, Volume 118, Issue 4, pp 401–409 | Cite as

LSD and structural analogs: pharmacological evaluation at D1 dopamine receptors

  • V. J. Watts
  • R. B. Mailman
  • C. P. Lawler
  • K. A. Neve
  • D. E. Nichols
Original Investigation


The hallucinogenic effects of lysergic acid diethylamide (LSD) have been attributed primarily to actions at serotonin receptors. A number of studies conducted in the 1970s indicated that LSD also has activity at dopamine (DA) receptors. These latter studies are difficult to interpret, however, because they were completed before the recognition of two pharmacologically distinct DA receptor subtypes, D1 and D2. The availability of subtype-selective ligands (e.g., the D1 antagonist SCH23390) and clonal cell lines expressing a homogeneous receptor population now permits an assessment of the contributions of DA receptor subtypes to the DA-mediated effects of LSD. The present study investigated the binding and functional properties of LSD and several lysergamide analogs at dopamine D1 and D2 receptors. Several of these compounds have been reported previously to bind with high affinity to serotonin 5HT2 (i.e.,3H-ketanserin) sites in the rat frontal cortex (K0.5 5–30 nM). All tested compounds also competed for both D1-like (3H-SCH 23390) and D2-like (3H-spiperone plus unlabeled ketanserin) DA receptors in rat striatum, with profiles indicative of agonists (nH<1.0). The affinity of LSD and analogs for D2 like receptors was similar to their affinity for 5HT2 sites. The affinity for D1 like receptors was slightly lower (2- to 3-fold), although LSD and several analogs bound to D1 receptors with affinity similar to the prototypical D1 partial agonist SKF38393 (K0.5 ca. 25 nM). A second series of experiments tested the binding and functional properties of LSD and selected analogs in C-6 glioma cells expressing the rhesus macaque D1A receptor. LSD and the analogs tested bound to C-6 mD1A cells with affinity and kinetics similar to those obtained in rat straitum. Additionally, LSD and selected analogs were able to increase cAMP accumulation, albeit only as partial agonists. Similar to the actions of SKF38393, they could stimulate, as well as block, DA-stimulated cAMP synthesis. These results represent the first clear demonstration of the interaction of LSD with DA D1 receptors, and provide a basis for evaluating the contribution of D1 receptors to the biobehavioral actions of LSD.

Key words

LSD Lysergic acid diethylamide Hallucinogen Dopamine D1 receptor D2 receptor cAMP synthesis Adenylate cyclase Ergolines Lysergamides 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aghajanian GK (1994) Serotonin and the action of LSD in the brain. Psychiatr Ann 24:137–141Google Scholar
  2. Ahn HS, Makman MH (1979) Interaction of LSD and other hallucinogens with dopamine-sensitive adenylate cyclase in primate brain: regional differences. Brain Res 162:77–88Google Scholar
  3. Appel JB, White FJ, Holohean AM (1982) Analyzing mechanism(s) of hallucinogenic drug action with drug discrimination procedures, Neurosci Biobehav Rev 6:529–536Google Scholar
  4. Berger B (1992) Dopaminergic innervation of the frontal cerebral cortex: evolutionary trends and functional implications. Adv Neurol 57:525–544Google Scholar
  5. Berger B, Gaspar P, Verney C (1991) Dopaminergic innervation of the cerebral cortex: unexpected differences between rodents and primates. Trends Neurosci 14:21–27Google Scholar
  6. Boess FG, Martin IL (1994) Molecular biology of serotonin receptors. Neuropharmacology 33:275–317Google Scholar
  7. Braun AR, Chase TN (1986) Obligatory D-1/D-2 receptor interaction in the generation of dopamine agonist related behaviors. Eur J Pharmacol 131:301–306Google Scholar
  8. Brewster WK, Nichols DE, Riggs RM, Mottola DM, Lovenberg TW, Lewis MH, Mailman RB (1990)trans-10,11-Dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine: a highly potent selective dopamine D1 full agonist. J Med Chem 33:1756–1764Google Scholar
  9. Burt DR, Creese I, Snyder SH (1976) Binding interactions of lysergic acid diethylamide and related agents with dopamine receptors in the brain. Mol Pharmacol 12:631–638Google Scholar
  10. Civelli O, Bunzow JR, Grandy DK, Zhou Q-Y, Van Tol HHM (1991) Molecular biology of the dopamine receptors Eur J Pharmacol 207:277–286Google Scholar
  11. Creese I, Burt DR, Snyder SH (1976) The dopamine receptor: differential binding ofd-LSD and related agents to agonist and antagonist states. Life Sci 17:1715–1720Google Scholar
  12. Christoph GR, Kuhn DM, Jacobs BL (1977) Electrophysiological evidence for a dopaminergic action of LSD: depression of unit activity in the substantia nigra of the rat. Life Sci 21:1585–1596Google Scholar
  13. DaPrada M, Saner A, Burkard WP, Bartholini G, Pletscher A (1975) Lysergic acid diethylamide: evidence for stimulation of cerebral dopamine receptors. Brain Res 94:67–73Google Scholar
  14. Dixon AK (1968) Evidence of catecholaminergic mediation in the “aberrant” behaviour induced by lysergic acid diethylamide (LSD) in the rat. Experienta 15:743–747Google Scholar
  15. Fog R, (1969) Stereotyped and non-stereotyped behaviour in rats induced by various stimulant drugs. Psychopharmacologia 14:299–304Google Scholar
  16. Freedman DX, Boggan WO (1982) Biochemical pharmacology of psychotomimetics. In: Hoffmeister F, Stille G (eds) Psychotropic agents: alcohol and psychotomimetics, psychotropic effects of central acting drugs, vol 55/III. Springer New York, pp 57–88Google Scholar
  17. Garau L, Govoni S, Stefanini E, Trabucchi M, Spano PF (1978) Dopamine receptors: pharmacological and anatomical evidence indicate that two distinct dopamine receptor populations are present in rat striatum. Life Sci 23:1745–1750Google Scholar
  18. Gingrich JA, Caron MG (1993) Recent advances in the molecular biology of dopamine receptors. Annu Rev Neurosci 16:299–321Google Scholar
  19. Glennon R, Titeler M, McKenney JD (1984) Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sci 35:2505–2511Google Scholar
  20. Goldman-Rakic PS, Lidow MS, Smiley JF, Williams MS (1992) The anatomy of dopamine in monkey and human prefrontal cortex. J Neural Transm 36:S163–177Google Scholar
  21. Harper JF, Brooker G (1975) Femtomole sensitive radioimmunoassay for cyclic AMP and cyclic GMP after 2'Oacetylation by acetic anhydride in aqueous solution. J Cyclic Nucl Res 1:207–218Google Scholar
  22. Heffner TG, Hartman JA, Seiden LS (1980) A rapid method for the regional dissection of the rat brain. Pharmacol Biochem Behav 13:453–456Google Scholar
  23. Hoffman AJ, Nichols DE (1985) Synthesis and LSD-like discrimantive stimulus properties in a series ofN(6)-alkyl norlysergic acidN,N-diethylamide derivatives. J Med Chem 28:1252–1255Google Scholar
  24. Holohean AM, White FJ, Appel JB (1982) Dopaminergic and serotonergic mediation of the discriminable effects of ergot alkaloids, Eur J Pharmacol 81:595–602Google Scholar
  25. Hu X-T, Wang RY (1988) Comparison of effects of D-1 and D-2 dopamine receptor agonists on neurons in the rat caudate-putamen: an electrophysiological study. J Neurosci 8:4340–4348Google Scholar
  26. Huang X, Marona-Lewicka D, Pfaff RC, Nichols DE (1994) Drug discrimination and receptor binding studies ofN-isopropyl lysergamide derivatives. Pharmacol Biochem Behav 47:667–673Google Scholar
  27. Joyce JN (1993) The dopamine hypothesis of schizophrenia: limbic interactions with serotonin and norepinephrine. Psychopharmacology 112:S16-S34Google Scholar
  28. Kebabian JW, Calne DB (1979) Multiple receptors for dopamine. Nature 277:93–96Google Scholar
  29. Kenakin TP (1987) Pharmacologic analysis of drug-receptor interaction Raven Press, New YorkGoogle Scholar
  30. Knoerzer TA, Nichols DE, Brewster WK, Watts VJ, Mottola DM, Mailmann RB (1994) Dopaminergic benzo[a]phenanthridines: resolution and pharmacological evaluation of the enantiomers of dihydrexidine, the full efficacy D1 dopamine receptor agonist. J Med Chem 37:2453–2460Google Scholar
  31. Leysen JE, Janssen PMF, Schotte A, Luyten WHML, Megens AAHP (1993) Interaction of antipsychotic drugs with neurotransmitter receptor sites in vitro and in vivo in relation to pharmacological and clinical effects: role of 5HT2 receptors. Psychopharmacology 112:S40-S54Google Scholar
  32. Lovenberg TW, Brewster WK, Mottola DM, Lee RC, Riggs RM, Nichols DE, Lewis MH, Mailman RB (1989). Dihydrexidine, a novel selective high potency full dopamine D1 receptor agonist. Eur J Pharmacol 166:111–113Google Scholar
  33. McKenna DJ, Repke DB, Lo L, Peroutka SJ (1990) Differential interactions of indolealkylamines with 5-hydroxytryptamine receptor subtypes, Neuropharmacology 29:193–198Google Scholar
  34. McPherson GA (1985) Analysis of radioligand binding experiments. A collection of computer programs for the IBM PC. J Pharmacol Methods 14:213–228Google Scholar
  35. McQuadde RD, Duffy RA, Coffin VL, Barnett A (1992) In vivo binding to dopamine receptors: a correlate of potential antipsychotic activity. Eur J Pharmacol 215:29–34Google Scholar
  36. Machida CA, Searles RP, Nipper V, Brown JA, Kozell LB, Neve KA (1992) Molecular cloning and expression of the rhesus macaque D1 dopamine receptor gene. Mol Pharmacol 41:652–659Google Scholar
  37. May T, Sugawa M (1993) Altered dopamine receptor mediated signal transduction in the striatum of aged rats. Brain Res 604:106–111Google Scholar
  38. Meltzer HY, Nash JF (1991) Effects of antipsychotic drugs on serotonin receptors. Pharmacol Rev 43:587–604Google Scholar
  39. Middlemiss DN, Fozard JR (1983) 8-Hydroxy-2-(di-n-propylamino)-tetralin discriminates between subtypes of the 5-HT1 recognition site. Eur J Pharmacol 90:151–153Google Scholar
  40. Mokler DJ, Commissaris RL, Warner MR, Rech RH (1983) Blockade of the behavioral effects of lysergic acid diethylamide, 2,5-dimethoxy-4-methylamphetamine, quipazine and lisuride by 5-hydroxytryptamine antagonists. J Pharmacol Exp Ther 22:557–562Google Scholar
  41. Mottola DM, Brewster WK, Cook LL, Nichols DE, Mailman RB (1992) Dihydrexidine, a novel full efficacy D1 dopamine receptor agonist. J Pharmacol Exp Ther 262:383–393Google Scholar
  42. Nichols DE, Oberlender R, McKenna DJ (1991) Stereochemical aspects of hallucinogenesis. In: Watson R (ed). Biochemistry and physiology of substance abuse. CRC Press, Boca Raton Fl., pp. 1–39Google Scholar
  43. Oberlender R, Pfaff RC, Johnson MP, Huang X, Nichols DE (1992) Stereoselective LSD-like activity ind-lysergic acid amides of (R)- and (S)-2-aminobutane. J Med Chem 35:203–211Google Scholar
  44. Patel A, Linden J (1988) Purification of125I-labelled succinyl cyclic nucleotide tyrosine methyl esters by high-performance liquid chromatography. Anal Biochem 168:417–420Google Scholar
  45. Persson S-A (1977) The effect of LSD and 2-bromo LSD on the striatal DOPA accumulation after decarboxylase inhibition in rats. Eur J Pharmacol 43:73–83Google Scholar
  46. Persson S-A (1978) Effects of LSD and BOL on the catecholamine synthesis and turnover in various brain regions. Psychopharmacology 59:113–116Google Scholar
  47. Pieri L, Keller HH, Burkard W, Da Prada M (1978) Effects of lisuride and LSD on cerebral monoamine systems and hallucinosis. Nature 272:278–280Google Scholar
  48. Pieri L, Pieri M, Haefely W (1974) LSD as an agonist of dopamine receptors in the striatum. Nature 252:586–588Google Scholar
  49. Pifl C, Reither H, Hornykiewicz O (1991) Lower efficacy of the dopamine D1 agonist, SKF38393, to stimulate adenylyl cyclase activity in primate than in rodent striatum. Eur J Pharmacol 202:273–276Google Scholar
  50. Sawaguchi T, Goldman-Rakic PS (1991) D1dopamine receptors in prefrontal cortex: involvement in working memory. Science 251:947–950Google Scholar
  51. Sanders-Bush E, Breeding M (1991) Choroid plexus epithelial cells in primary culture: a model of 5HT1C receptor activation by hallucinogenic drugs. Psychopharmacology 105:340–346Google Scholar
  52. Sibley DR, Monsma FJ (1990) Molecular biology of dopamine receptors. Trends Pharmacol Sci 13:61–69Google Scholar
  53. Spano PF, Kumakura K, Tonon GC, Govoni S, Trabucchi M (1975) LSD and dopamine-sensitive adenylate-cyclase in various rat brain areas. Brain Res 93:164–167Google Scholar
  54. Stoof JC, Kebabian JW (1981) Opposing roles for D-1 and D-2 dopamine receptors in efflux of cAMP from rat neostriatum. Nature 294:366–368Google Scholar
  55. Titeler M, Lyon RA, Glennon RA (1988) Radioligand binding evidence implicates the brain 5HT2 receptor as a site of action for LSD and phenylisopropylamine hallucinogens. Psychopharmacology 94:213–216Google Scholar
  56. Trulson Me, Stark AD, Jacobs BJ (1977) Comparative effects of hallucinogenic drugs on rotational behavior in rats with unilateral 6-hydroxydopamine lesions. Eur J Pharmacol 44:113–119Google Scholar
  57. Von Hungen K, Robers S, Hill DF (1974) LSD as an agonist and antagonist at central dopamine receptors. Nature 252:588–589Google Scholar
  58. Walters JR, Baring MD, Lakoski JM (1979) Effects of ergolines on dopaminergic and serotonergic single unit activity. In: Fuxe K, Calne DB (eds) Dopaminergic ergot derivatives and motor function. Pergamon Press, New York, pp 207–221Google Scholar
  59. Watts VJ, Lawler CP, Gonzales AJ, Zhou Q-Y, Civelli O, Nichols DE, Mailman RB (1993) Efficacy of D1 dopamine receptor agonists: the role of spare receptors. Soc Neurosci Abstr 18:75Google Scholar
  60. White FJ (1986) Comparative effects of LSD and lisuride: clues to specific hallucinogenic drug actions. Pharmacol Biochem Behav 24:365–379Google Scholar
  61. Wyrick S, Mailman RB (1985) Tritium labelled (±)-7-chloro-8-hydrozy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390). J Label Comp Radiopharmac 22:189–195Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • V. J. Watts
    • 1
    • 3
  • R. B. Mailman
    • 1
    • 2
    • 3
    • 4
  • C. P. Lawler
    • 3
    • 4
  • K. A. Neve
    • 5
  • D. E. Nichols
    • 6
  1. 1.Department of PharmacologyUniversity of North Carolina School of MedicineChapel HillUSA
  2. 2.Department of PsychiatryUniversity of North Carolina School of MedicineChapel HillUSA
  3. 3.Brain and Development Research CenterUniversity of North Carolina School of MedicineChapel HillUSA
  4. 4.Curriculum in ToxicologyUniversity of North Carolina School of MedicineChapel HillUSA
  5. 5.Veterans Affairs Medical CenterPortlandUSA
  6. 6.Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal SciencesPurdue UniversityWest LafayetteUSA

Personalised recommendations