, Volume 76, Issue 1, pp 29–35 | Cite as

Discriminative stimulus properties of l-5-hydroxytryptophan: Behavioral evidence for multiple serotonin receptors

  • Robert J. Barrett
  • M. Ann Blackshear
  • Elaine Sanders-Bush
Original Investigations


Rats were trained to discriminate the stimulus properties of l-5-hydroxytryptophan (l-5-HTP) (30 mg/kg SC), the immediate precursor of serotonin (5-HT). The peripheral decarboxylase inhibitor R04-4602, administered prior to l-5-HTP, greatly attenuated the disruptive effects observed on responding when l-5-HTP alone was injected. Following acquisition, the discrimination was dosedependent and generalized to fenfluramine, a 5-HT-releasing drug, but not to amphetamine, a catecholamine-releasing agent. Further evidence for the involvement of 5-HT receptor stimulation in mediating the discrimination was that pretreatment with fluoxetine, a highly specific 5-HT uptake inhibitor, markedly potentiated the cue. Nevertheless, the classical 5-HT antagonists methysergide, cyproheptadine, metergoline, and methiothepin did not block the l-5-HTP-related discriminative stimulus. This finding suggested that the cue properties of l-5-HTP might be mediated by a population of 5-HT receptors previously identified electrophysiologically in limbic structures. As in the present experiment, the putative 5-HT antagonists did not block the synaptic effects of 5-HT in these structures.

Key words

l-5-HTP Serotonin antagonists Drug discrimination Multiple serotonin receptors 


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  1. Aprison MH, Ferster CB (1960) Behavioral effects of 5-hydroxytryptophan. Experientia 16:159–162Google Scholar
  2. Aprison MH, Ferster CB (1961) Neurochemical correlates of behavior. I. Quantitative measurement of the behavioral effects of the serotonin precursor. J Pharmacol Exp Ther 131:100–107Google Scholar
  3. Bedard P, Pycock CJ (1977) Wet-dog shake behavior in the rat: A possible quantitative model of central 5-hydroxytryptamine activity. Neuropharmacology 16:663–670Google Scholar
  4. Browne RG (1978) The role of serotonin in the discriminative stimulus properties of mescaline. In: Ho BT, Richards DN, Chute DL (eds) Drug discrimination and state-dependent learning. Academic Press, New York, pp 79–101Google Scholar
  5. Browne RG, Ho BT (1975) Discriminative stimulus properties of mescaline: Mescaline or metabolite? Pharmacol Biochem Behav 3:109–114Google Scholar
  6. Butcher LL, Engel J, Fuxe K (1972) Behavioral, biochemical and histochemical analyses of the central effects of monoamine precursors after peripheral decarboxylase inhibition. Brain Res 41:387–411Google Scholar
  7. Carlsson A, Davis JN, Kehr W, Lindqvist M, Atack CV (1972) Simultaneous measurement of tyrosine and tryptophan hydroxylase activities in brain in vivo using an inhibition of the aromatic amino acid decarboxylase. Naunyn-Schmiedeberg's Arch Pharmacol 275: 153–168Google Scholar
  8. Carter RB, Appel JB (1976) Blockade of the behavioral effects of 5-HTP by the decarboxylase inhibitor R04-4602. Pharmacol Biochem Behav 4:407–409Google Scholar
  9. Carter RB, Dykstra LA, Leander JD, Appel JB (1978) role of peripheral mechanisms in the behavioral effects of 5-hydroxytryptophan. Pharmacol Biochem Behav 9:240–253Google Scholar
  10. Corne SJ, Pickerine RW, Wagner BT (1963) A method for assessing the effects of drugs on the central actions of 5-hydroxytryptamine. Br J Pharmacol 20:106–120Google Scholar
  11. Fuller RW, Snoddy HD, Molloy BB (1975) Potentiation of the l-5-hydroxytryptophan-induced elevation of plasma corticosterone levels in rats by a specific inhibition of serotonin uptake. Res Commun Chem Pathol Pharmacol 10:193–196Google Scholar
  12. Fuller RW, Perry KW, Molloy BB (1974) Effect of an uptake inhibitor on serotonin metabolism in rat brain: Studies with 3-(trifluoro-methylphenoxy)-N-methyl-3-phenylpropylamine (Lilly 110140). Life Sci 15:1161–1171Google Scholar
  13. Glennon RA, Rosecrans JA, Young R, Gaines J (1979) Hallucinogens as discriminative stimuli: Generalization of DOM to a 5-methoxy-N,N-dimethyltryptamine stimulus. Life Sci 24:993–998Google Scholar
  14. Greenberg I, Kuhn DM, Appel JB (1975) Behaviorally induced sensitivity to the discriminable properties of LSD. Psychopharmacologia 43:229–232Google Scholar
  15. Gyermek L (1961) 5-Hydroxytryptamine antagonists. Pharmacol Rev 13:399–439Google Scholar
  16. Haigler HJ, Aghajanian GK (1974) Peripheral serotonin antagonists: Lack of antagonism of serotonin at identified serotonergic synapses in rat brain. J Neurol Transm 35:257–273Google Scholar
  17. Jacobs BL (1976) Minireview: An animal behavior model for studying serotonergic synapses. Life Sci 19:777–786Google Scholar
  18. Jacobs BL, Klemfuss H (1975) Brain stem and spinal cord mediation of a serotonergic behavioral syndrome. Brain Res 100:450–457Google Scholar
  19. Kuhn DM, White FJ, Appel JB (1978) The discriminative stimulus properties of LSD: Mechanisms of action. Neuropharmacology 17:257–263Google Scholar
  20. Matthews WD, Smith CD (1980) Pharmacological profile of a model for central serotonin receptor activation. Life Sci 26:1397–1403Google Scholar
  21. McCall RB, Aghajanian GK (1979) Serotonergic facilitation of facial motoneuron excitation. Brain Res 169:11–27Google Scholar
  22. Nagayama H, Hingtgen JN, Aprison MH (1980) Pre- and postsynaptic serotonergic manipulations in an animal model of depression. Pharmacol Biochem Behav 13:575–579Google Scholar
  23. Ng LKY, Chase TN, Colburn RW, Kopin IJ (1972) Release of 3H-dopamine by l-5-hydroxytryptophan. Brain Res 45:499–505Google Scholar
  24. Peroutka SJ, Snyder SH (1979) Multiple serotonin receptors: Differential binding of 3H-5-hydroxytryptamine, 3H-lysergic acid diethylamide and 3H-spiroperidol. Mol Pharmacol 16:687–699Google Scholar
  25. Porter CC (1971) Aromatic amino acid decarboxylase inhibitors. Fed Proc 30:871–876Google Scholar
  26. Rosecrans JA, Glennon RA (1979) Drug-induced cues in studying mechanisms of drug action. Neuropharmacology 18:981–989Google Scholar
  27. Sloviter RS, Drust EG, Conner JD (1978) Specificity of a rat behavioral model for serotonin receptor activation. J Pharmacol Exp Ther 206:339–347Google Scholar
  28. Tessel RE, Rutledge CO (1976) Specificity of release of biogenic amines from isolated rat brain tissue as a function of the meta-substituent of N-ethylamphetamine derivatives. J Pharmacol Exp Ther 197:253–262Google Scholar
  29. Trulson ME, Jacobs BL, (1976) Behavioral evidence for the rapid release of CNS serotonin by PCA and fenfluramine. Eur J Pharmacol 36:149–154Google Scholar
  30. Wang RY, Aghajanian GK (1977) Inhibition of neurons in the amygdala by dorsal raphe stimulation: Mediation through a direct serotonergic pathway. Brain Res 120:85–102Google Scholar
  31. White FJ, Appel JB, Kuhn DM (1979) Discriminative stimulus properties of quipazine: Direct serotonin mediation. Neuropharmacology 18:143–151Google Scholar
  32. White FJ, Kuhn DM, Appel JB (1977) Discriminative stimulus properties of quipazine. Neuropharmacology 16:827–832Google Scholar
  33. Winter JC (1975) Blockade of the stimulus properties of mescaline by a serotonin antagonist. Arch Int Pharmacodyn Ther 214:250–253Google Scholar
  34. Winter JC (1979) Quipazine-induced stimulus control in the rat. Psychopharmacology 60:265–269Google Scholar

Copyright information

© Springer-Verlag 1982

Authors and Affiliations

  • Robert J. Barrett
    • 1
  • M. Ann Blackshear
    • 2
    • 3
  • Elaine Sanders-Bush
    • 2
    • 3
  1. 1.Veterans Administration Medical Center and Departments Psychology and PharmacologyVanderbilt UniversityNashvilleUSA
  2. 2.Department of PharmacologyVanderbilt University School of MedicineNashvilleUSA
  3. 3.Tennessee Neuropsychiatric InstituteNashvilleUSA

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