Release of Neurotransmitters from the Brain in Vivo by Amphetamine, Methylphenidate and Cocaine

  • K. E. Moore
  • C. C. Chiueh
  • G. Zeldes
Part of the Advances in Behavioral Biology book series (ABBI, volume 21)


During the past 15 years the results of indirect in vivo and direct in vitro studies suggest that a variety of central stimulant drugs exert their characteristic pharmacological effects by interacting with aminergic neuronal systems in the brain. Early behavioral and biochemical experiments indicated that amphetamines exerted central stimulant actions by releasing norepinephrine (Stein, 1964; Carr and Moore, 1969), but more recent studies suggest that the release of dopamine is more important for many of the central actions of this drug (e.g., Carlsson, 1970; Thornburg and Moore, 1937b; Hollister, Breese, and Cooper, 1974). Since the central stimulation of amphetamine is blocked by α-methyltyrosine but not by reserpine (Rech, 1964; Smith, 1965; Weissman, Koe, and Tenen, 1966), it has been postulated that amphetamine acts by preferentially releasing dopamine from a newly synthesized pool of this amine in the nerve terminals. On the other hand, the central stimulant actions of methylphenidate and cocaine are reduced by reserpine pretreatment but not by α-methyltyrosine (van Rossum, van der Schoot, and Hurkmans, 1962; Scheel-Krüger, 1971; Simon, Sultan, Chermat, and Boissier, 1972) suggesting that the actions of these two stimulants are dependent upon a storage or reserpine-sensitive pool of brain catecholamines. There has been less interest in the interactions of these central stimulants with 5-hydroxytryptamine (5HT) neuronal systems, but recent behavioral-biochemical studies (Green and Harvey, 1974; Breese, Cooper, and Mueller, 1974) suggest that tryptaminergic neurons exert an inhibitory action on amphetamine stimulation; there are few reports on the interactions of cocaine or methylphenidate with 5HT neurons.


Tyrosine Hydroxylase Caudate Nucleus Nigrostriatal Pathway Central Stimulant Brain Catecholamine 


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  1. Azzaro, A.J. and Rutledge, C.O.: Selectivity of release of nor-epinephrine, dopamine and 5-hydroxytryptamine by amphetamine in various regions of rat brain, Biochem. Pharmacol. 22, 2801–2813 (1973).PubMedCrossRefGoogle Scholar
  2. Azzaro, A.J., Ziance, R.J., and Rutledge, C.O.: The importance of neuronal uptake of amines for amphetamine-induced release of 3H-norepinephrine from isolated brain tissue, J. Pharmac. exp. Ther. 189, 110–118 (1974).Google Scholar
  3. Besson, M.J., Cheramy, A., Feltz, P., and Glowinski, J.: Dopamine: Spontaneous and drug-induced release from the caudate nucleus in the cat, Brain Res. 32, 407–424 (1971).Google Scholar
  4. Breese, G.R., Cooper, B.R., and Mueller, R.A.: Evidence for involve- ment of 5-hydroxytryptamine in the actions of amphetamine, Br. J. Pharmacol. 52, 307–314 (1974).PubMedGoogle Scholar
  5. Carlsson, A.: Amphetamine and brain catecholamines. In: Am hetaamines and Related Compounds. Costa, E. and Garattini, 3, Eds., pp. 289–300. New York: Raven Press, 1970.Google Scholar
  6. Carmichael, E.A., Feldberg, W., and Fleischauer, K.: Methods for perfusing different parts of the cat’s cerebral ventricles with drugs, J. Physiol., Lond. 173, 354–367 (1964).PubMedGoogle Scholar
  7. Carr, L.A. and Moore, K.E.: Norepinephrine: Release from brain by d-amphetamine in vivo, Science 164, 322–323 (1969).Google Scholar
  8. Carr, L.A. and Moore, K.E.: Effects of amphetamine on the contents of norepinephrine and metabolites in the effluent of perfused cerebral ventricles of the cat, Biochem. Pharmacol. 19, 2361–2374 (1970).PubMedCrossRefGoogle Scholar
  9. Chiueh, C.C. and Moore, K.E.: Effects of a-methyltyrosine on damphetamine-induced release of endogenously synthesized and exogenously administered catecholamines from the cat brain in vivo,J. Pharmac. exp. Ther. 190, 100–108 (1974a).Google Scholar
  10. Chiueh, C.C. and Moore, K.E.: Relative potencies of d-and 1-amphetamine on the release of dopamine from cat brain in vivo,Res. Comm. Chem. Path. Pharmac. 7, 189–199 (1974b).Google Scholar
  11. Chiueh, C.C. and Moore, K.E.: Blockade by reserpine of methylphenidate-induced release of brain dopamine, J. Pharmac. exp. Ther. 193, 559–563 (1975).Google Scholar
  12. Chiueh, C.C. and Moore, K.E.: Effects of dopaminergic agonists and electrical stimulation of the midbrain raphé on the release of 5-hydroxytryptamine from the cat brain in vivo,J. Neurochem. in press.Google Scholar
  13. Creese, I. and Iversen, S.D.: The pharmacological and anatomical substrates of the amphetamine response in the rat, Brain Res. 83, 419–436 (1975).PubMedCrossRefGoogle Scholar
  14. Ferris, R.M., Tang, F.L.M., and Maxwell, R.A.: A comparison of the capacities of isomers of amphetamine, deoxypipradrol and methylphenidate to inhibit the uptake of tritiated catecholamines into rat cerebral cortex slices, synaptosomal preparations of rat cerebral cortex, hypothalamus and striatum and into adrenergic nerves of rabbit aorta, J. Pharmac. exp. Ther. 181, 407–416 (1972).Google Scholar
  15. Fuxe, K. and Ungerstedt, U.: Histochemical, biochemical and functional studies on central monoamine neurons after acute and chronic amphetamine administration. In: Amphetamines and Related Compounds. Costa, E. and Garattini, S., Eds., pp. 257288. New York: Raven Press, 1970.Google Scholar
  16. Green, T.K. and Harvey, J.A.: Enhancement of amphetamine action after interruption of ascending serotonergic pathways, J. Pharmac. exp. Ther. 190, 109–117 (1974).Google Scholar
  17. Harris, J.E. and Baldessarini, R.J.: Uptake of (3H)-catecholamines by homogenates of rat corpus striatum and cerebral cortex: Effects of amphetamine analogues, Neuropharmacol. 12, 669–179 (1973).Google Scholar
  18. Heikkila, R.E., Orlansky, H., and Cohen, G.: Studies on the distinction between uptake inhibition and release of 3H-dopamine in rat brain tissue slices, Biochem. Pharmacol. 24, 847–852 (1975).PubMedCrossRefGoogle Scholar
  19. Hollister, A.S., Breese, G.R., and Cooper, B.R.: Comparison of tyrosine hydroxylase inhibition with the effects of various 6-hydroxydopamine treatments on d-amphetamine induced motor activity, Psychopharmacologia 36, 1–16 (1974).Google Scholar
  20. Kelly, P.H., Seviour, P.W., and Iversen, S.D.: Amphetamine and apo- morphine responses in the rat following 6-hydroxydopamine lesions of the nucleus accumbens septi and corpus striatum, Brain Res. 94, 507–522 (1975).Google Scholar
  21. McKenzie, G.M. and Szerb, J.C.: The effect of dihydroxyphenylalanine, pheniprazine and dextroamphetamine on the in vivo release of dopamine from the caudate nucleus, J. Pharmac. exp. Ther. 162, 302–308 (1968).Google Scholar
  22. Myers, R.D.: Methods of perfusing different structures of the brain. In: Methods in Psychobiology. Myers, R.D., Ed., Vol. 2, pp. 169–211. New York: Academic Press, 1972.Google Scholar
  23. Rech, R.H.: Antagonism of reserpine behavioral depression by d- amphetamine, J. Pharmac. exp. Ther. 146, 369–376 (1964).Google Scholar
  24. Scheel-Krüger, J.: Comparative studies of various amphetamine analogues demonstrating different interactions with the metabolism of catecholamines in the brain, Eur. J. Pharmacol. 14, 47–59 (1971).PubMedCrossRefGoogle Scholar
  25. Simon, P. Sultan, Z., Chermat, R., and Boissier, J.R.: La cocaine, une substance amphétaminique? Un problème de psychopharmacologie expérimentale, J. Pharmacol. 3, 129–142 (1972).Google Scholar
  26. Smith, C.B.: Effects of d-amphetamine upon brain amine content and locomotor activity of mice, J. Pharmac. exp. Ther. 147, 96–102 (1965).Google Scholar
  27. Stein, L.: Self-stimulation of the brain and the central stimulant action of amphetamine, Fed. Proc. 23, 836–850 (1964).PubMedGoogle Scholar
  28. Taylor, K.M. and Snyder, S.H.: Differential effects of d-and 1-amphetamine on behavior and on catecholamine disposition in dopamine and norepinephrine containing neurons of rat brain, Brain Res. 28, 295–309 (1971).Google Scholar
  29. Thornburg, J.E. and Moore, K.E.: Dopamine and norepinephrine uptake by rat brain synaptosomes: Relative inhibitory potencies of 1- and d-amphetamine and amantadine, Res. Comm. Chem. Path. Pharmac. 5, 81–89 (1973a).Google Scholar
  30. Thornburg, J.E. and Moore, K.E.: The relative importance of dopaminergic and noradrenergic neuronal systems for the stimulation of locomotor activity induced by amphetamine and other drugs, Neuropharmacol .12, 853–866 (1973b).Google Scholar
  31. Ungerstedt, U.: Striatal dopamine release after amphetamine or nerve degeneration revealed by rotational behavior, Acta Physiol. Scand., Suppl. 367, 49–68 (1971).Google Scholar
  32. van Rossum, J.M., van der Schoot, J.B., and Hurkmans, J.A.T.M.: Mechanisms of action of cocaine and amphetamine in the brain, Experientia 18, 229–231 (1962).Google Scholar
  33. Von Voigtlander, P.F. and Moore, K.E.: The release of 3H-dopamine from cat brain following electrical stimulation of the substantia nigra and caudate nucleus, Neuropharmacol. 10, 733–841 (1971a).Google Scholar
  34. Von Voigtlander, P.F. and Moore, K.E.: Nigro-striatal pathway: Stimulation-evoked release of 3H-dopamine from caudate nucleus, Brain Res. 35, 580–583 (1971b).Google Scholar
  35. Von Voigtlander, P.F. and Moore, K.E.: Involvement of nigro-striatal neurons in the in vivo release of dopamine by amphetamine, amantadine and tyramine, J. Pharmac. exp. Ther. 184, 542–552 (1973a).Google Scholar
  36. Von Voigtlander, P.F. and Moore, K.E.: Turning behavior of mice with unilateral 6-hydroxydopamine lesions in the striatum: Effects of apomorphine, L-dopa, amantadine, amphetamine and other psychomotor stimulants, Neuropharmacol. 12, 451–462 (1973b).Google Scholar
  37. Wallach, M.D.: Drug-induced stereotyped behavior: Similarities and differences. In: Neuropsychopharmacology of Monoamines and their Regulatory Enzymes. Usdin, E., Ed., pp. 241–260. New York: Raven Press, 1974.Google Scholar
  38. Weissman, A., Koe, K.B., and Tenen, S.S.: Antiamphetamine effects following inhibition of tyrosine hydroxylase, J. Pharmac. exp. Ther. 151, 339–352 (1966).Google Scholar

Copyright information

© Plenum Press, New York 1977

Authors and Affiliations

  • K. E. Moore
    • 1
  • C. C. Chiueh
    • 1
  • G. Zeldes
    • 1
  1. 1.Michigan State UniversityEast LansingUSA

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