, Volume 234, Issue 5, pp 739–747 | Cite as

Voluntary inhalation of methamphetamine: a novel strategy for studying intake non-invasively

  • C. Juarez-Portilla
  • R. D. Kim
  • M. Robotham
  • M. Tariq
  • M. Pitter
  • J. LeSauter
  • R. SilverEmail author
Original Investigation



The abuse of the psychostimulant methamphetamine (MA) is associated with substantial costs and limited treatment options. To understand the mechanisms that lead to abuse, animal models of voluntary drug intake are crucial.


We aimed to develop a protocol to study long-term non-invasive voluntary intake of MA in mice.


Mice were maintained in their home cages and allowed daily 1 h access to an attached tunnel leading to a test chamber in which nebulized MA was available. Restated, if they went to the nebulizing chamber, they self-administered MA by inhalation. This protocol was compared to injected and to imposed exposure to nebulized MA, in a series of seven experiments.


We established a concentration of nebulized MA at which motor activity increases following voluntary intake resembled that following MA injection and imposed inhalation. We found that mice regulated their exposure to MA, self-administering for shorter durations when concentrations of nebulized MA were increased. Mice acquire the available MA by repeatedly running in and out of the nebulizing chamber for brief bouts of intake. Such exposure to nebulized MA elevated plasma MA levels. There was limited evidence of sensitization of locomotor activity. Finally, blocking access to the wheel did not affect time spent in the nebulizing chamber.


We conclude that administration of MA by nebulization is an effective route of self-administration, and our new protocol represents a promising tool for examining the transitions from first intake to long-term use and its behavioral and neural consequences in a non-invasive protocol.


Addiction Voluntary intake Self-administration Nasal administration Nebulization Non-invasive Sensitization 



This study is supported by the Postdoctoral fellowship award from the Consejo Nacional de Ciencia y Tecnología (CONACYT) 186902 and CONACYT travel grants I010/152/2014 and C-133/2014 (C.J.P.), NSF grant 1256105 (RS), the American Physiological Society (APS) Summer Undergraduate Research Fellowship, the Barnard College Doris Schloss Rosenthal Internship (RS&MR), the Columbia University Summer Undergraduate Research Fellowship (RDK, MR, MT), the Barnard College Summer Research Internship (RDK, MT). We thank Dr. Shan Xie, PhD, of the Nathan Kline Research Institute Orangeburg NY for performing the MA assays.

Compliance with ethical standards

All experimental procedures were approved and conducted according to the Columbia University Institutional Animal Care and Use Committee.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

213_2016_4510_MOESM1_ESM.docx (156 kb)
ESM 1 (DOCX 155 kb)


  1. Aarde SM, Miller ML, Creehan KM, Vandewater SA, Taffe MA (2015) One day access to a running wheel reduces self-administration of D-methamphetamine, MDMA and methylone. Drug Alcohol Depend 151:151–158CrossRefPubMedPubMedCentralGoogle Scholar
  2. Ahmed SH (2012) The science of making drug-addicted animals. Neuroscience 211:107–125CrossRefPubMedGoogle Scholar
  3. Badiani A (2013) Substance-specific environmental influences on drug use and drug preference in animals and humans. Curr Opin Neurobiol 23:588–596CrossRefPubMedGoogle Scholar
  4. Bardo MT, Valone JM, Bevins RA (1999) Locomotion and conditioned place preference produced by acute intravenous amphetamine: role of dopamine receptors and individual differences in amphetamine self-administration. Psychopharmacology 143:39–46CrossRefPubMedGoogle Scholar
  5. Brackins T, Brahm NC, Kissack JC (2011) Treatments for methamphetamine abuse: a literature review for the clinician. J Pharm Pract 24:541–550CrossRefPubMedGoogle Scholar
  6. Caprioli D, Celentano M, Paolone G, Lucantonio F, Bari A, Nencini P, Badiani A (2008) Opposite environmental regulation of heroin and amphetamine self-administration in the rat. Psychopharmacology 198:395–404CrossRefPubMedGoogle Scholar
  7. Carneiro BT, Araujo JF (2012) Food entrainment: major and recent findings. Front Behav Neurosci 6:83CrossRefPubMedPubMedCentralGoogle Scholar
  8. Carroll ME, France CP, Meisch RA (1979) Food deprivation increases oral and intravenous drug intake in rats. Science 205:319–321CrossRefPubMedGoogle Scholar
  9. Carroll ME, Meisch RA (1984) Increased drug-reinforced behavior due to food deprivation. In: Thompson T, Dews PB, Barrett JE (eds) Advances in behavioral pharmacology. Academic Press Inc., Orlando, FL, pp. 47–88Google Scholar
  10. Cosgrove KP, Hunter RG, Carroll ME (2002) Wheel-running attenuates intravenous cocaine self-administration in rats: sex differences. Pharmacol Biochem Behav 73:663–671CrossRefPubMedGoogle Scholar
  11. Couper FJ, Logan BK (2004) Drugs and human performance fact sheets. In: Bureau WSPLS (ed). National Highway Traffic Safety Administration, Washington, DCGoogle Scholar
  12. Cruickshank CC, Dyer KR (2009) A review of the clinical pharmacology of methamphetamine. Addiction 104:1085–1099CrossRefPubMedGoogle Scholar
  13. Davis CM, Riley AL (2010) Conditioned taste aversion learning: implications for animal models of drug abuse. Ann N Y Acad Sci 1187:247–275CrossRefPubMedGoogle Scholar
  14. de la Garza R, Johanson CE (1987) The effects of food deprivation on the self-administration of psychoactive drugs. Drug Alcohol Depend 19:17–27CrossRefPubMedGoogle Scholar
  15. DeCoursey PJ (1986) Light-sampling behavior in photoentrainment of a rodent circadian rhythm. J Comp Physiol A 159:161–169CrossRefPubMedGoogle Scholar
  16. Eastwood EC, Phillips TJ (2014) Opioid sensitivity in mice selectively bred to consume or not consume methamphetamine. Addict Biol 19:370–379CrossRefPubMedGoogle Scholar
  17. Flagel SB, Robinson TE (2007) Quantifying the psychomotor activating effects of cocaine in the rat. Behav Pharmacol 18:297–302CrossRefPubMedGoogle Scholar
  18. Fudala PJ, Iwamoto ET (1990) Conditioned aversion after delay place conditioning with amphetamine. Pharmacol Biochem Behav 35:89–92CrossRefPubMedGoogle Scholar
  19. Hart CL, Gunderson EW, Perez A, Kirkpatrick MG, Thurmond A, Comer SD, Foltin RW (2008) Acute physiological and behavioral effects of intranasal methamphetamine in humans. Neuropsychopharmacology 33:1847–1855CrossRefPubMedGoogle Scholar
  20. Hassan SF, Wearne TA, Cornish JL, Goodchild AK (2016) Effects of acute and chronic systemic methamphetamine on respiratory, cardiovascular and metabolic function, and cardiorespiratory reflexes. J Physiol 594:763–780CrossRefPubMedGoogle Scholar
  21. Hemby SE, Co C, Koves TR, Smith JE, Dworkin SI (1997) Differences in extracellular dopamine concentrations in the nucleus accumbens during response-dependent and response-independent cocaine administration in the rat. Psychopharmacology 133:7–16CrossRefPubMedGoogle Scholar
  22. Jacobsen JH, Hutchinson MR, Mustafa S (2016) Drug addiction: targeting dynamic neuroimmune receptor interactions as a potential therapeutic strategy. Curr Opin Pharmacol 26:131–137CrossRefPubMedGoogle Scholar
  23. Keith DR, Hart CL, Robotham M, Tariq M, Le Sauter J, Silver R (2013) Time of day influences the voluntary intake and behavioral response to methamphetamine and food reward. Pharmacol Biochem Behav 110:117–126CrossRefPubMedPubMedCentralGoogle Scholar
  24. Kosobud AE, Pecoraro NC, Rebec GV, Timberlake W (1998) Circadian activity precedes daily methamphetamine injections in the rat. Neurosci Lett 250:99–102CrossRefPubMedGoogle Scholar
  25. Le Moal M (2009) Drug abuse: vulnerability and transition to addiction. Pharmacopsychiatry 42(Suppl 1):S42–S55CrossRefPubMedGoogle Scholar
  26. Marshall JF, O’Dell SJ (2012) Methamphetamine influences on brain and behavior: unsafe at any speed? Trends Neurosci 35:536–545CrossRefPubMedPubMedCentralGoogle Scholar
  27. Meijer JH, Robbers Y (2014) Wheel running in the wild. Proc Biol Sci 281:20140210CrossRefPubMedPubMedCentralGoogle Scholar
  28. Miller ML, Vaillancourt BD, Wright MJ Jr, Aarde SM, Vandewater SA, Creehan KM, Taffe MA (2012) Reciprocal inhibitory effects of intravenous d-methamphetamine self-administration and wheel activity in rats. Drug Alcohol Depend 121:90–96CrossRefPubMedGoogle Scholar
  29. Mrosovsky N, Hattar S (2003) Impaired masking responses to light in melanopsin-knockout mice. Chronobiol Int 20:989–999CrossRefPubMedGoogle Scholar
  30. Paladini CA, Mitchell JM, Williams JT, Mark GP (2004) Cocaine self-administration selectively decreases noradrenergic regulation of metabotropic glutamate receptor-mediated inhibition in dopamine neurons. J Neurosci 24:5209–5215CrossRefPubMedGoogle Scholar
  31. Patton DF, Parfyonov M, Gourmelen S, Opiol H, Pavlovski I, Marchant EG, Challet E, Mistlberger RE (2013) Photic and pineal modulation of food anticipatory circadian activity rhythms in rodents. PLoS One 8:e81588CrossRefPubMedPubMedCentralGoogle Scholar
  32. Phillips TJ, Mootz JR, Reed C (2016) Identification of treatment targets in a genetic mouse model of voluntary methamphetamine drinking. Int Rev Neurobiol 126:39–85CrossRefPubMedGoogle Scholar
  33. Pittendrigh CS (1981) Circadian systems: entrainment. In: Aschoff J (ed) Biological rhythms. Springer US, New York, pp. 94–124Google Scholar
  34. Pittendrigh CS, Minis DH (1964) The entrainment of circadian oscillations by light and their role as photoperiodic clocks. Am Nat 98:261–294CrossRefGoogle Scholar
  35. Post RM, Rose H (1976) Increasing effects of repetitive cocaine administration in the rat. Nature 260:731–732CrossRefPubMedGoogle Scholar
  36. Ricoy UM, Martinez JL Jr (2009) Local hippocampal methamphetamine-induced reinforcement. Front Behav Neurosci 3:47CrossRefPubMedPubMedCentralGoogle Scholar
  37. Rosenwasser AM, Fixaris MC, McCulley WD III (2015) Photoperiodic modulation of voluntary ethanol intake in C57BL/6 mice. Physiol Behav 147:342–347CrossRefPubMedGoogle Scholar
  38. SAMHSA (2014) National Survey on Drug Use and Health. Behavioral health trends in the United States: results from the 2014 National Survey on Drug Use and HealthGoogle Scholar
  39. Segal DS, Mandell AJ (1974) Long-term administration of d-amphetamine: progressive augmentation of motor activity and stereotypy. Pharmacol Biochem Behav 2:249–255CrossRefPubMedGoogle Scholar
  40. Sheridan J, Butler R, Wheeler A (2009) Initiation into methamphetamine use: qualitative findings from an exploration of first time use among a group of New Zealand users. J Psychoactive Drugs 41:11–17CrossRefPubMedGoogle Scholar
  41. Smith MA, Pennock MM, Walker KL, Lang KC (2012) Access to a running wheel decreases cocaine-primed and cue-induced reinstatement in male and female rats. Drug Alcohol Depend 121:54–61CrossRefPubMedGoogle Scholar
  42. Solinas M, Thiriet N, Chauvet C, Jaber M (2010) Prevention and treatment of drug addiction by environmental enrichment. Prog Neurobiol 92:572–592CrossRefPubMedGoogle Scholar
  43. Spyraki C, Fibiger HC, Phillips AG (1982) Dopaminergic substrates of amphetamine-induced place preference conditioning. Brain Res 253:185–193CrossRefPubMedGoogle Scholar
  44. Stefanski R, Ladenheim B, Lee SH, Cadet JL, Goldberg SR (1999) Neuroadaptations in the dopaminergic system after active self-administration but not after passive administration of methamphetamine. Eur J Pharmacol 371:123–135CrossRefPubMedGoogle Scholar
  45. Stefanski R, Lee SH, Yasar S, Cadet JL, Goldberg SR (2002) Lack of persistent changes in the dopaminergic system of rats withdrawn from methamphetamine self-administration. Eur J Pharmacol 439:59–68CrossRefPubMedGoogle Scholar
  46. Thiriet N, Gennequin B, Lardeux V, Chauvet C, Decressac M, Janet T, Jaber M, Solinas M (2011) Environmental enrichment does not reduce the rewarding and neurotoxic effects of methamphetamine. Neurotox Res 19:172–182CrossRefPubMedGoogle Scholar
  47. Thomas DM, Walker PD, Benjamins JA, Geddes TJ, Kuhn DM (2004) Methamphetamine neurotoxicity in dopamine nerve endings of the striatum is associated with microglial activation. J Pharmacol Exp Ther 311:1–7CrossRefPubMedGoogle Scholar
  48. United Nations Office on Drugs and Crime: World drug report (2011)
  49. Volkow ND, Morales M (2015) The brain on drugs: from reward to addiction. Cell 162:712–725CrossRefPubMedGoogle Scholar
  50. Webb IC, Baltazar RM, Lehman MN, Coolen LM (2009a) Bidirectional interactions between the circadian and reward systems: is restricted food access a unique zeitgeber? Eur J Neurosci 30:1739–1748CrossRefPubMedGoogle Scholar
  51. Webb IC, Baltazar RM, Wang X, Pitchers KK, Coolen LM, Lehman MN (2009b) Diurnal variations in natural and drug reward, mesolimbic tyrosine hydroxylase, and clock gene expression in the male rat. J Biol Rhythm 24:465–476CrossRefGoogle Scholar
  52. Webb IC, Lehman MN, Coolen LM (2015) Diurnal and circadian regulation of reward-related neurophysiology and behavior. Physiol Behav 143:58–69CrossRefPubMedGoogle Scholar
  53. Wheeler JM, Reed C, Burkhart-Kasch S, Li N, Cunningham CL, Janowsky A, Franken FH, Wiren KM, Hashimoto JG, Scibelli AC, Phillips TJ (2009) Genetically correlated effects of selective breeding for high and low methamphetamine consumption. Genes Brain Behav 8:758–771CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • C. Juarez-Portilla
    • 1
    • 3
  • R. D. Kim
    • 2
  • M. Robotham
    • 2
  • M. Tariq
    • 2
  • M. Pitter
    • 2
  • J. LeSauter
    • 2
    • 3
  • R. Silver
    • 2
    • 3
    • 4
    Email author
  1. 1.Centro de Investigaciones BiomédicasUniversidad VeracruzanaVeracruzMexico
  2. 2.Neuroscience Program and Department of PsychologyBarnard College of Columbia UniversityNew YorkUSA
  3. 3.Department of PsychologyColumbia UniversityNew YorkUSA
  4. 4.Department of Pathology and Cell BiologyColumbia University Health SciencesNew YorkUSA

Personalised recommendations