, Volume 121, Issue 3, pp 364–372 | Cite as

The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of hallucinogenic drugs III: the mechanistic basis for supersensitivity to the LSD stimulus following serotonin depletion

  • D. Fiorella
  • S. Helsley
  • D. S. Lorrain
  • R. A. Rabin
  • J. C. Winter
Original Investigation


The present study was designed to determine the effects ofp-chlorophenylalanine (PCPA) andp-chloroamphetamine (PCA) administration on (1) the levels of serotonin (5-hydroxytryptamine, 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in rat brain, (2) the sensitivity of LSD-trained rats to the stimulus effects of LSD, and (3) the maximal levels of 5-HT2A and 5-HT2C receptor mediated phosphoinositide (PI) hydrolysis in rat brain. PCA and PCPA both produced a significant depletion of whole brain 5-HT and 5-HIAA concentrations. The depletion of serotonin with PCPA, but not PCA, resulted in supersensitivity of LSD-trained subjects to the stimulus effects of LSD. Neither PCPA nor PCA treatment altered the maximal level of 5-HT2A receptor-mediated PI hydrolysis. However, PCPA, but not PCA, treatment resulted in a significant upregulation (46%,P<0.05) of the maximal level of 5-HT2C receptor mediated PI hydrolysis. These data suggest that upregulation of the 5-HT2C receptor mediates the supersensitivity to LSD discriminative stimulus which follows the depletion of central nervous system serotonin by PCPA.

Key words

Serotonin Hallucinogens LSD p-Chloroamphetamine (PCA) p-Chlorophenylalanine (PCPA) Drug-induced stimulus control Phosphoinositide hydrolysis 5-HT2A 5-HT2C 


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  1. Aghajanian G, Foote WE, Sheard MH (1968) Lysergic acid diethylamide: Sensitive neuronal units in the midbrain raphe. Science 161:706–708Google Scholar
  2. Appel JB, Freedman DX (1964) Chemically-induced alterations in the behavioral effects of LSD-25. Biochem Pharmacol 13:861–869Google Scholar
  3. Appel JB, Lovell RA, Freedman DX (1970a) Alterations in the behavioral effects of lysergic acid diethylamide by pretreatment withp-chlorophenylalanine and alpha-methyl-p-tyrosine. Psychopharmacologia 18:387–406Google Scholar
  4. Appel JB, Sheard MH, Freedman DX (1970b) Alterations in the behavioral effects of LSD by midbrain raphe lesions. Commun Behav Biol 5:237–241Google Scholar
  5. Appel JB, Joseph JA, Utsey E, Hernardez LL, Boggan WO (1977) Sensitivity to psychoactive drugs and the serotonergic neuronal system. Commun Psychopharmacol 1:541–551Google Scholar
  6. Appel JB, White FJ, Holohean AM (1982) Analyzing mechanisms of hallucinogenic drug action with drug discrimination procedures. Neurosci Biobehav Rev 6:529–536Google Scholar
  7. Baumgarten HG (1973) Evaluation of the effects of 5,7-DHT on serotonin and CA neurons in the rat CNS. Acta Physiol Scand Suppl 391:3–9Google Scholar
  8. Berendsen HHG, Broekkamp CLE, Van Delft AML (1991) Depletion of brain serotonin differentially affects behaviors induced by 5-HT1A, 5-HT1C and 5-HT2 receptor activation in rats. Behav Neural Biol 55:214–226Google Scholar
  9. Berridge MJ, Downes PC, Hanley MR (1982) Lithium amplifies agonist-dependent phosphatidylinositol responses in brain and salivary glands. J Biochem 206:587–595Google Scholar
  10. Bertilsson L, Koslow SH, Costa E (1975) 5-hydroxytryptamine depletion in mesencephalic nuclei of rat brain following a single injection ofp-chloroamphetamine. Brain Res 91:348–350Google Scholar
  11. Bjorkland A, Baumgarten HB, Rensch A (1975) 5,7-Dihydroxytryptamine: improvement of its selectivity for serotonin neurons in the CNS by pretreatment with desipramine. J Neurochem 24:833–835Google Scholar
  12. Blackshear MA, Steranka LR, Sanders-Bush E (1981) Multiple serotonin receptors: regional distribution and effect of raphe lesions. Eur J Pharmacol 76:325–334Google Scholar
  13. Browne RG, Ho BT (1975) Role of serotonin in the discriminative stimulus properties of mescaline. Pharmacol Biochem Behav 3:429–435Google Scholar
  14. Burris KD, Breeding M, Sanders-Bush E (1991) (+)Lysergic acid diethylamide, but not its non-hallucinogenic congeners, is a potent serotonin 5-HT1C receptor agonist. J Pharmacol Exp Ther 258:891–896Google Scholar
  15. Callahan PM, Cunningham KA (1994) Involvement of 5-HT2C receptors in mediating the discriminative stimulus properties ofm-chlorophenylpiperazine. Eur J Pharmacol 257:27–38Google Scholar
  16. Cameron OG, Appel JB (1973) A behavioral and pharmacological analysis of some of the discriminable properties ofd-LSD in rats. Psychopharmacologia 33:117–134Google Scholar
  17. Colpaert FC, Niemegeers CJE, Kuyps JJMD, Janssen PAJ (1977) Narcotic cue and narcotic state: differential involvement in brain 5-hydroxytryptamine. Neuropharmacology 16:65–70Google Scholar
  18. Commissaris R, Lyness WH, Rech RH, Moore KE (1979) Central aminergic neuronal systems and the behavioral effects of hallucinogens. Soc Neurosci Abstr 5:2190Google Scholar
  19. Conn PJ, Sanders-Bush E (1986) Regulation of serotonin-stimulated phosphoinositide hydrolysis: relation to the serotonin 5-HT2 binding site. J Neurosci 6:3669–3675Google Scholar
  20. Conn PJ, Sanders-Bush E (1987) Relative efficacies of piperazines at the phosphoinositide hydrolysis-linked serotonergic (5-HT2 and 5- HT1C) receptors. J Pharmacol Exp Ther 242:552–557Google Scholar
  21. Conn PJ, Janowsky A, Sanders-Bush E (1987) Denervation supersensitivity of the 5-HT1C receptors in rat choroid plexus. Brain Res 400:396–398Google Scholar
  22. Fiorella D, Rabin RA, Winter JC (1995a) The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects ofm-chlorophenylpiperazine. Psychopharmacology 119:222–230Google Scholar
  23. Fiorella D, Palumbo PA, Rabin RA, Winter JC (1995b) The time dependent stimulus effects of (−)2,5-dimethoxy-4-methylamphetamine: implications for drug-induced stimulus controls as a method for the study of hallucinogenic drugs. Psychopharmacology 119:239–245Google Scholar
  24. Fiorella D, Rabin RA, Winter JC (1995c) The role of the 5-HT2A and 5- HT2C receptors in the stimulus effects of hallucinogenic drugs I: Antagonist correlation analysis. Psychopharmacology (in press)Google Scholar
  25. Fiorella D, Rabin RA, Winter JC (1995d) The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of hallucinogenic drugs II: Reassessment of LSD false positives. Psychopharmacology (in press)Google Scholar
  26. Freedman DX (1961) Effects of LSD-25 on brain serotonin. J Pharmacol Exp Ther 134:160–166Google Scholar
  27. Fuxe K, Ogren S, Agnati LF, Jonsson G, Gustafsson J (1978) 5,7-Dihydroxytryptamine as a tool to study the functional role of central 5-hydroxytryptamine neurons. Ann NY Acad Sci 305L:346–369Google Scholar
  28. Glennon RA (1990) Do hallucinogens act as 5-HT2 agonists or antagonists? Neuropsychopharmacology 3:509–517Google Scholar
  29. Glennon RA (1994) Classical hallucinogens: an introductory overview. In: Lin GC, Glennon RA (eds) Hallucinogens, an update. NIDA Research Monograph 146, Washington, DC, pp 4–32Google Scholar
  30. Glennon RA, Dukat M (1991) Serotonin receptors and their ligands: a lack of selective agents. Pharmacol Biochem Behav 40:1009–1016Google Scholar
  31. Glennon RA, Hauck AE (1985) Mechanistic studies on DOM as a discriminative stimulus. Pharmacol Biochem Behav 23:937–941Google Scholar
  32. Glennon RA, Darmani NA, Martin BR (1991) Multiple populations of serotonin receptors may modulate the behavioral effects of serotonergic agents. Life Sci 48:2493–2498Google Scholar
  33. Hall H, Wedel I (1985) The effects of manipulation of presynaptic 5-HT nerve terminals on postsynaptic 5-HT1 and 5-HT2 binding sites of the rat brain. J Neural Transm 64:129–143Google Scholar
  34. Harvey JA, McMaster SE, Yunger LM (1975)p-Chloroamphetamine: selective neurotoxic action in brain. Science 187:841–843Google Scholar
  35. Ismaiel AM, De Los Angeles J, Titeler M, Ingher S, Glennon RA (1993) Antagonism of the 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane stimulus with a newly identified 5-HT2- versus 5-HT1C-selective antagonist. J Med Chem 36:2519–2525Google Scholar
  36. Jacobs BL (1987) How hallucinogenic drugs work. Am Sci 75:386–392Google Scholar
  37. Jarbe TUC, Johansson JO, Henriksson DG (1975) Drug discrimination in rats: the effects of phencyclidine and ditran. Psychopharmacologia 42:33–39Google Scholar
  38. Jequier E, Lovenberg W, Sjoerdsma A (1967) Tryptophan hydroxylase inhibition: the mechanism by whichp-chlorophenylalanine depletes rat brain serotonin. Mol Pharmacol 3:274–278Google Scholar
  39. Joseph JA, Appel JB (1976) Alterations in the behavioral effects of LSD by motivational and neurohumoral variables. Pharmacol Biochem Behav 5:35–37Google Scholar
  40. Joseph JA, Appel JB (1977) Behavioral sensitivity of LSD: dependency upon the pattern of central 5-HT depletion. Pharmacol Biochem Behav 6:499–504Google Scholar
  41. Kalkman HO (1990) Discriminative stimulus properties of 8-OH-DPAT in rats are not altered by pretreatment withpara-chlorophenylalanine. Psychopharmacology 101:39–42Google Scholar
  42. Koe BK, Weisman A (1966)p-Chlorophenylalanine: a specific depletor of brain serotonin. J Pharmacol Exp Ther 154:499–516Google Scholar
  43. Kohler C, Ross SB, Sebro B, Ogren SO (1978) Long-term biochemical and behavioral effects ofp-chloroamphetamine in the rat. Ann NY Acad Sci 305:645–663Google Scholar
  44. Leysen (1990) Gaps and peculiarities in 5-HT2 receptor studies. Neuropsychopharmacology 3:361–369Google Scholar
  45. Lorrain DS, Hull EM (1993) Nitric oxide increases dopamine and serotonin release in the medial preoptic area. Neuro Report 5:87–89Google Scholar
  46. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275Google Scholar
  47. Lucki I (1992) 5-HT1 receptors and behavior. Neurosci Biobehav Rev 16:83–93Google Scholar
  48. Lucki I, Ward HR, Frazer A (1989) Effect of 1-(m-chlorophenyl) piperazine and 1-(m-trifluoromethylphenyl) piperazine on locomotor activity. J pharmacol Exp Ther 249:155–164Google Scholar
  49. Meek JL (1978) Studies of serotonin neurotoxins in discrete brain nuclei. Ann NY Acad Sci 305:190–196Google Scholar
  50. Neckers LH, Bertilsson L, Koslow SH, Meek JL (1976) Reduction of tryptophan hydroxylase activity and 5-hydroxytryptamine concentrations in certain rat brain nuclei afterp-chloroamphetamine. J Pharmacol Exp Ther 196:333–338Google Scholar
  51. Pranzatelli MR (1990) Neonatal 5,7-DHT lesions upregulate (3H)mesulergine-labelled spinal 5-HT1C binding sites in the rat. Brain Res Bull 25:151–153Google Scholar
  52. Quick M, Azmita E (1983) Selective destruction of serotonergic fibers of the fornix-fimbria and cingulum bundle increases 5HT1, but not 5HT2 receptors in rat midbrain. Eur J Pharmacol 90:377–384Google Scholar
  53. Resnick O, Krus DM, Raskin M (1965) Accentuation of the psychological effects of LSD-25 in normal subjects treated with reserpine. Life Sci 4:1433–7Google Scholar
  54. Sahin-Erdemli I, Schoeffter P, Hoyer D (1991) Competitive antagonism by recognized 5-HT2 receptor antagonists at 5-HT1C receptors in pig choroid plexus. Naunyn-Schmiedeberg's Arch Pharmacol 244:137–142Google Scholar
  55. Sanders-Bush E, Breeding M (1988) Putative selective 5-HT2 receptor antagonists block serotonin 5-HT1C receptors. J Pharmacol Exp Ther 247:169–173Google Scholar
  56. Sanders-Bush E, Burris KD, Knoth K (1988) Lysergic acid diethylamide and 2,5-dimethoxy-4-methamphetamine are partial agonists at serotonin receptors linked to phosphoinositide hydrolysis. J Pharmacol Exp Ther 246:924–928Google Scholar
  57. Schechter MD (1991) Effect of serotonin depletion byp-chlorophenylalanine upon discriminative behaviors. Gen Pharmacol 22:889–893Google Scholar
  58. Schechter MD, Rosecrans JA (1972) Nicotine as a discriminative stimulus in rats depleted of norepinephrine or 5-hydroxytryptamine. Psychopharmacologia 24:417–429Google Scholar
  59. Schreiber R, Brocco M, Millan MJ (1994) Blockade of the discriminative stimulus effects of DOI and MDL 100,907 and the “atypical” antipsychotics, clozapine and risperidone. Eur J Pharmacol 264:99–102Google Scholar
  60. Titeler M, Lyon RA, Glennon RA (1988) Radioligand binding evidence implicates the brain 5-HT2 receptors as a site of action for LSD and phenylisopropylamine hallucinogens. Psychopharmacology 94:213–216Google Scholar
  61. Van Wijngaarden I, Tulp MTM, Soudijin W (1990) The concept of selectivity in 5-HT research. Eur J Pharmacol 188:301–312Google Scholar
  62. White FJ, Simmons MA, West KB, Holohean AM, Appel JB (1980) The effect of serotonin depletion on the discriminability of LSD. Pharmacol Biochem Behav 13:569–574Google Scholar
  63. Winter JC (1994) The stimulus effects of serotonergic hallucinogens in animals. In: Lin GC, Glennon RA (eds) Hallucinogens, an update. NIDA Research Monograph 146, Washington, DC, pp 157–182Google Scholar
  64. Winter JC, Rabin RA (1993) The stimulus effects ofm-chlorophenylpiperazine in the rat. Pharmacol Biochem Behav 45:221–225Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • D. Fiorella
    • 1
  • S. Helsley
    • 1
  • D. S. Lorrain
    • 1
  • R. A. Rabin
    • 1
  • J. C. Winter
    • 1
  1. 1.Department of Pharmacology and Toxicology, School of Medicine and Biomedical SciencesState University of New York at BuffaloBuffaloUSA

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