, Volume 236, Issue 12, pp 3557–3565 | Cite as

Effects of methamphetamine isomers on d-methamphetamine self-administration and food-maintained responding in male rats

  • M. T. BardoEmail author
  • E. D. Denehy
  • L. R. Hammerslag
  • L. P. Dwoskin
  • B. E. Blough
  • A. Landavazo
  • J. Bergman
  • S. J. Kohut
Original Investigation



Methamphetamine (METH) abuse is generally attributed to the d-isomer. Self-administration of l-METH has been examined only in rhesus monkeys with a history of cocaine self-administration or drug-naïve rats using high toxic doses.


In this study, the ability of l-METH and, for comparison, d-METH to engender self-administration in experimentally naïve rats, as well as to decrease d-METH self-administration and food-maintained responding, was examined.


Male Sprague-Dawley rats were used in 3 separate experiments. In experiment 1, the acquisition of l- or d-METH self-administration followed by dose-response determinations was studied. In experiment 2, rats were trained to self-administer d-METH (0.05 mg/kg/infusion) and, then, various doses of l- or d-METH were given acutely prior to the session; the effect of repeated l-METH (30 mg/kg) also was examined. In experiment 3, rats were trained to respond for food reinforcement and, then, various doses of l- or d-METH were given acutely prior to the session; the effect of repeated l-METH (3 mg/kg) also was examined.


Reliable acquisition of l- and d-METH self-administration was obtained at unit doses of 0.5 and 0.05 mg/kg/infusion respectively. The dose-response function for l-METH self-administration was flattened and shifted rightward compared with d-METH self-administration, with peak responding for l- and d-METH occurring at unit doses of 0.17 and 0.025 respectively. l-METH also was approximately 10-fold less potent than d-METH in decreasing d-METH self-administration and 2-fold lower in decreasing food-maintained responding. Tolerance did not occur to repeated l-METH pretreatments on either measure.


As a potential pharmacotherapeutic, l-METH has less abuse liability than d-METH and its efficacy in decreasing d-METH self-administration and food-maintained responding is sustained with repeated treatment.


l-Methamphetamine d-Methamphetamine Self-administration Stimulant use disorders Food reinforcement Dose-response Rat 


Funding information

This study is financially supported by NIH grants K01 DA039306 (SJK), P50 DA05312 (MTB), U01 DA13519 (LPD), U01 DA043908 (LPD), and T32 DA016176 (LPD).

Compliance with ethical standards

All experimental procedures were approved by the Institutional Animal Care and Use Committee at the University of Kentucky and conformed to the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

213_2019_5327_MOESM1_ESM.docx (61 kb)
ESM 1 (DOCX 60 kb)


  1. Banks ML, Hutsell BA, Schwienteck KL, Negus SS (2015) Use of preclinical drug vs. food choice procedures to evaluate candidate medications for cocaine addiction. Curr Treat Options psychiatry 2:136–150CrossRefGoogle Scholar
  2. Beckmann JS, Denehy ED, Zheng G, Crooks PA, Dwoskin LP, Bardo MT (2012) The effect of a novel VMAT2 inhibitor, GZ-793A, on methamphetamine reward in rats. Psychopharmacology 220:395–403CrossRefGoogle Scholar
  3. Bondareva TS, Young R, Glennon RA (2002) Central stimulants as discriminative stimuli. Asymmetric generalization between (-)ephedrine and S(+)methamphetamine. Pharmacol Biochem Behav 74:157–162CrossRefGoogle Scholar
  4. Carroll ME, Lac ST (1993) Autoshaping i.v. cocaine self-administration in rats: effects of nondrug alternative reinforcers on acquisition. Psychopharmacology 110:5–12CrossRefGoogle Scholar
  5. Castells X, Casas M, Perez-Mana C, Roncero C, Vidal X, Capella D (2010) Efficacy of psychostimulant drugs for cocaine dependence. Cochrane Database Syst Rev:Cd007380Google Scholar
  6. Fleckenstein AE, Volz TJ, Riddle EL, Gibb JW, Hanson GR (2007) New insights into the mechanism of action of amphetamines. Annu Rev Pharmacol Toxicol 47:681–698CrossRefGoogle Scholar
  7. Greenwald MK, Lundahl LH, Steinmiller CL (2010) Sustained release d-amphetamine reduces cocaine but not ‘speedball’-seeking in buprenorphine-maintained volunteers: a test of dual-agonist pharmacotherapy for cocaine/heroin polydrug abusers. Neuropsychopharmacology 35:2624–2637CrossRefGoogle Scholar
  8. Harrod SB, Dwoskin LP, Crooks PA, Klebaur JE, Bardo MT (2001) Lobeline attenuates d-methamphetamine self-administration in rats. J Pharmacol Exp Ther 298:172–179PubMedGoogle Scholar
  9. Kohut SJ, Bergman J, Blough BE (2016) Effects of L-methamphetamine treatment on cocaine- and food-maintained behavior in rhesus monkeys. Psychopharmacology 233:1067–1075CrossRefGoogle Scholar
  10. Kohut SJ, Blough BE, Bergman J (2017a) Reinforcing effects of l-methamphetamine in non-human primates. Poster presented at: Annual meeting of the college of problems of drug dependence; June 20th, 2017; San Diego CAGoogle Scholar
  11. Kohut SJ, Jacobs DS, Rothman RB, Partilla JS, Bergman J, Blough BE (2017b) Cocaine-like discriminative stimulus effects of “norepinephrine-preferring” monoamine releasers: time course and interaction studies in rhesus monkeys. Psychopharmacology 234:3455–3465CrossRefGoogle Scholar
  12. Kuczenski R, Segal DS, Cho AK, Melega W (1995) Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioral responses to the stereoisomers of amphetamine and methamphetamine. J Neurosci 15:1308–1317CrossRefGoogle Scholar
  13. Lawlor RB, Trivedi MC, Yelnosky J (1969) A determination of the anorexigenic potential of dl-amphetamine, d-amphetamine, l-amphetamine and phentermine. Arch Int Pharmacodyn Ther 179:401–407PubMedGoogle Scholar
  14. Mendelson J, Uemura N, Harris D, Nath RP, Fernandez E, Jacob P 3rd, Everhart ET, Jones RT (2006) Human pharmacology of the methamphetamine stereoisomers. Clin Pharmacol Ther 80:403–420CrossRefGoogle Scholar
  15. Mooney ME, Herin DV, Specker S, Babb D, Levin FR, Grabowski J (2015) Pilot study of the effects of lisdexamfetamine on cocaine use: a randomized, double-blind, placebo-controlled trial. Drug Alcohol Depend 153:94–103CrossRefGoogle Scholar
  16. Partilla JS, Dempsey AG, Nagpal AS, Blough BE, Baumann MH, Rothman RB (2006) Interaction of amphetamines and related compounds at the vesicular monoamine transporter. J Pharmacol Exp Ther 319:237–246CrossRefGoogle Scholar
  17. Robinson JB (1985) Stereoselectivity and isoenzyme selectivity of monoamine oxidase inhibitors. Enantiomers of amphetamine, N-methylamphetamine and deprenyl. Biochem Pharmacol 34:4105–4108CrossRefGoogle Scholar
  18. Rothman RB, Baumann MH (2003) Monoamine transporters and psychostimulant drugs. Eur J Pharmacol 479:23–40CrossRefGoogle Scholar
  19. Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS (2001) Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse (New York, NY) 39:32–41CrossRefGoogle Scholar
  20. Rush CR, Stoops WW, Sevak RJ, Hays LR (2010) Cocaine choice in humans during D-amphetamine maintenance. J Clin Psychopharmacol 30:152–159CrossRefGoogle Scholar
  21. Sanger DJ, Blackman DE (1976) Rate-dependent effects of drugs: a review of the literature. Pharmacol Biochem Behav 4:73–83CrossRefGoogle Scholar
  22. Shearer J, Wodak A, van Beek I, Mattick RP, Lewis J (2003) Pilot randomized double blind placebo-controlled study of dexamphetamine for cocaine dependence. Addiction 98:1137–1141CrossRefGoogle Scholar
  23. Siemian JN, Xue Z, Blough BE, Li JX (2017) Comparison of some behavioral effects of d- and l-methamphetamine in adult male rats. Psychopharmacology 234:2167–2176CrossRefGoogle Scholar
  24. Sulzer D, Sonders MS, Poulsen NW, Galli A (2005) Mechanisms of neurotransmitter release by amphetamines: a review. Prog Neurobiol 75:406–433CrossRefGoogle Scholar
  25. Wellman PJ (2005) Modulation of eating by central catecholamine systems. Curr Drug Targets 6:191–199CrossRefGoogle Scholar
  26. Yokel RA, Pickens R (1973) Self-administration of optical isomers of amphetamine and methylamphetamine by rats. J Pharmacol Exp Ther 187:27–33PubMedGoogle Scholar
  27. Zheng G, Dwoskin LP, Crooks PA (2006) Vesicular monoamine transporter 2: role as a novel target for drug development. AAPS J 8:E682–E692CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of PsychologyUniversity of KentuckyLexingtonUSA
  2. 2.Department of Pharmaceutical Sciences, College of PharmacyUniversity of KentuckyLexingtonUSA
  3. 3.Research Triangle Institute, Center for Drug DiscoveryResearch Triangle ParkUSA
  4. 4.McLean Hospital - Harvard Medical SchoolBelmontUSA

Personalised recommendations