Skip to main content

Radioligand binding evidence implicates the brain 5-HT2 receptor as a site of action for LSD and phenylisopropylamine hallucinogens

Abstract

Alterations in brain serotonergic function have been implicated in the mechanism of action of LSD, mescaline, and other similarly acting hallucinogenic drugs of abuse such as STP (2,5-dimethoxyphenylisopropylamine; DOM). In order to test the hypothesis that the mechanism of action of LSD and phenylisopropylamine hallucinogens is through stimulation of a specific brain serotonin receptor sub-type, the affinities of these compounds for radiolabelled 5-HT2, 5-HT1A, 5-HT1B, and 5-HT1C receptors have been determined using recently developed in vitro radioligand binding methodologies. The 5-HT2 receptor was labelled with the agonist/hallucinogen radioligand 3H-DOB (4-bromo-2,5-dimethoxyphenylisopropylamine). The 5-HT1A, 5-HT1B, and 5-HT1C receptors were labelled with 3H-OH-DPAT, 3H-5-HT, and 3H-mesulergine, respectively. In general, the phenylisopropylamines displayed 10–100 fold higher affinities for the 5-HT2 receptor than for the 5-HT1C receptor and 100–1000 fold higher affinities for the 5-HT2 receptor than for the 5-HT1A or 5-HT1B receptor. There was a strong correlation between hallucinogenic potencies and 5-HT2 receptor affinities of the phenylisopropylamines (r=0.90); the correlation coefficients for the 5-HT1A, 5-HT1B, and 5-HT1C were 0.73, 0.85, and 0.78, respectively. Because there is no evidence that 5-HT1A-selective or 5-HT1B-selective agonists are hallucinogenic and because the phenylisopropylamines are potent hallucinogens, a 5-HT2 receptor interaction is implicated and supports our previous suggestions to this effect. A secondary role for 5-HT1C receptors cannot be discounted at this time. These results, when integrated with other receptor pharmacological information, indicate that an important component of the mechanism of action of LSD and the phenylisopropylamine hallucinogens is through stimulation of brain 5-HT2 receptors.

This is a preview of subscription content, access via your institution.

References

  • Aghajanian GK, Foote WE, Sheard MH (1968) Lysergic acid diethylamide; sensitive neuronal units in midbrain raphe. Science 161:706–708

    Google Scholar 

  • Aghajanian GK, Foote WE, Sheard MH (1970) Actions of psychotogenic drugs on single midbrain raphe neurons. J Pharmacol Exp Ther 171:178–187

    Google Scholar 

  • Aghajanian GK, Haigler HJ, Bloom FE (1972) Lysergic acid diethylamide and serotonin: direct actions on serotonin-containing neurons in rat brain. Life Sci 11:615–622

    Google Scholar 

  • Battaglia G, Shannon M, Borgundvaag B, Titeler M (1984) Guanyl nucleotide and divalent cation regulation of cortical 5-HT2 serotonin receptors. J Neurochem 43:1213–1219

    Google Scholar 

  • Cheng YC, Prusoff WH (1973) Relationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50% inhibition (I50). Biochem Pharmacol 22:3099–3108

    Article  CAS  PubMed  Google Scholar 

  • DeVivo M, Maayani S (1986) Characterization of the 5-hydroxytryptamine1A receptor-mediated inhibition of forskolin-stimulated adenylate cyclase activity in guinea pig and rat hippocampal membranes. J Pharmacol Exp Ther 238:248–253

    Google Scholar 

  • Gammans RE, Mayol RF, Labudde JA (1986) Metabolism and disposition of buspirone. Am J Med 80:41–51

    Google Scholar 

  • Glennon RA (1987) Site-selective serotonin agonists as discriminative stimuli. In: Colpaert FC, Balster R (eds) Transduction mechanisms of drug stimuli. Springer, Berlin Heidelberg New York Tokyo (in press)

    Google Scholar 

  • Glennon RA, Rosecrans JA, Young R (1984a) Drug-induced discrimination: a description of the paradigm and a review of its specific application to the study of hallucinogenic agents. Med Res Rev 3:289–376

    Google Scholar 

  • Glennon RA, Titeler M, McKenney JD (1984b) Evidence for 5-HT2 receptor involvement in the mechanism of action of hallucinogenic agents. Life Sci 35:2205–2511

    Google Scholar 

  • Lyon RA, Davis KH, Titeler M (1987) 3H-DOB (4-bromo-2,5-dimethoxyphenylisopropylamine) labels a guanyl nucleotide sensitive state of cortical 5-HT2 receptors. Mol Pharmacol 31:194–199

    Google Scholar 

  • McPherson GA (1983) A practical computer-based approach to the analysis of radioligand binding experiments. Comput Programs Biomed 17:107–114

    Google Scholar 

  • Mueller EA, Murphy DL, Sunderland T (1986) Further studies of the putative serotonin agonist m-chlorophenylpiperazine: evidence for a serotonin receptor mediated mechanism of action in humans. Psychopharmacology 89:388–391

    Google Scholar 

  • Nichols DE, Glennon RA (1984) Medicinal chemistry and structure-activity relationships of hallucinogens. In: Jacobs BL (ed) Hallucinogens: neurochemical, behavioral and clinical perspectives. Raven Press, New York, pp 95–142

    Google Scholar 

  • Sanders-Bush E, Conn PJ (1986) Effector systems coupled to 5-HT receptors in brain: 5-HT stimulated phosphatidylinositol hydrolysis. Psychopharmacol Bull 22:829–839

    Google Scholar 

  • Shannon M, Battaglia G, Glennon RA, Titeler M (1984) 5-HT1 and 5-HT2 binding properties of the hallucinogen 1-(2,5-dimethoxyphenyl)2-aminopropane (2,5-DMA). Eur J Pharmacol 102:23–29

    Google Scholar 

  • Shulgin AT (1978) Psychotomimetic drugs: structure-activity relationships. In: Iversen LL, Iversen SD, Snyder SH (eds) Handbook of psychopharmacology, vol 11. Plenum Press, New York, pp 243–333

    Google Scholar 

  • Titeler M (1987) Receptor binding theory and methodology. In: Williams M, Glennon RA, Timmermans PBMW (eds) Receptor pharmacology and function. Dekker, New York (in press)

    Google Scholar 

  • Titeler M, Battaglia G, Shannon M (1984) Guanine nucleotides modulate cortical 5-HT2 receptors. J Receptor Res 7:705–712

    Google Scholar 

  • Titeler M, Herrick K, Lyon RA, McKenney JD, Glennon RA (1985) 3H-DOB: a specific agonist radioligand for 5-HT2 serotonin receptors. Eur J Pharmacol 117:145–146

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Additional information

Offprint requests to: M. Titeler

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Titeler, M., Lyon, R.A. & Glennon, R.A. Radioligand binding evidence implicates the brain 5-HT2 receptor as a site of action for LSD and phenylisopropylamine hallucinogens. Psychopharmacology 94, 213–216 (1988). https://doi.org/10.1007/BF00176847

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00176847

Key words

  • 5-HT2 receptor
  • LSD
  • Phenylisopropylamines
  • Hallucinogens