, Volume 74, Issue 1, pp 23–28 | Cite as

Self-stimulation and amphetamine: Tolerance to d and l isomers and cross tolerance to cocaine and methylphenidate

  • Nancy J. Leith
  • Robert J. Barrett
Original Investigations


The effects of the d and l isomers of amphetamine on self-stimulation responding were tested following acute and chronic administration. Tolerance and post-drug depression of responding occurred in tests with both isomers, indicating no role for p-hydroxynorephedrine (PHN) which is one of the metabolites of d-amphetamine. In the second experiment, d-amphetamine, methylphenidate and cocaine all produced quantitatively and qualitatively similar effects on self-stimulation responding following acute administration. Following chronic administration of d-amphetamine, animals showed tolerance to all three drugs, indicating cross-tolerance among them. These data are consistent with an hypothesis that tolerance and post-drug depression following chronic amphetamine treatment are the result of decreases in postsynaptic receptor sensitivity, which would lead to a decreased effectiveness of all three drugs, regardless of their pre-synaptic mechanisms.

Key words

Self-stimulation d-Amphetamine l-Amphetamine Methylphenidate Cocaine Tolerance Post-drug depression p-Hydroxynorephedrine 


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  1. Anderson JL, Leith NJ, Barrett RJ (1978) Tolerance to amphetamine's facilitation of self-stimulation responding: anatomical specificity. Brain Res 145:37–48Google Scholar
  2. Arbuthnott G, Fuxe K, Ungerstedt U (1971) Central catecholamine turnover and self-stimulation behavior. Brain Res 27:406–413Google Scholar
  3. Barrett RJ, White DK (1980) Reward system depression following chronic amphetamine: antagonism by haloperidol. Pharmacol Biochem Behav 13:555–559Google Scholar
  4. Brodie BB, Cho AK, Gessa GL (1970) Possible role of p-hydroxynorephedrine in the depletion of norepinephrine induced by d-amphetamine and in tolerance to this drug. In: Costa E, Garattini S (eds) Amphetamines and related compounds. Raven Press, New York, p 217Google Scholar
  5. Campbell JC, Seiden LS (1973) Performance influence on the development of tolerance to amphetamine. Pharmacol Biochem Behav 1:703–708Google Scholar
  6. Goldstein M, Anagnoste B (1965) The conversion in vivo of d-amphetamine to (+) p-hydroxynorephedrine. Biochem Biophys Acta 107:166–168Google Scholar
  7. Goldstein A, Aronow L, Kalman SM (1974) Principles of drug action. Wiley, New York, p 569Google Scholar
  8. Kokkinidis L, Anisman H (1978) Behavioral specific tolerance following chronic d or l-amphetamine treatment: lack of involvement of p-hydroxynorephedrine. Neuropharmacology 17:95–102Google Scholar
  9. Kokkinidis L, Walsh MD, Lahue R, Anisman H (1976) Tolerance to d-amphetamine: behavioral specificity. Life Sci 18:913–918Google Scholar
  10. König JFR, Klippel RA (1963) The rat brain. Williams and Wilkins. BaltimoreGoogle Scholar
  11. Kosman ME, Unna KR (1968) Effects of chronic administration of the amphetamines and other stimulants on behavior. Clin Pharmacol Ther 9:240–254Google Scholar
  12. Leith NJ, Barrett RJ (1976) Amphetamine and the reward system: evidence for tolerance and post-drug depression. Psychopharmacologia 46:19–25Google Scholar
  13. Leith NJ, Barrett RJ (1980) Effects of chronic amphetamine or reserpine on self-stimulation responding: animal model of depression? Psychopharmacology 72:9–15Google Scholar
  14. Leith NJ, Kuczenski R (1979) Behavioral and biochemical studies of amphetamine tolerance and reverse tolerance. Society for Neuroscience Abstract 5:653Google Scholar
  15. Lewander T (1971) Displacement of brain and heart noradrenaline by p-hydroxynorephedrine after administration of p-hydroxyamphetamine. Acta Pharmacol Toxicol 29:20–32Google Scholar
  16. Lewander T (1972) On the accumulation of p-hydroxynorephedrine in noradrenalin neurons during chronic administration of amphetamine in the rat in relation to amphetamine tolerance. Psychiat Neurol Neurochir 75:215–218Google Scholar
  17. Lu TC, Ho BT, McIssac WM (1972) Effects of repeated administration of dl-amphetamine and methamphetamine on tolerance to hyperactivity. Experientia 28:1461Google Scholar
  18. Magour S, Coper H, Fähndrich Ch (1973) The effects of chronic treatment with d-amphetamine on food intake, body weight, locomotor activity and subcellular distribution of the drug in rat brain. Psychopharmacologia 34:45–54Google Scholar
  19. Mobley PL, Sanders-Bush E, Smith HE, Sulser F (1979) Modification of the noradrenergic cyclic AMP generating system in the rat limbic forebrain by amphetamine: role of its hydroxylated metabolites. Naunyn-Schmiedebergs Arch Pharmacol 306:267–273Google Scholar
  20. Moore KE, Chiueh CC, Zeldes G (1977) Release of neurotransmitters from the brain in vivo by amphetamine, methylphenidate and cocaine. In: Ellinwood EH, Jr, Kilbey MM (eds) Cocaine and other stimulants. Plenum Press, New York, p 143Google Scholar
  21. Scheel-Krüger J (1971) Comparative studies of various amphetamine analogues demonstrating different interactions with the metabolism of the catecholamines in the brain. Eur J Pharmacol 14:47–59Google Scholar
  22. Schuster CR, Zimmerman J (1961) Timing behavior during prolonged treatment with dl-amphetamine. J Exp Anal Behav 4:327–330Google Scholar
  23. Segal DS (1975) Behavioral and neurochemical correlates of repeated d-amphetamine administration. In: Mandell AJ (ed) Neurobiological mechanisms of adaptation and behavior. Raven Press. New York, p 247Google Scholar
  24. Sparber SB, Tilson HA (1972) Tolerance and cross-tolerance to mescaline and amphetamine as a function of central and peripheral administration. Psychopharmacologia 23:220–230Google Scholar
  25. Taylor D, Ho BT (1978) Comparison of inhibition of monoamine uptake by cocaine, methylphenidate and amphetamine. Res Commun. Chem Pathol Pharmacol 21:67–75Google Scholar
  26. Thoenen H, Hürlimann A, Gey KF, Haefley W (1966) Liberation of p-hydroxynorephedrine from cat spleen by sympathetic nerve stimulation after pretreatment with amphetamine. Life Sci 5:1715–1722Google Scholar
  27. Wise CD, Stein L (1970) Amphetamine: facilitation of behavior by augmented release of norephinephrine from the medial forebrain bundle. In: Costa E, Garattini S (eds) Amphetamines and related compounds. Raven Press, New York, p 463Google Scholar
  28. Wise CD, Berger BD, Stein L (1973) Evidence of alpha-noradrenergic reward receptors and serotonergic punishment receptors in rat brain. Biol Psychiatry 6:3–21Google Scholar
  29. Wise RA (1978) Catecholamine therories of reward: a critical review. Brain Res 152:215–247Google Scholar

Copyright information

© Springer-Verlag 1981

Authors and Affiliations

  • Nancy J. Leith
    • 1
    • 2
  • Robert J. Barrett
    • 1
    • 2
  1. 1.Department of PharmacologyVanderbilt University Medical SchoolUSA
  2. 2.Psychology Research LaboratoriesVeterans Administration Hospital NashvilleUSA

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