/10.1124/jpet.114.221945
Paula L. Vieira-Brock
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.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lisa M. McFadden
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.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shannon M. Nielsen
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.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jonathan D. Ellis
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.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Elliot T. Walters
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.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kristen A. Stout
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.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
J. Michael McIntosh
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.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Diana G. Wilkins
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.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Glen R. Hanson
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.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Annette E. Fleckenstein
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.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

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 [125I]epibatidine. Both METH and nicotine decreased striatal α6β2 expression, as assessed using [125I]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.

Introduction

Methamphetamine (METH) is a potent psychostimulant abused among adolescents and young adults (Grant et al., 2007; Johnston et al., 2014). Repeated METH administrations to humans (Sekine et al., 2001; Volkow et al., 2001; McCann et al., 2008) and rodents (McFadden et al., 2012; Kousik et al., 2014) cause long-term striatal dopaminergic deficits resembling some aspects of Parkinson’s disease (PD) (McCann et al., 1998; Lotharius and Brundin, 2002; Kish et al., 2008). In fact, individuals with a history of amphetamine (AMPH)/METH abuse have an increased risk for developing PD (Callaghan et al., 2010, 2012; Curtin et al., 2015). Although the majority of patients with PD have never abused METH, overlapping neuropathologies may underlie the degenerative processes involving these two conditions (for review, see Granado et al., 2013; Kousik et al., 2014). Preclinical studies indicate that aberrant dopamine (DA) sequestration and release leading to oxidative stress might be one of the mechanisms that likely contribute to this dopaminergic damage (Fleckenstein et al., 1997; Lotharius and Brundin, 2002; for review, see Riddle et al., 2006).

Clinical evidence suggests that PD is less likely to occur among cigarette smokers (Hernán et al., 2001, 2002; Chen et al., 2010) and preclinical research indicates that nicotine is neuroprotective against nigrostriatal dopaminergic deficits (Huang et al., 2009; García-Montes et al., 2012; for review, see Quik et al., 2012). However—and despite the fact that the majority of METH abusers smoke cigarettes (approximately 80%; McCann et al., 2008) and thus self-administer nicotine—few studies have specifically assessed the effect of nicotine on METH-induced dopaminergic deficits. Of these studies, results reveal that acute nicotine injections protect against METH-induced striatal dopaminergic deficits (Maggio et al., 1998; Ryan et al., 2001). The effect of chronic nicotine exposure has not been explored.

Previous studies have suggested that α4β2 and α6β2 subtypes of nicotinic acetylcholine receptors (nAChRs) contribute to the neuroprotective effects of the stimulant, although other nicotinic subunits also likely contribute (Ryan et al., 2001; Khwaja et al., 2007; Takeuchi et al., 2009; Quik et al., 2011). For example, α4β2 antagonist administration inhibits the protection afforded by nicotine in rotenone-treated mice (Takeuchi et al., 2009). Furthermore, the protective effect of chronic nicotine against 6-hydroxy-DA was lost in α4-knockout mice (Ryan et al., 2001). Of note, however, are other studies demonstrating that α6β2 nAChR binding is increased in α4-knockout mice, leading to the suggestion that the loss of protection in α4-knockout mice was due to the increase in α6β2 expression (Perez et al., 2008). Similarly, others have suggested that nicotine-induced reductions in α6β2 nAChRs expression mediate neuroprotection against paraquat-induced dopaminergic damage (Khwaja et al., 2007). Overall, these and other studies suggest that α4β2 and/or α6β2 nAChRs contribute to the neuroprotective effects of nicotine. Given that these receptor subtypes modulate DA release (Meyer et al., 2008) and aberrant DA release contributes to METH-induced dopaminergic deficit (Di Chiara and Imperato, 1988; Howard et al., 2011), the potential role of these receptor subtypes merits attention.

It is important to note that the majority of humans addicted to cigarettes initiate smoking during adolescence (Kandel and Logan, 1984; Chen and Kandel, 1995; Breslau and Peterson, 1996; Centers for Disease Control and Prevention, 2002). Furthermore, epidemiologic studies indicate that those who did not develop PD were more likely to have smoked before the age of 20 years (Chen et al., 2010). These data suggest that cigarette smoking (and thus nicotine exposure) starting at a young age may contribute to neuroprotection. However, whether age of nicotine initiation is a factor in neuroprotection is unknown.

This series of studies aimed to investigate any potential age-related effect of nicotine neuroprotection in the METH model of striatal dopaminergic dysfunction. To more closely mimic the intermittent and chronic nature of nicotine exposure in smoking, nicotine was given long-term via drinking water. The data described herein demonstrate that prolonged oral nicotine exposure 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.

Materials and Methods

Animals.

Male Sprague-Dawley rats (Charles River Breeding Laboratories, Raleigh, NC) initially weighing 125–150 g [corresponding to postnatal day (PND) 40] or 245–270 g [corresponding to PND 60] (for reviews, see Spear, 2000; Tirelli et al., 2003) were housed two to three rats per cage and maintained under a controlled light/dark cycle (14:10 hours) and in an ambient environment of 20°C (with the exception of the 6-hour period during which METH or saline vehicle was administered, during which the ambient environment was maintained at 24°C). Food and water were available ad libitum. During METH or saline administrations, core body (rectal) temperatures were measured using a digital thermometer (Physitemp Instruments, Clifton, NJ) every 1 hour beginning 30 minutes before the first saline or METH administration and continuing until 30 minutes after the final saline or METH administration. Rats were placed ion a cooler environment during METH exposure if their body temperature exceeded 40.5°C and were returned to their home cage once their body temperature dropped to 40°C. All experiments were approved by the University of Utah Institutional Animal Care and Use Committee, in accordance with the 2011 National Institutes of Health Guide for the Care and Use of Laboratory Animals, Eighth Edition.

Drug Treatments.

METH hydrochloride was provided by the National Institutes of Health National Institute on Drug Abuse (Research Triangle Institute, Research Triangle Park, NC) and was administered at 4 × 7.5 mg/kg s.c., at 2-hour intervals calculated as free base. (−)-Nicotine (1.010 g/ml; Sigma-Aldrich, St. Louis, MO) was administered ad libitum p.o. at concentrations of 10, 20, 50, or 75 µg/ml via the water bottles, as delineated in Fig. 1. To increase palatability, 1% saccharin (Sweet & Low; Cumberland Packing Corp., Brooklyn, NY) was added to the animals’ drinking water in experiments in which nicotine concentration started at the highest concentration (i.e., 75 µg/ml; experiments in Fig. 1, B–D) or during the highest escalating rate (Fig. 1E). In these studies, nicotine water consumption was approximately 30 ml/rat per day, tap water consumption was approximately 45 ml/rat per day, and saccharin water consumption was approximately 60 ml/rat per day, similar to previous reports (Bordia et al., 2008). These nicotine doses in rats yield plasma concentrations similar to plasma nicotine and cotinine concentrations typically found in human smokers (10–50 ng/ml for nicotine and 300 ng/ml for cotinine) (Benowitz, 1994; Matta et al., 2007).

Fig. 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Fig. 1.

Experimental designs. (A) In paradigm A, rats received tap water or nicotine water (10–75 µg/ml) from PND 40 to PND 96 and METH (4 × 7.5 mg/kg per injection s.c., 2 hours apart) or saline (1 ml/kg per injection) at PND 89. (B) In paradigm B, rats received saccharin water or nicotine plus saccharin water (at 75 µg/ml) from PND 40 to PND 61 and METH (4 × 7.5 mg/kg per injection s.c., 2 hours apart) or saline (1 ml/kg per injection) at PND 54. (C) In paradigm C, rats received saccharin water or nicotine plus saccharin water (at 75 µg/ml) from PND 40 to PND 61 and METH (4 × 7.5 mg/kg/injection s.c., 2 hours apart) or saline (1 ml/kg per injection) at PND 82. (D) In paradigm D, rats received saccharin water or nicotine plus saccharin water (at 75 µg/ml) from PND 61 to PND 82 and METH (4 × 7.5 mg/kg per injection s.c., 2 hours apart) or saline (1 ml/kg per injection) at PND 75. (E) In paradigm E, rats received saccharin water or nicotine plus saccharin water (10–75 µg/ml) from PND 61 to PND 100 and METH (4 × 7.5 mg/kg per injection s.c., 2 hours apart) or saline (1 ml/kg per injection) at PND 93.

Tissue Preparation.

Rats were decapitated 7 days after METH treatment. Brains were hemisected, and the left striatum was dissected out on ice, placed in cold sucrose buffer (0.32 M sucrose, 3.8 mM NaH2PO4, and 12.7 mM Na2HPO4), and used for [3H]DA uptake and Western blotting as described below. The contralateral brains were rapidly removed and frozen in isopentane on dry ice and stored at −80°C. Frozen right hemisected brains were sliced at 12-µm thick at the level of the anterior striatum (1.5 mm from bregma; Paxinos and Watson, 2006) using a cryostat. Eight slices (four per rat) were mounted on each Superfrost Plus glass microslide (VWR International, Radnor, PA) and stored at −80°C for subsequent use in autoradiography assays. Hippocampal and perirhinal cortex tissues were also analyzed and data were reported in a separate article (Vieira-Brock et al., 2015).

[3H]DA Uptake Assay.

Striatal synaptosomes were prepared as previously described (Hanson et al., 2009). After decapitation, the striatum was quickly dissected out and homogenized in ice-cold sucrose buffer (0.32 M sucrose, 3.8 mM NaH2PO4, and 12.7 mM Na2HPO4). [3H]DA uptake assays were conducted according to Hanson et al. (2009). For plasmalemmal uptake of [3H]DA, striatal synaptosomes were prepared accordingly and resuspended in ice-cold Krebs’ buffer (126 nM NaCl, 4.8 mM KCl, 1.3 mM CaCl2, 16 mM sodium phosphate, 1.4 mM MgSO4, 11 mM dextrose, and 1 mM ascorbic acid, pH 7.4). Assay tubes containing 1.5 mg striatal tissue and 1 μM pargyline were incubated (3 minutes, 37°C; Sigma-Aldrich) with [7,8-3H]DA (0.5 nM final concentration; Perkin Elmer, Boston, MA). Nonspecific values were ascertained in the presence of 10 μM cocaine. Samples were filtered using a filtering manifold (Brandel Inc., Gaithersburg, MD) through Whatman GF/B filters (Whatman International LTD, Maidstone, UK) soaked previously in 0.05% polyethylenimine and washed three times with 3 ml ice-cold 0.32 M sucrose. Protein concentration was used for normalization and determined by the Bradford Protein Assay.

Dopamine Transporter Western Blotting.

Western blotting was conducted according to our previous method (Hadlock et al., 2009). Equal quantities of protein (8 μg) were loaded into each well of a 4%–12% NuPAGE Novex Bis-Tris Midi gradient gel (Invitrogen, Carlsbad, CA) and electrophoresed by using a XCell4 SureLock Midi-Cell (Invitrogen). Membranes were blocked for 30 minutes with StartingBlock Blocking Buffer (Thermo Fisher Scientific, Waltham, MA) and incubated for 1 hour at room temperature with a rabbit polyclonal N-terminal dopamine transporter (DAT) antibody at 1:5000 dilution (a generous gift from Dr. Roxanne Vaughan, University of North Dakota, Grand Forks, ND; Freed et al., 1995). The polyvinylidene difluoride membrane was then washed five times in Tris-buffered saline with Tween (250 mM NaCl, 50 mM Tris, pH 7.4, and 0.05% Tween 20). The membranes were then incubated for 1 hour with a horseradish peroxidase–conjugated secondary antibody (BioSource International, Camarillo, CA). After five washes in Tris-buffered saline with Tween, the bands were visualized by using Western Lightning Plus chemiluminescence reagent (PerkinElmer Life and Analytical Sciences, Waltham, MA) and quantified by densitometry using a FluorChem SP imaging system (Alpha Innotech, San Leandro, CA). Protein concentrations were determined by using the Bradford Protein Assay.

Brain METH and AMPH Concentrations.

Brain concentrations of METH and its metabolite, AMPH, were measured by liquid chromatography–tandem mass spectrometry as described previously (Truong et al., 2005). The whole brains (except for the striatum) were weighed and homogenized separately in 10 ml water. A VibraCell homogenizer (Sonics, Newton, CT) was used for the homogenization. A 0.5-ml volume of the homogenate was used for the analysis. An Agilent liquid chromatograph (Agilent Technologies, Santa Clara, CA) coupled to a ThermoQuest Finnigan TSQ 7000 tandem mass spectrometer (Thermo Fisher Scientific) was used for the analysis. Electrospray ionization was used. The lower limit of quantification was 1 ng/ml in the homogenates.

[125I]RTI-55 Autoradiography.

DAT density was used as a marker of dopaminergic integrity and assessed via [125I]3β-(4′-iodophenyl)tropan-2β-carboxylic acid methyl ester ([125I]RTI-55) binding to striatal slices as previously described (O'Dell et al., 2012). Briefly, slides were thawed on a slide warmer (5–10 minutes) and preincubated in sucrose buffer (10 mM sodium phosphate, 120 mM sodium chloride, and 320 mM sucrose, pH 7.4) containing 100 nM fluoxetine at room temperature for 5 minutes, followed by a 2-hour incubation in sucrose buffer containing 25 pM [125I]RTI-55 (2200 Ci/mmol; PerkinElmer Life and Analytical Sciences). Nonspecific binding was determined by slides incubated in sucrose buffer containing 25 pM [125I]RTI-55 and 100 nM fluoxetine plus 100 µM nomifensine (Sigma-Aldrich). Slides were rinsed twice in ice-cold buffer and distilled water for 2 minutes and air dried. Sample slides and standard 125I microscale slides (American Radiolabeled Chemicals, St. Louis, MO) were placed on one cassette and exposed to the same Kodak MR film (Eastman Kodak Co., Rochester, NY) for 24 hours to keep variables constant.

[125I]Epibatidine Autoradiography.

α4β2 nAChR density was assessed via [125I]epibatidine binding to striatal slices as previously described (Lai et al., 2005; Huang et al., 2009). Briefly, slides were thawed on a slide warmer (5–10 minutes) and preincubated in binding buffer (50 mM Tris, 120 mM NaCl, 5 mM KCl, 2.5 mM CaCl2, and 1.0 mM MgCl2, pH 7.5) plus 100 nM α-conotoxin MII (αCtxMII) (synthesized as previously described by Whiteaker et al., 2000) at room temperature for 30 minutes. The nonradiolabeled αCtxMII was used to inhibit epibatidine binding to α6β2 nAChR, followed by a 40-minute incubation in binding buffer containing 0.015 nM [125I]epibatidine (2200 Ci/mmol; PerkinElmer Life and Analytical Sciences) in the presence of 100 nM αCtxMII. Nonspecific binding was determined by slides incubated in binding buffer containing 0.015 nM [125I]epibatidine plus 0.1 mM nicotine. Slides were rinsed twice in ice-cold buffer for 5 minutes, followed by a 10-second rinse in distilled water. Slides were air dried. Sample slides and standard 125I microscale slides (American Radiolabeled Chemicals) were placed on one cassette and exposed to the same Kodak MR film (Eastman Kodak Co.) for 24 hour to keep variables constant.

[125I]αCtxMII Autoradiography.

α6β2 nAChR density was assessed via [125I]αCtxMII binding to striatal slices as previously described (Lai et al., 2005; Huang et al., 2009). Briefly, slides were thawed on a slide warmer (5–10 minutes) and preincubated in buffer A (pH 7.5, 20 nM HEPES, 144 mM NaCl, 1.5 mM KCl, 2 mM CaCl2, 1 mM MgSO4, 0.1% bovine serum albumin, and 1 mM phenylmethylsulfonyl fluoride) at room temperature for 2 × 15 minutes, followed by a 1-hour incubation in buffer B (pH 7.5, 20 nM HEPES, 144 mM NaCl, 1.5 mM KCl, 2 mM CaCl2, 1 mM MgSO4, 0.2% bovine serum albumin, 5 mM EDTA, 5 mM EGTA, and 10 µg/ml each of aprotinin, leupeptin, and pepstatin A; Sigma-Aldrich) containing 0.5 nM [125I]αCtxMII (approximately 2200 Ci/mmol, which was synthesized as previously described; Whiteaker et al., 2000). Nonspecific binding was determined by slides incubated in 0.5 nM [125I]αCtxMII buffer B also containing 0.1 mM nicotine (Sigma-Aldrich). Slides were rinsed in room temperature buffer A for 10 minutes, then in ice-cold buffer A for another 10 minutes, followed by 2 × 10 minutes in 0.1× ice-cold buffer A, and finally in 4°C distilled water for 2 × 10 seconds. Slides were air dried. Sample slides and standard 125I microscale slides (American Radiolabeled Chemicals) were placed on one cassette and exposed to the same Kodak MR film (Eastman Kodak Co.) for 4 days to keep variables constant.

Statistical Analyses.

Statistical analyses were conducted using GraphPad Prism 5.01 software (GraphPad Software Inc., La Jolla, CA). For autoradiography, optical densities from four replicate slices per rat were quantified using ImageJ software (National Institutes of Health, Bethesda, MD) by an analyst blinded to the experimental groups. Specific binding was obtained by subtracting film background from mean density values and was converted to femtomoles per milligram using the standard curve generated from 125I standards. The optical densities of the samples were within the linear range of the standards. Data were analyzed using two-way analysis of variance, except for temperature data, for which one-way analysis of variance was used followed by the Newman–Keuls post hoc test. Bonferroni adjustments were applied as appropriate. For comparisons between two groups, data were analyzed using the t test. Differences among groups were considered significant if the probability of error was less than 5%.

Results

Figure 1 depicts the experimental design of the studies presented herein, with additional details provided in the Materials and Methods. As shown in Fig. 1A, rats were exposed to an escalating-dose regimen of nicotine for a total of 56 days beginning in adolescence (PND 40) until young adulthood (PND 96), with METH administered on PND 89. As shown in Fig. 1B, the focus then shifted to assessing the effects of high-dose (75 µg/ml) nicotine exposure for 21 days beginning at PND 40 through PND 61, with METH administered on PND 54. As presented in Fig. 1C, rats were similarly exposed to high-dose nicotine for 21 days beginning at PND 40 through PND 61, with METH administered 21 days later on PND 82. In Fig. 1D, rats received high-dose nicotine for 21 days beginning at PND 61 through PND 82, with METH administered on PND 75. Finally, as shown in Fig. 1E, rats received an escalating-dose regimen beginning at PND 61 through PND 100, with METH administered at PND 93.

Results presented in Fig. 2 demonstrate that ad libitum exposure to an escalating-dose regimen of nicotine (10–75 µg/ml; see Fig. 1, paradigm A for details) from PND 40 to PND 96 attenuated the persistent (e.g., 7-day) METH-induced decrease in striatal [3H]DAT uptake, DAT immunoreactivity, and [125I]RTI-55 binding. For data presented in Fig. 2A, there was no interaction effect of METH and nicotine (P = 0.169), and there were main effects of nicotine (P = 0.029) and METH (P < 0.0001) per se. A post hoc comparison revealed significant differences between the saline/METH and nicotine/METH groups (P < 0.05). As shown in Fig. 2B, there was an interaction effect of METH and nicotine (P = 0.038) and main effects of nicotine (P = 0.020) and METH (P < 0.0001) per se, and a post hoc comparison revealed differences between the saline/METH and nicotine/METH groups (P < 0.01). In Fig. 2C, there was no interaction effect of METH and nicotine (P = 0.052), no main effect of nicotine (P = 0.249), and a main effect of METH (P < 0.0001). A post hoc comparison revealed differences between the saline/METH and nicotine/METH groups (P < 0.05). This nicotine regimen generally did not attenuate METH-induced hyperthermia (Fig. 2D).

Fig. 2.
  • Download figure
  • Open in new tab
  • Download powerpoint
Fig. 2.

Chronic nicotine administration attenuates METH-induced deficits in striatal DAT function (A), immunoreactivity (B), and expression (C), with no change in METH-induced hyperthermia (D). These data are derived from the paradigm described in Fig. 1A. Data are expressed as mean values ± S.E.M. of n = 6–10 subjects. *P<0.05 (significantly different from saline control); #P < 0.05 (significantly different from SM); ##P<0.01 (significantly different from SM). NM, nicotine water/METH injections; NS, nicotine water/saline injections; SM, tap water/METH injections; SS, tap water/saline injections.

Results presented in Fig. 3A demonstrate that ad libitum exposure to nicotine (75 µg/ml; see the Materials and Methods and Fig. 1, paradigm B for details) from PND 40 to PND 61 attenuated the persistent (e.g., 7-day) METH-induced decrease in striatal [3H]DA uptake when METH was administered on PND 54. In particular, there was an interaction effect of METH and nicotine (P = 0.019), and a post hoc comparison tests revealed differences between the saline/METH and nicotine/METH groups (P < 0.01). Similarly, for striatal [125I]RTI-55 autoradiography (mean ± S.E.M. tap water/saline injections, 3.32 ± 0.06 fmol/mg; tap water/METH injections, 1.26 ± 0.24 fmol/mg; nicotine water/saline injections, 3.28 ± 0.03 fmol/mg; and nicotine water/METH injections, 2.44 ± 0.15 fmol/mg), there was an interaction effect of METH and nicotine (P = 0.001), and a post hoc comparison revealed differences between the saline/METH and nicotine/METH groups (P < 0.001). In other words, 21 days of nicotine exposure afforded protection when (as was accomplished as shown in Fig. 2) exposure was initiated on PND 40. This nicotine regimen did not attenuate METH-induced hyperthermia (data not shown).

Fig. 3.
  • Download figure
  • Open in new tab
  • Download powerpoint
Fig. 3.

(A) Short-term (i.e., 21-day) nicotine administration starting in adolescence attenuates METH-induced deficits in striatal DAT function. These data are derived from paradigm B described in Fig. 1B. (B) Nicotine neuroprotective effects on METH-induced deficits in striatal DAT function do not persist for 4 weeks. These data are derived from paradigm C described in Fig. 1C. (C) Short-term (i.e., 21-day) NIC administration starting in adulthood does not attenuate METH-induced deficits in striatal DAT function. These data are derived from paradigm D described in Fig. 1D. (D) Long-term (i.e., 39-day) nicotine administration starting in adulthood attenuates METH-induced deficits in striatal DAT function. These data are derived from paradigm E described in Fig.1E. Data are expressed as mean values ± S.E.M. of n = 8 to 10 (A), n = 8 to 11 (B), n = 6 to 7 (C), or 9 to 10 (D) subjects. ##P < 0.01 (significantly different from SM). NM, nicotine water/METH injections; NS, nicotine water/saline injections; SM, tap water/METH injections; SS, tap water/saline injections.

To note, the protection afforded by 21-day nicotine exposure (75 µg/ml; Fig. 3B) does not persist when nicotine exposure is initiated on PND 40 but terminated on PND 61 (see Fig. 1, paradigm C for details). In particular, there was no interaction effect of METH and nicotine (P = 0.691) and no main effect of nicotine (P = 0.304), although there was a main effect of METH (P < 0.0001). A post hoc comparison revealed no differences between the saline/METH and nicotine/METH groups (P > 0.05). This nicotine regimen did not attenuate METH-induced hyperthermia (data not shown).

In contrast with the results presented in Fig. 3A, 21 days of nicotine (75 µg/ml) exposure was not sufficient to attenuate the persistent (7-day) METH-induced decrease in striatal [3H]DA uptake when nicotine exposure was initiated on PND 61 (Fig. 3C; see Fig. 1, paradigm D for details). In particular, there was no interaction effect of METH and nicotine (P = 0.122) and no main effect of nicotine (P = 0.456), although there was a main effect of METH (P < 0.0001). A post hoc comparison revealed no differences between the saline/METH and nicotine/METH groups (P > 0.05). This nicotine regimen did not attenuate METH-induced hyperthermia (data not shown).

Results presented in Fig. 3D demonstrate that ad libitum exposure to an escalating-dose regimen of nicotine (10–75 µg/ml; see the Materials and Methods and Fig. 1, paradigm E for details) from PND 61 to PND 100 attenuated the persistent (e.g., 7-day) METH-induced decrease in striatal [3H]DA uptake. In particular, there was an interaction effect of METH and nicotine (P = 0.004), and a post hoc comparison revealed differences between the saline/METH and nicotine/METH groups (P < 0.05). For striatal [125I]RTI-55 autoradiography (mean ± S.E.M. tap water/saline injections, 3.44 ± 0.05 fmol/mg; tap water/METH injections, 1.57 ± 0.25 fmol/mg; nicotine water/saline injections, 3.31 ± 0.06 fmol/mg; and nicotine water/METH injections, 2.16 ± 0.26 fmol/mg), there was a trend for an interaction effect of METH and nicotine (P = 0.063), and there was a main effect of METH (P < 0.0001) and no main effect of nicotine (P > 0.05). A post hoc comparison also revealed differences between the saline/METH and nicotine/METH groups (P < 0.05). This NIC regimen did not attenuate METH-induced hyperthermia (data not shown).

The concentrations of METH and its metabolite, AMPH, were evaluated in rats exposed to tap or nicotine water to investigate whether NIC alters METH pharmacokinetics. From PND 40, rats received increasing concentrations of NIC via drinking water (10–75 µg/ml) for 49 days as described for PND 40 to PND 89 in Fig. 1 (paradigm A). METH (4 × 7.5 mg/kg per injection) or saline (4 × 1 ml/kg per injection) was administered on PND 89 and rats were euthanized 1 hour later. Results revealed that neither METH nor AMPH concentrations differed between METH-treated rats preexposed to tap water or nicotine water [for METH, 8.08 ± 0.52 and 6.73 ± 0.66 ng/mg tissue for saline and nicotine pretreatment, respectively; t(10) = 1.61, P = 0.14; for AMPH, 1.62 ± 0.15 and 1.64 ± 0.21 ng/mg tissue for saline and nicotine pretreatment, respectively; t(10) = 0.08, P = 0.93]. Neither METH nor AMPH was detected in the saline-treated rats preexposed to tap or nicotine water (below the lower limit of quantification).

Results presented in Fig. 4 indicate that chronic nicotine treatment increased striatal [125I]epibatidine binding density, as assessed by autoradiography in the striatum of both saline- and METH-treated rats. For data presented in Fig. 4A (i.e., rats treated as described in paradigm A), there was no interaction effect of METH and nicotine (P = 0.124). There were main effects of nicotine (P < 0.0001) and METH (P = 0.007). A post hoc comparison revealed differences between the saline/saline and nicotine/saline groups (P < 0.05) and the saline/METH and nicotine/METH groups (P < 0.001). As shown in Fig. 4B (i.e., rats treated as described in paradigm B), there was no interaction effect of METH and nicotine (P = 0.960), and there was a main effect of nicotine (P < 0.0001) and METH (P < 0.007) per se. A post hoc comparison revealed differences between the saline/saline and nicotine/saline groups (P < 0.001) and the saline/METH and nicotine/METH groups (P < 0.001). As presented in Fig. 4C (i.e., rats treated as described in paradigm E), there was no interaction effect of METH and nicotine (P = 0.249) and there was a main effect of nicotine (P < 0.0001). A post hoc comparison revealed differences between the saline/saline and nicotine/saline groups (P < 0.001) and the saline/METH and nicotine/METH groups (P < 0.001).

Fig. 4.
  • Download figure
  • Open in new tab
  • Download powerpoint
Fig. 4.

Long-term nicotine administration increases striatal α4β2 nAChR binding in saline-treated and METH-treated rats. (A) Rats received tap water or nicotine water (10–75 µg/ml) from PND 40 to PND 96 and METH (4 × 7.5 mg/kg per injection s.c., 2 hours apart) or saline (1 ml/kg per injection) at PND 89, as delineated in paradigm A in Fig. 1A. (B) Rats received saccharin water or nicotine plus saccharin water (75 µg/ml) from PND 40 to PND 61 and METH (4 × 7.5 mg/kg per injection s.c., 2 hours apart) or saline (1 ml/kg per injection) at PND 54, as delineated in paradigm B in Fig. 1B. (C) Rats received saccharin water or nicotine plus saccharin water (10–75 µg/ml) from PND 61 to PND 100 and METH (4 × 7.5 mg/kg per injection s.c., 2 hours apart) or saline (1 ml/kg per injection) at PND 93, as delineated in paradigm E in Fig. 1E. Brains were harvested 7 days after METH and α4β2 density was assessed via [125I]epibatidine autoradiography. Data are expressed as mean values ± S.E.M. of n = 8–12 subjects (A), n = 8–10 subjects (B), and n = 10 subjects (C). ^P<0.05 (significantly different from SS); ^^^P < 0.001 (significantly different from SS); ###P < 0.001 (significantly different from SM). NM, nicotine water/METH injections; NS, nicotine water/saline injections; SM, tap water/METH injections; SS, tap water/saline injections.

Results presented in Fig. 5 indicate that both nicotine and METH treatment decreased striatal [125I]αCtxMII binding density, as assessed by autoradiography. For data presented in Fig. 5A (i.e., rats treated as described in Fig. 1, paradigm A), there was no interaction effect of METH and nicotine (P = 0.275). There was a main effect of METH (P < 0.0001) and nicotine (P < 0.003) per se. A post hoc comparison revealed differences between the saline/saline and nicotine/saline (P < 0.05), the saline/saline and saline/METH (P < 0.001) and the nicotine/saline and nicotine/METH groups (P < 0.05), but not the saline/METH and nicotine/METH groups (P > 0.05). As shown in Fig. 5B (i.e., rats treated as described in paradigm B), there was no interaction effect of METH and nicotine (P = 0.179), and there was a main effect of nicotine (P = 0.003) and METH (P < 0.0001) per se. A post hoc comparison revealed differences between the saline/saline and nicotine/saline (P < 0.01), the saline/saline and saline/METH (P < 0.001), and the nicotine/saline and nicotine/METH groups (P < 0.01), but not the saline/METH and nicotine/METH groups (P > 0.05). As shown in Fig. 5C (i.e., rats treated as described in paradigm E), there was no interaction effect of METH and nicotine (P = 0.066), and there was a main effect of nicotine (P = 0.0002) and METH (P < 0.0001) per se. A post hoc comparison revealed differences between the saline/saline and nicotine/saline (P < 0.001), the saline/saline and saline/METH (P < 0.001), and the nicotine/saline and nicotine/METH groups (P < 0.05), but not the saline/METH and nicotine/METH groups (P > 0.05).

Fig. 5.
  • Download figure
  • Open in new tab
  • Download powerpoint
Fig. 5.

Nicotine or METH administration reduces striatal α6β2 nAChR binding. (A) Rats received tap water or NIC water (10–75 µg/ml) from PND 40 to 96 and METH (4 × 7.5 mg/kg per injection s.c., 2 hours apart) or saline (1 ml/kg per injection) at PND 89, as delineated in paradigm A in Fig. 1A. (B) Rats received saccharin water or nicotine plus saccharin water (75 µg/ml) from PND 40 to PND 61 and METH (4 × 7.5 mg/kg per injection s.c., 2 hours apart) or saline (1 ml/kg per injection) at PND 54, as delineated in paradigm B in Fig. 1B. (C) Rats received saccharin water or nicotine plus saccharin water (10–75 µg/ml) from PND 61 to PND 100 and METH (4 × 7.5 mg/kg per injection s.c., 2 hours apart) or saline (1 ml/kg per injection) at PND 93, as delineated in paradigm E in Fig. 1E. Brains were harvested 7 days after METH and α6β2 density was assessed via [125I]αCtxMII autoradiography. Data are expressed as mean values ± S.E.M. of n = 8–12 subjects (A), n = 8–10 subjects (B), and n = 10 subjects (C). ^P < 0.05 (significantly different from SS); ^^P < 0.01 (significantly different from SS); ^^^P < 0.001 (significantly different from SS); +P < 0.05 (significantly different from NS); ++P < 0.01 (significantly different from NS). NM, nicotine water/METH injections; NS, nicotine water/saline injections; SM, tap water/METH injections; SS, tap water/saline injections.

Representative autoradiograms of the [125I]RTI-55, [125I]epibatidine, and [125I]αCtxMII studies are presented in Fig. 6.

Fig. 6.
  • Download figure
  • Open in new tab
  • Download powerpoint
Fig. 6.

Representative autoradiographs depicting the effects of nicotine and METH treatments. (A) DAT ([125I]RTI-55 binding). (B) α4β2 nAChR ([125I]epibatidine binding). (C) α6β2 nAChR ([125I]αCtxMII) densities. Blank indicates nonspecific binding. NM, nicotine water/METH injections; NS, nicotine water/saline injections; SM, tap water/METH injections; SS, tap water/saline injections.

Discussion

Previous studies have demonstrated dopaminergic neuroprotection afforded by chronic oral nicotine exposure. For example, rats exposed for 7 weeks to escalating doses (12.5–50 μg/ml) of nicotine in drinking water beginning in adolescence are partially protected against 6-hydroxy-DA–induced loss of striatal DAT (Huang et al., 2009). In addition, 6 weeks of nicotine exposure to mice via drinking water attenuated paraquat-induced deficits in striatal DAT density deficits when nicotine was initiated during adulthood (Khwaja et al., 2007). Given the clinical relevance of evaluating chronic nicotine exposure as described in the Introduction, our studies extended this work to determine the effects of chronic nicotine exposure on METH-induced dopaminergic deficits.

The first of our studies demonstrated that long-term (i.e., 56 days), escalating-dose (i.e., 10–75 µg/ml) oral nicotine exposure, initiated during a period corresponding to human adolescence (i.e., paradigm A), attenuates the persistent (7-day) striatal dopaminergic deficits in rats treated with METH during young adulthood. In these studies, nicotine was administered before and during the 7-day period after METH exposure. This effect does not appear to be attributable to nicotine-mediated alterations in METH pharmacokinetics.

A second series of experiments was conducted to address the question as to whether shorter-term nicotine administration also affords protection. Results revealed that exposure to nicotine (75 µg/ml), initiated during adolescence and administered for 21 days, likewise attenuates METH-induced persistent (7-day) striatal dopaminergic deficits. In these studies, nicotine was administered before and during the 7-day period after METH exposure (paradigm B). However, this protective effect does not persist. In particular, if nicotine exposure occurred during adolescence and METH was administered as rats approach young adulthood, protection was lost (paradigm C). These data are consistent with clinical findings indicating that the reduced risk for PD diminishes as time since quitting cigarette smoking increases (Chen et al., 2010). One possible explanation for these data is that nicotine must be present during the period during and after METH exposure to afford protection. However, our data that long-term nicotine exposure affords neuroprotection even when nicotine exposure is halted 2 or 24 hours before METH treatment research (Vieira-Brock et al., unpublished observations), suggesting that the protective effects afforded by nicotine are not a direct effect of having the drug “on board” during and after METH treatment.

To investigate the effect of age of onset of nicotine exposure, a third series of studies was conduced wherein nicotine exposure occurred postadolescence (i.e., for 21 days during the period approaching young adulthood). Results revealed that in this scenario, nicotine no longer affords protection against striatal METH-induced dopaminergic deficits (paradigm D). However, postadolescent exposure to an escalating-dose paradigm with longer-term (i.e., 39-day) nicotine exposure afforded protection (paradigm E). These data demonstrate that protection can be engendered postadolescence but requires an escalating-dose paradigm and/or (more likely) longer-term exposures.

Our studies also demonstrate that oral nicotine administration per se did not alter striatal DAT function and/or expression when assessed during adulthood. These data are consistent with previous findings demonstrating that chronic nicotine administration via drinking water beginning in adolescence did not affect striatal DAT expression when assessed in adulthood (Huang et al., 2009). Similarly, 7 days of nicotine administration via osmotic minipumps had no effect on striatal DAT function and expression in adult rats (Izenwasser and Cox, 1992; Collins et al., 2004).

It is well established that attenuation of METH-induced hyperthermia protects the persistent dopaminergic deficits caused by the stimulant. For example, exposure of animals to a low ambient temperature attenuates both METH-induced hyperthermia and neurotoxicity (Bowyer et al., 1994; Ali et al., 1995). Prevention of METH-induced hyperthermia attenuates reactive species formation as well (Fleckenstein et al., 1997). Furthermore, selective inhibition of dopaminergic receptors by various agents also attenuates METH-induced hyperthermia and affords dopaminergic neuroprotection (Sonsalla et al., 1986). However, our results reveal that chronic nicotine exposure had little effect on METH-induced hyperthermia, thus indicating that mechanisms beyond alterations in body temperature contribute to its protection.

The α4β2 and α6β2 nAChRs are highly expressed on dopaminergic projections and regulate striatal DA release (Champtiaux et al., 2002; Marks et al., 2014). As noted in the Introduction, preclinical studies indicate that METH causes aberrant DA sequestration and release, leading to oxidative stress that, in turn, contributes to the persistent dopaminergic deficits caused by the stimulant (Cubells et al., 1994; for review, see Fleckenstein et al., 2007 for review). Thus, the effects of nicotine and METH on these subtypes were investigated. Of note, preclinical associations between chronic nicotine exposure, the expression of these subtypes, and dopaminergic protection have been reported (Khwaja et al., 2007; Huang et al., 2009). Furthermore, chronic nicotine exposure increases α4β2 nAChR density in human smokers (Benwell et al., 1988).

Results revealed that long-term nicotine exposure increased striatal α4β2 nAChR density in both saline- and METH-treated rats. These data are consistent with reports that chronic nicotine administration upregulates α4β2 nAChR binding in several brain regions (Marks et al., 1992; McCallum et al., 2006; Perez et al., 2008), with the upregulation accompanied by increased function (for review, see Buisson and Bertrand, 2002). Furthermore, and consistent with previous reports (Lai et al., 2005; Khwaja et al., 2007), our study revealed that chronic nicotine administration reduces striatal α6β2 nAChR density. This alteration in the balance between α4β2 and α6β2 receptor subtypes is consistent with the suggestion that nicotine upregulates α4β2 nAChRs by increasing assembly of β2 with α4 subunits and consequently reducing assembly of β2 with α6 subunits (Kuryatov et al., 2005; Sallette et al., 2005; Colombo et al., 2013).

It is interesting to speculate that an upregulation of α4β2 nAChR expression/signaling afforded by nicotine at the time of METH treatment may have contributed to neuroprotection. Importantly, METH causes acetylcholine release and thus indirectly activates nAChRs (Tsai and Chen, 1994; Taguchi et al., 1998; Dobbs and Mark, 2008). α4β2 nAChRs are found on dopaminergic terminals and increase tonic DA release when they are activated (Meyer et al., 2008). Because it is widely hypothesized that METH causes long-term dopaminergic deficits through accumulation of cytoplasmic DA that readily oxidizes and forms reactive species, α4β2 nAChR activation could protect against METH-induced dopaminergic deficits through increased release of tonic DA (or basal firing) during the high-dose METH treatment. Noteworthy, however, are findings that α4β2 nAChR activation has antioxidant effects (Linert et al., 1999), and nicotine administration to rats suppresses the formation of dihydrobenzoacetic acid (Obata et al., 2002), an index of hydroxyl radical formation that is increased after high-dose METH treatment (Fleckenstein et al., 1997).

An increase in α4β2 nAChR expression/signaling at the time of METH treatment likely occurred at the expense of α6β2 signaling. Thus, neurons expressing a greater α6β2/α4β2 ratio would be predictably more vulnerable to METH-induced deficits. Consistent with this postulation are findings that METH caused long-term deficits in α6β2 expression, perhaps indicating a loss of dopaminergic neurons that preferentially expressed this subtype at the time of METH exposure.

Of interest are findings that nicotine-induced changes in nAChRs differ between adolescent and adult rats. Particularly, upregulation of the α4β2 subtypes and downregulation of the α6β2 subtypes of nAChRs are more robust in adolescent rats compared with adult rats (Doura et al., 2008). Assuming that these alterations in nAChRs contribute to protection, then the protection observed in our studies would be affected by age and could explain the shorter nicotine exposure necessary for neuroprotection to occur in adolescent versus adult rats.

In conclusion, these data indicate that nicotine protects against METH-induced striatal dopaminergic deficits, and that both age of onset and duration of nicotine exposure affect this protection. These data extend past studies indicating a role for α7 nAChRs in contributing to the neurotoxic effects of METH (Northrop et al., 2011), by implicating α4β2 nAChRs as contributing to this phenomenon. The lack of α6β2 nAChRs, owing to a shift in balance with α4β2 nAChRs, may also affect this phenomenon. Future studies investigating correlations between the timing of, and paradigms displaying or lacking, shifts in the balance of these receptor subtypes will be important for investigating their roles in affording protection. Additional studies involving the impact of nicotine after treatment (as well as selective α4β2 and α6β2 agonists and antagonists) will also be of importance, because these could suggest treatment strategies for METH-induced toxicities as well as degenerative disorders such as PD.

Acknowledgments

The authors thank Dr. Roxanne Vaughan for providing the DAT antibody. The authors also thank Drs. Maryka Quik, Tanuja Bordia, and Kristen Keefe for extensive assistance with the autoradiography technique.

Authorship Contributions

Participated in research design: Vieira-Brock, Hanson, Fleckenstein.

Conducted experiments: Vieira-Brock, McFadden, Nielsen, Ellis, Walters, Stout.

Performed data analysis: Vieira-Brock, McFadden, Ellis, Walters, Stout, Wilkins, Fleckenstein.

Wrote or contributed to the writing of the manuscript: Vieira-Brock, McFadden, McIntosh, Wilkins, Hanson, Fleckenstein

Footnotes

    • Received April 27, 2015.
    • Accepted September 18, 2015.
  • This research was supported by the National Institutes of Health National Institute on Drug Abuse [Grants R01-DA031883, R01-DA11389, P-01 DA13367, and K02-DA019447], the National Institutes of Health National Institute of General Medical Sciences [Grants R01-GM103801 and P01-GM48677], the Howard Hughes Medical Institute [HHMI Med into Grad Initiative Grant 560067777], the American Foundation for Pharmaceutical Education, and the University of Utah [Graduate Research Fellowship (to P.B.)].

  • dx.doi.org/10.1124/jpet.114.221945.

Abbreviations

[125I]RTI-55
[125I]3β-(4′-iodophenyl)tropan-2β-carboxylic acid methyl ester
αCtxMII
α-conotoxin MII
AMPH
amphetamine
DA
dopamine
DAT
dopamine transporter
METH
methamphetamine
nAChR
nicotinic acetylcholine receptor
PD
Parkinson’s disease
PND
postnatal day
  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics

References

  1. ↵
    1. Ali SF,
    2. Newport RR,
    3. Holson W,
    4. Slikker W Jr., and
    5. Bowyer JF
    (1995) Low environmental temperatures or pharmacologic agents that produce hyperthermia decrease methamphetamine neurotoxicity in mice. Ann N Y Acad Sci 765:338.
    OpenUrlCrossRefPubMed
  2. ↵
    1. Benowitz NL
    (1994) Biomarkers of cigarette smoking, smoking and tobacco control, in Monograph 7: The FTC Cigarette Test Method For Determining Tar, Nicotine and Carbon Monoxide Yields of U.S. Cigarettes, pp 93–111, National Institutes of Health, Bethesda, MD.
  3. ↵
    1. Benwell ME,
    2. Balfour DJ, and
    3. Anderson JM
    (1988) Evidence that tobacco smoking increases the density of (-)-[3H]nicotine binding sites in human brain. J Neurochem 50:1243–1247.
    OpenUrlCrossRefPubMed
  4. ↵
    1. Bordia T,
    2. Campos C,
    3. Huang L, and
    4. Quik M
    (2008) Continuous and intermittent nicotine treatment reduces L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias in a rat model of Parkinson’s disease. J Pharmacol Exp Ther 327:239–247.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Bowyer JF,
    2. Davies DL,
    3. Schmued L,
    4. Broening HW,
    5. Newport GD,
    6. Slikker W Jr., and
    7. Holson RR
    (1994) Further studies of the role of hyperthermia in methamphetamine neurotoxicity. J Pharmacol Exp Ther 268:1571–1580.
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Buisson B and
    2. Bertrand D
    (2002) Nicotine addiction: the possible role of functional upregulation. Trends Pharmacol Sci 23: 130–136.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Breslau N and
    2. Peterson EL
    (1996) Smoking cessation in young adults: age at initiation of cigarette smoking and other suspected influences. Am J Public Health 86:214–220.
    OpenUrlCrossRefPubMed
  8. ↵
    1. Callaghan RC,
    2. Cunningham JK,
    3. Sajeev G, and
    4. Kish SJ
    (2010) Incidence of Parkinson’s disease among hospital patients with methamphetamine-use disorders. Mov Disord 25:2333–2339.
    OpenUrlCrossRefPubMed
  9. ↵
    1. Callaghan RC,
    2. Cunningham JK,
    3. Sykes J, and
    4. Kish SJ
    (2012) Increased risk of Parkinson’s disease in individuals hospitalized with conditions related to the use of methamphetamine or other amphetamine-type drugs. Drug Alcohol Depend 120:35–40.
    OpenUrlCrossRefPubMed
  10. ↵
    1. Centers for Disease Control and Prevention
    (2002) Tobacco Information and Prevention Sources (TIPS), National Center for Chronic Disease Prevention and Health Promotion, Atlanta, GA.
  11. ↵
    1. Champtiaux N,
    2. Han ZY,
    3. Bessis A,
    4. Rossi FM,
    5. Zoli M,
    6. Marubio L,
    7. McIntosh JM, and
    8. Changeux JP
    (2002) Distribution and pharmacology of alpha 6-containing nicotinic acetylcholine receptors analyzed with mutant mice. J Neurosci 22:1208–1217.
    OpenUrlAbstract/FREE Full Text
  12. ↵
    1. Chen H,
    2. Huang X,
    3. Guo X,
    4. Mailman RB,
    5. Park Y,
    6. Kamel F,
    7. Umbach DM,
    8. Xu Q,
    9. Hollenbeck A,
    10. Schatzkin A,
    11. et al.
    (2010) Smoking duration, intensity, and risk of Parkinson disease. Neurology 74:878–884.
    OpenUrlCrossRef
  13. ↵
    1. Chen K and
    2. Kandel DB
    (1995) The natural history of drug use from adolescence to the mid-thirties in a general population sample. Am J Public Health 85:41–47.
    OpenUrlCrossRefPubMed
  14. ↵
    1. Collins SL,
    2. Wade D,
    3. Ledon J, and
    4. Izenwasser S
    (2004) Neurochemical alterations produced by daily nicotine exposure in periadolescent vs. adult male rats. Eur J Pharmacol 502:75–85.
    OpenUrlCrossRefPubMed
  15. ↵
    1. Colombo SF,
    2. Mazzo F,
    3. Pistillo F, and
    4. Gotti C
    (2013) Biogenesis, trafficking and up-regulation of nicotinic ACh receptors. Biochem Pharmacol 86: 1063–1073.
    OpenUrlCrossRefPubMed
  16. ↵
    1. Cubells JF,
    2. Rayport S,
    3. Rajendran G, and
    4. Sulzer D
    (1994) Methamphetamine neurotoxicity involves vacuolation of endocytic organelles and dopamine-dependent intracellular oxidative stress. J Neurosci 14: 2260–2271.
    OpenUrlAbstract
  17. ↵
    1. Curtin K,
    2. Fleckenstein AE,
    3. Robison RJ,
    4. Crookston MJ,
    5. Smith KR, and
    6. Hanson GR
    (2015) Methamphetamine/amphetamine abuse and risk of Parkinson’s disease in Utah: a population-based assessment. Drug Alcohol Depend 146:30–38.
    OpenUrlCrossRefPubMed
  18. ↵
    1. Di Chiara G and
    2. Imperato A
    (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 85:5274–5278.
    OpenUrlAbstract/FREE Full Text
  19. ↵
    1. Dobbs LK and
    2. Mark GP
    (2008) Comparison of systemic and local methamphetamine treatment on acetylcholine and dopamine levels in the ventral tegmental area in the mouse. Neuroscience 156: 700–711.
    OpenUrlCrossRefPubMed
  20. ↵
    1. Doura MB,
    2. Gold AB,
    3. Keller AB, and
    4. Perry DC
    (2008) Adult and periadolescent rats differ in expression of nicotinic cholinergic receptor subtypes and in the response of these subtypes to chronic nicotine exposure. Brain Res 1215:40–52.
    OpenUrlCrossRefPubMed
  21. ↵
    1. Fleckenstein AE,
    2. Volz TJ,
    3. Riddle EL,
    4. Gibb JW, and
    5. Hanson GR
    (2007) New insights into the mechanism of action of amphetamines. Annu Rev Pharmacol Toxicol 47: 681–698.
    OpenUrlCrossRefPubMed
  22. ↵
    1. Fleckenstein AE,
    2. Wilkins DG,
    3. Gibb JW, and
    4. Hanson GR
    (1997) Interaction between hyperthermia and oxygen radical formation in the 5-hydroxytryptaminergic response to a single methamphetamine administration. J Pharmacol Exp Ther 283:281–285.
    OpenUrlAbstract/FREE Full Text
  23. ↵
    1. Freed C,
    2. Revay R,
    3. Vaughan RA,
    4. Kriek E,
    5. Grant S,
    6. Uhl GR, and
    7. Kuhar MJ
    (1995) Dopamine transporter immunoreactivity in rat brain. J Comp Neurol 359:340–349.
    OpenUrlCrossRefPubMed
  24. ↵
    1. García-Montes JR,
    2. Boronat-García A,
    3. López-Colomé AM,
    4. Bargas J,
    5. Guerra-Crespo M, and
    6. Drucker-Colín R
    (2012) Is nicotine protective against Parkinson’s disease? An experimental analysis. CNS Neurol Disord Drug Targets 11:897–906.
    OpenUrlCrossRef
  25. ↵
    1. Granado N,
    2. Ares-Santos S, and
    3. Moratalla R
    (2013) Methamphetamine and Parkinson’s disease. Parkinsons Dis 2013:308052.
    OpenUrl
  26. ↵
    1. Grant KM,
    2. Kelley SS,
    3. Agrawal S,
    4. Meza JL,
    5. Meyer JR, and
    6. Romberger DJ
    (2007) Methamphetamine use in rural Midwesterners. Am J Addict 16:79–84.
    OpenUrlCrossRefPubMed
  27. ↵
    1. Hadlock GC,
    2. Baucum AJ 2nd.,
    3. King JL,
    4. Horner KA,
    5. Cook GA,
    6. Gibb JW,
    7. Wilkins DG,
    8. Hanson GR, and
    9. Fleckenstein AE
    (2009) Mechanisms underlying methamphetamine-induced dopamine transporter complex formation. J Pharmacol Exp Ther 329:169–174.
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. Hanson JE,
    2. Birdsall E,
    3. Seferian KS,
    4. Crosby MA,
    5. Keefe KA,
    6. Gibb JW,
    7. Hanson GR, and
    8. Fleckenstein AE
    (2009) Methamphetamine-induced dopaminergic deficits and refractoriness to subsequent treatment. Eur J Pharmacol 607:68–73.
    OpenUrlCrossRefPubMed
  29. ↵
    1. Hernán MA,
    2. Takkouche B,
    3. Caamaño-Isorna F, and
    4. Gestal-Otero JJ
    (2002) A meta-analysis of coffee drinking, cigarette smoking, and the risk of Parkinson’s disease. Ann Neurol 52:276–284.
    OpenUrlCrossRefPubMed
  30. ↵
    1. Hernán MA,
    2. Zhang SM,
    3. Rueda-deCastro AM,
    4. Colditz GA,
    5. Speizer FE, and
    6. Ascherio A
    (2001) Cigarette smoking and the incidence of Parkinson’s disease in two prospective studies. Ann Neurol 50:780–786.
    OpenUrlCrossRefPubMed
  31. ↵
    1. Howard CD,
    2. Keefe KA,
    3. Garris PA, and
    4. Daberkow DP
    (2011) Methamphetamine neurotoxicity decreases phasic, but not tonic, dopaminergic signaling in the rat striatum. J Neurochem 118:668–676.
    OpenUrlCrossRefPubMed
  32. ↵
    1. Huang LZ,
    2. Parameswaran N,
    3. Bordia T,
    4. Michael McIntosh J, and
    5. Quik M
    (2009) Nicotine is neuroprotective when administered before but not after nigrostriatal damage in rats and monkeys. J Neurochem 109:826–837.
    OpenUrlCrossRefPubMed
  33. ↵
    1. Izenwasser S and
    2. Cox BM
    (1992) Inhibition of dopamine uptake by cocaine and nicotine: tolerance to chronic treatments. Brain Res 573:119–125.
    OpenUrlCrossRefPubMed
  34. ↵
    1. Johnston LD,
    2. O’Malley PM,
    3. Miech RA,
    4. Bachman JG, and
    5. Schulenberg JE
    (2014) Monitoring the Future Results on Adolescent Drug Use: Overview of Key Findings, 2013, Institute for Social Research, University of Michigan, Ann Arbor, MI.
  35. ↵
    1. Kandel DB and
    2. Logan JA
    (1984) Patterns of drug use from adolescence to young adulthood: I. Periods of risk for initiation, continued use, and discontinuation. Am J Public Health 74:660–666.
    OpenUrlCrossRefPubMed
  36. ↵
    1. Khwaja M,
    2. McCormack A,
    3. McIntosh JM,
    4. Di Monte DA, and
    5. Quik M
    (2007) Nicotine partially protects against paraquat-induced nigrostriatal damage in mice; link to alpha6beta2* nAChRs. J Neurochem 100:180–190.
    OpenUrlCrossRefPubMed
  37. ↵
    1. Kish SJ,
    2. Tong J,
    3. Hornykiewicz O,
    4. Rajput A,
    5. Chang LJ,
    6. Guttman M, and
    7. Furukawa Y
    (2008) Preferential loss of serotonin markers in caudate versus putamen in Parkinson’s disease. Brain 131:120–131.
    OpenUrlAbstract/FREE Full Text
  38. ↵
    1. Kousik SM,
    2. Carvey PM, and
    3. Napier TC
    (2014) Methamphetamine self-administration results in persistent dopaminergic pathology: implications for Parkinson’s disease risk and reward-seeking. Eur J Neurosci 40:2707–2714.
    OpenUrlCrossRefPubMed
  39. ↵
    1. Kuryatov A,
    2. Luo J,
    3. Cooper J, and
    4. Lindstrom J
    (2005) Nicotine acts as a pharmacological chaperone to up-regulate human alpha4beta2 acetylcholine receptors. Mol Pharmacol 68: 1839–1851. doi: 10.1124/mol.105.012419.
    OpenUrlAbstract/FREE Full Text
  40. ↵
    1. Lai A,
    2. Parameswaran N,
    3. Khwaja M,
    4. Whiteaker P,
    5. Lindstrom JM,
    6. Fan H,
    7. McIntosh JM,
    8. Grady SR, and
    9. Quik M
    (2005) Long-term nicotine treatment decreases striatal alpha 6* nicotinic acetylcholine receptor sites and function in mice. Mol Pharmacol 67: 1639–1647
    OpenUrlAbstract/FREE Full Text
  41. ↵
    1. Linert W,
    2. Bridge MH,
    3. Huber M,
    4. Bjugstad KB,
    5. Grossman S, and
    6. Arendash GW
    (1999) In vitro and in vivo studies investigating possible antioxidant actions of nicotine: relevance to Parkinson's and Alzheimer's diseases. Biochim Biophys Acta 1454: 143–152.
    OpenUrlPubMed
  42. ↵
    1. Lotharius J and
    2. Brundin P
    (2002) Pathogenesis of Parkinson’s disease: dopamine, vesicles and alpha-synuclein. Nat Rev Neurosci 3:932–942.
    OpenUrlCrossRefPubMed
  43. ↵
    1. Maggio R,
    2. Riva M,
    3. Vaglini F,
    4. Fornai F,
    5. Molteni R,
    6. Armogida M,
    7. Racagni G, and
    8. Corsini GU
    (1998) Nicotine prevents experimental parkinsonism in rodents and induces striatal increase of neurotrophic factors. J Neurochem 71:2439–2446.
    OpenUrlPubMed
  44. ↵
    1. Marks MJ,
    2. Grady SR,
    3. Salminen O,
    4. Paley MA,
    5. Wageman CR,
    6. McIntosh JM, and
    7. Whiteaker P
    (2014) α6β2*-subtype nicotinic acetylcholine receptors are more sensitive than α4β2*-subtype receptors to regulation by chronic nicotine administration. J Neurochem 130:185–198.
    OpenUrlCrossRefPubMed
  45. ↵
    1. Marks MJ,
    2. Pauly JR,
    3. Gross SD,
    4. Deneris ES,
    5. Hermans-Borgmeyer I,
    6. Heinemann SF, and
    7. Collins AC
    (1992) Nicotine binding and nicotinic receptor subunit RNA after chronic nicotine treatment. J Neurosci 12:2765–2784.
    OpenUrlAbstract
  46. ↵
    1. Matta SG,
    2. Balfour DJ,
    3. Benowitz NL,
    4. Boyd RT,
    5. Buccafusco JJ,
    6. Caggiula AR,
    7. Craig CR,
    8. Collins AC,
    9. Damaj MI,
    10. Donny EC,
    11. et al.
    (2007) Guidelines on nicotine dose selection for in vivo research. Psychopharmacology (Berl) 190:269–319.
    OpenUrlCrossRefPubMed
  47. ↵
    1. McCallum SE,
    2. Parameswaran N,
    3. Bordia T,
    4. Fan H,
    5. Tyndale RF,
    6. Langston JW,
    7. McIntosh JM, and
    8. Quik M
    (2006) Increases in alpha4* but not alpha3*/alpha6* nicotinic receptor sites and function in the primate striatum following chronic oral nicotine treatment. J Neurochem 96:1028–1041.
    OpenUrlCrossRefPubMed
  48. ↵
    1. McCann UD,
    2. Kuwabara H,
    3. Kumar A,
    4. Palermo M,
    5. Abbey R,
    6. Brasic J,
    7. Ye W,
    8. Alexander M,
    9. Dannals RF,
    10. Wong DF,
    11. et al.
    (2008) Persistent cognitive and dopamine transporter deficits in abstinent methamphetamine users. Synapse 62:91–100.
    OpenUrlCrossRefPubMed
  49. ↵
    1. McCann UD,
    2. Wong DF,
    3. Yokoi F,
    4. Villemagne V,
    5. Dannals RF, and
    6. Ricaurte GA
    (1998) Reduced striatal dopamine transporter density in abstinent methamphetamine and methcathinone users: evidence from positron emission tomography studies with [11C]WIN-35,428. J Neurosci 18:8417–8422.
    OpenUrlAbstract/FREE Full Text
  50. ↵
    1. McFadden LM,
    2. Hadlock GC,
    3. Allen SC,
    4. Vieira-Brock PL,
    5. Stout KA,
    6. Ellis JD,
    7. Hoonakker AJ,
    8. Andrenyak DM,
    9. Nielsen SM,
    10. Wilkins DG,
    11. et al.
    (2012) Methamphetamine self-administration causes persistent striatal dopaminergic alterations and mitigates the deficits caused by a subsequent methamphetamine exposure. J Pharmacol Exp Ther 340:295–303.
    OpenUrlAbstract/FREE Full Text
  51. ↵
    1. Meyer EL,
    2. Yoshikami D, and
    3. McIntosh JM
    (2008) The neuronal nicotinic acetylcholine receptors alpha 4* and alpha 6* differentially modulate dopamine release in mouse striatal slices. J Neurochem 105:1761–1769.
    OpenUrlCrossRefPubMed
  52. ↵
    1. Northrop NA,
    2. Smith LP,
    3. Yamamoto BK, and
    4. Eyerman DJ
    (2011) Regulation of glutamate release by α7 nicotinic receptors: differential role in methamphetamine-induced damage to dopaminergic and serotonergic terminals. J Pharmacol Exp Ther 336:900–907.
    OpenUrlAbstract/FREE Full Text
  53. ↵
    1. O'Dell SJ,
    2. Galvez BA,
    3. Ball AJ, and
    4. Marshall JF
    (2012) Running wheel exercise ameliorates methamphetamine-induced damage to dopamine and serotonin terminals. Synapse 66: 71–80.
    OpenUrlCrossRefPubMed
  54. ↵
    1. Obata T,
    2. Aomine M,
    3. Inada T, and
    4. Kinemuchi H
    (2002) Nicotine suppresses 1-methyl-4-phenylpyridinium ion-induced hydroxyl radical generation in rat striatum. Neurosci Lett 330: 122–124.
    OpenUrlCrossRefPubMed
  55. ↵
    1. Paxinos G and
    2. Watson C
    (2006) The Rat Brain in Stereotaxic Coordinates, 6th ed, Academic Press, London.
  56. ↵
    1. Perez XA,
    2. Bordia T,
    3. McIntosh JM,
    4. Grady SR, and
    5. Quik M
    (2008) Long-term nicotine treatment differentially regulates striatal alpha6alpha4beta2* and alpha6(nonalpha4)beta2* nAChR expression and function. Mol Pharmacol 74:844–853.
    OpenUrlAbstract/FREE Full Text
  57. ↵
    1. Quik M,
    2. Perez XA, and
    3. Bordia T
    (2012) Nicotine as a potential neuroprotective agent for Parkinson’s disease. Mov Disord 27:947–957.
    OpenUrlCrossRefPubMed
  58. ↵
    1. Quik M,
    2. Perez XA, and
    3. Grady SR
    (2011) Role of α6 nicotinic receptors in CNS dopaminergic function: relevance to addiction and neurological disorders. Biochem Pharmacol 82:873–882.
    OpenUrlCrossRefPubMed
  59. ↵
    1. Riddle EL,
    2. Fleckenstein AE, and
    3. Hanson GR
    (2006) Mechanisms of methamphetamine-induced dopaminergic neurotoxicity. AAPS J 8:E413–E418.
    OpenUrlCrossRefPubMed
  60. ↵
    1. Ryan RE,
    2. Ross SA,
    3. Drago J, and
    4. Loiacono RE
    (2001) Dose-related neuroprotective effects of chronic nicotine in 6-hydroxydopamine treated rats, and loss of neuroprotection in alpha4 nicotinic receptor subunit knockout mice. Br J Pharmacol 132:1650–1656.
    OpenUrlCrossRefPubMed
  61. ↵
    1. Sallette J,
    2. Pons S,
    3. Devillers-Thiery A,
    4. Soudant M,
    5. Prado de Carvalho L,
    6. Changeux JP, and
    7. Corringer PJ
    (2005) Nicotine upregulates its own receptors through enhanced intracellular maturation. Neuron 46: 595–607. doi: 10.1016/j.neuron.2005.03.029.
    OpenUrlCrossRefPubMed
  62. ↵
    1. Sekine Y,
    2. Iyo M,
    3. Ouchi Y,
    4. Matsunaga T,
    5. Tsukada H,
    6. Okada H,
    7. Yoshikawa E,
    8. Futatsubashi M,
    9. Takei N, and
    10. Mori N
    (2001) Methamphetamine-related psychiatric symptoms and reduced brain dopamine transporters studied with PET. Am J Psychiatry 158:1206–1214.
    OpenUrlCrossRefPubMed
  63. ↵
    1. Sonsalla PK,
    2. Gibb JW, and
    3. Hanson GR
    (1986) Roles of D1 and D2 dopamine receptor subtypes in mediating the methamphetamine-induced changes in monoamine systems. J Pharmacol Exp Ther 238:932–937.
    OpenUrlAbstract/FREE Full Text
  64. ↵
    1. Spear LP
    (2000) The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24:417–463.
    OpenUrlCrossRefPubMed
  65. ↵
    1. Tsai TH and
    2. Chen CF
    (1994) Simultaneous measurement of acetylcholine and monoamines by two serial on-line microdialysis systems: effects of methamphetamine on neurotransmitters release from the striatum of freely moving rats. The order of the author names in the manuscript is different from the cover sheet. Neurosci Lett 175–177.
  66. ↵
    1. Taguchi K,
    2. Atobe J,
    3. Kato M,
    4. Chuma T,
    5. Chikuma T,
    6. Shigenaga T, and
    7. Miyatake T
    (1998) The effect of methamphetamine on the release of acetylcholine in the rat striatum. Eur J Pharmacol 360: 131–137.
    OpenUrlCrossRefPubMed
  67. ↵
    1. Takeuchi H,
    2. Yanagida T,
    3. Inden M,
    4. Takata K,
    5. Kitamura Y,
    6. Yamakawa K,
    7. Sawada H,
    8. Izumi Y,
    9. Yamamoto N,
    10. Kihara T,
    11. et al.
    (2009) Nicotinic receptor stimulation protects nigral dopaminergic neurons in rotenone-induced Parkinson’s disease models. J Neurosci Res 87:576–585.
    OpenUrlCrossRefPubMed
  68. ↵
    1. Tirelli E,
    2. Laviola G, and
    3. Adriani W
    (2003) Ontogenesis of behavioral sensitization and conditioned place preference induced by psychostimulants in laboratory rodents. Neurosci Biobehav Rev 27:163–178.
    OpenUrlCrossRefPubMed
  69. ↵
    1. Truong JG,
    2. Wilkins DG,
    3. Baudys J,
    4. Crouch DJ,
    5. Johnson-Davis KL,
    6. Gibb JW,
    7. Hanson GR, and
    8. Fleckenstein AE
    (2005) Age-dependent methamphetamine-induced alterations in vesicular monoamine transporter-2 function: implications for neurotoxicity. J Pharmacol Exp Ther 314:1087–1092.
    OpenUrlAbstract/FREE Full Text
  70. ↵
    1. Vieira-Brock PL,
    2. McFadden LM,
    3. Nielsen SM,
    4. Smith MD,
    5. Hanson GR, and
    6. Fleckenstein AE
    (2015) Nicotine administration attenuates methamphetamine-induced novel object recognition deficits. Int J Neuropsychopharmacol DOI: 10.1093/ijnp/pyv073 [published ahead of print].
  71. ↵
    1. Volkow ND,
    2. Chang L,
    3. Wang GJ,
    4. Fowler JS,
    5. Leonido-Yee M,
    6. Franceschi D,
    7. Sedler MJ,
    8. Gatley SJ,
    9. Hitzemann R,
    10. Ding YS,
    11. et al.
    (2001) Association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers. Am J Psychiatry 158:377–382.
    OpenUrlCrossRefPubMed
  72. ↵
    1. Whiteaker P,
    2. McIntosh JM,
    3. Luo S,
    4. Collins AC, and
    5. Marks MJ
    (2000) 125I-alpha-conotoxin MII identifies a novel nicotinic acetylcholine receptor population in mouse brain. Mol Pharmacol 57:913–925.
    OpenUrlAbstract/FREE Full Text
View Abstract
PreviousNext
Back to top

In this issue

Journal of Pharmacology and Experimental Therapeutics: 355 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 355, Issue 3
1 Dec 2015
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Journal of Pharmacology and Experimental Therapeutics article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Chronic Nicotine Exposure Attenuates Methamphetamine-Induced Dopaminergic Deficits
(Your Name) has forwarded a page to you from Journal of Pharmacology and Experimental Therapeutics
(Your Name) thought you would be interested in this article in Journal of Pharmacology and Experimental Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleNeuropharmacology

Nicotine, Methamphetamine, Age, and Nicotinic Receptors

Paula L. Vieira-Brock, Lisa M. McFadden, Shannon M. Nielsen, Jonathan D. Ellis, Elliot T. Walters, Kristen A. Stout, J. Michael McIntosh, Diana G. Wilkins, Glen R. Hanson and Annette E. Fleckenstein
Journal of Pharmacology and Experimental Therapeutics December 1, 2015, 355 (3) 463-472; DOI: https://doi.org/10.1124/jpet.114.221945

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Research ArticleNeuropharmacology

Nicotine, Methamphetamine, Age, and Nicotinic Receptors

Paula L. Vieira-Brock, Lisa M. McFadden, Shannon M. Nielsen, Jonathan D. Ellis, Elliot T. Walters, Kristen A. Stout, J. Michael McIntosh, Diana G. Wilkins, Glen R. Hanson and Annette E. Fleckenstein
Journal of Pharmacology and Experimental Therapeutics December 1, 2015, 355 (3) 463-472; DOI: https://doi.org/10.1124/jpet.114.221945
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Oxysterols and ethanol
  • P-glycoprotein Apical Efflux Ratio for Compound Optimization
  • Pharmacology of Carbamate Insecticides at MT1 & MT2
Show more Neuropharmacology

Similar Articles

  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About JPET
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0103 (Online)

Copyright © 2021 by the American Society for Pharmacology and Experimental Therapeutics