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Distinct temporal phases in the behavioral pharmacology of LSD: dopamine D2 receptor-mediated effects in the rat and implications for psychosis

Abstract

Rationale

The effect of LSD in humans has been described as occurring in two temporal phases. The behavioral effects in rats also occur in two temporal phases: an initial suppression of exploration followed by increased locomotor activity.

Objectives

We decided to investigate this phenomenon from the perspective that the pharmacology might have relevance to the neurochemical mechanisms underlying psychosis.

Methods

Twenty-five male Sprague–Dawley rats were trained to discriminate LSD (186 nmol/kg, 0.08 mg/kg, i.p.) with a 30-min preinjection time (LSD-30, N=12) and LSD (372 nmol/kg, 0.16 mg/kg, i.p.) with a 90-min preinjection time (LSD-90, N=13) from saline, using a two-lever, food-reinforced operant conditioning task.

Results

LSD (186 or 372 nmol/kg, 0.08 or 0.16 mg/kg) given 30 min prior to training produced a cue that was completely antagonized by 5-HT2A antagonists and lasted no longer than 1 h. LSD (372 nmol/kg, 0.16 mg/kg) injected 90 min before training produced a cue that was not fully blocked by 5-HT2A antagonists, but instead was significantly inhibited by haloperidol. In these rats, substitution no longer occurred with the 5-HT2 agonists DOI or LSD (30 min preinjection), but full substitution was obtained with the D2 agonists apomorphine, N-propyldihydrexidine, and quinelorane.

Conclusion

The discriminative stimulus effect of LSD in rats occurs in two phases, and these studies provide evidence that the later temporal phase is mediated by D2 dopamine receptor stimulation. A second temporal phase that involves dopaminergic pathways would be consistent with the widespread belief that excessive dopaminergic activity may be an underlying cause of paranoid psychosis.

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References

  1. Adams LM, Geyer MA (1982) LSD-induced alterations of locomotor patterns and exploration in rats. Psychopharmacology 77:179–185

    Google Scholar 

  2. Adams LM, Geyer MA (1985) A proposed animal model for hallucinogens based on patterns of exploration in rats. Psychopharmacologia 77:179–185

    Google Scholar 

  3. Appel JB, West WB, Rolandi WG, Alici T, Pechersky K (1999) Increasing the selectivity of drug discrimination procedures. Pharmacol Biochem Behav 64:353–358

    Article  CAS  PubMed  Google Scholar 

  4. Arnt J (1986) Effects of neuroleptics on the amphetamine and LSD cue in rats. Psychopharmacology 89:S44

    Google Scholar 

  5. Bennett MR (1998) Monoaminergic synapses and schizophrenia: 45 years of neuroleptics. J Psychopharmacol 12:289–304

    Google Scholar 

  6. 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]phenanthidrine: a highly potent selective dopamine D1 full agonist. J Med Chem 33:1756–1764

    Google Scholar 

  7. Callahan PM, Appel JB (1990) Differentiation between the stimulus effects of (+)-lysergic acid diethylamide and lisuride using a three-choice, drug discrimination procedure. Psychopharmacology 100:13–18

    Google Scholar 

  8. Carlsson A (2001) A half-century of neurotransmitter research: Impact on neurology and psychiatry. Nobel lecture. Biosci Rep 21:691–710

    Google Scholar 

  9. Colpaert FC (1984) Cross generalization with LSD and yohimbine in the rat. Eur J Pharmacol 102:541–544

    Google Scholar 

  10. Colpaert FC, Janssen PA (1983) A characterization of LSD-antagonist effects of pirenperone in the rat. Neuropharmacology 22:1001–1005

    Google Scholar 

  11. Colpaert FC, Niemegeers CJ, Janssen PA (1982) A drug discrimination analysis of lysergic acid diethylamide (LSD): in vivo agonist and antagonist effects of purported 5-hydroxytryptamine antagonists and of pirenperone, a LSD-antagonist. J Pharmacol Exp Ther 221:206–214

    Google Scholar 

  12. Cunningham KA, Callahan PM, Appel JB (1985) Differentiation between the stimulus effects of 1-5-hydroxytryptophan and LSD. Eur J Pharmacol 108:179–186

    Google Scholar 

  13. Doat MM, Rabin RA, Winter JC (2003) Characterization of the discriminative stimulus properties of centrally administered (−)-DOM and LSD. Pharmacol Biochem Behav 74:713–721

    Google Scholar 

  14. Fiorella D, Palumbo PA, Rabin RA, Winter JC (1995) The time-dependent stimulus effects of R(−)-2,5-dimethoxy-4-methamphetamine (DOM): implications for drug induced stimulus control as a method for the study of hallucinogenic agents. Psychopharmacology 119:239–245

    Google Scholar 

  15. Freedman DX (1984) LSD: the bridge from human to animal. In: Jacobs BL (ed) Hallucinogens: neurochemical, behavioral, and clinical perspectives. Raven Press, New York, pp 203–226

    Google Scholar 

  16. Freedman DX (1986) Hallucinogenic drug research—if so, so what?: symposium summary and commentary. Pharmacol Biochem Behav 24:407–415

    Google Scholar 

  17. Glennon RA (1999) Arylalkylamine drugs of abuse: an overview on drug discrimination studies. Pharmacol Biochem Behav 64:251–256

    Google Scholar 

  18. Glennon RA, Young R, Rosecrans JA (1983) Antagonism of the effect of the hallucinogen DOM and purported 5-HT agonist quipazine by 5-HT2 antagonists. Eur J Pharmacol 91:189–196

    Article  Google Scholar 

  19. Glennon RA, Titeler M, McKenney JD (1984) Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sci 35:2505–2511

    Google Scholar 

  20. Holohean AM, White FJ, Appel JB (1982) Dopaminergic and serotonergic mediation of the discriminable effects of ergot alkaloids. Eur J Pharmacol 81:595–602

    Google Scholar 

  21. Ichikawa J, Ishii H, Bonaccorso S, O’Laughlin IA, Fowler WL, Meltzer HY (2001) 5-HT2A and D2 receptor blockade increases cortical DA release via 5-HT1A receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J Neurochem 76:1521–1531

    Article  CAS  PubMed  Google Scholar 

  22. Ismaiel AM, De Los AJ, Teitler M, Ingher S, Glennon RA (1993) Antagonism of 1-(2.5-dimethoxy-4-methylphenyl)-2-aminopropane stimulus with a newly identified 5-HT2- versus 5-HT1C-selective antagonist. J Med Chem 36:2519–2525

    CAS  PubMed  Google Scholar 

  23. Jarbe TUC (1980) LSD-25 as a discriminative stimulus for response selection by pigeons. Pharmacol Biochem Behav 13:549–554

    Google Scholar 

  24. Koerner J, Appel JB (1982) Psilocybin as a discriminative stimulus: lack of specificity in an animal behavior model for “hallucinogens”. Psychopharmacology 76:130–135

    Google Scholar 

  25. Kuhn DM, White FJ, Appel JB (1978) The discriminative stimulus properties of LSD: mechanism of action. Neuropharmacology 17:257–263

    Google Scholar 

  26. Leysen JE, Niemegeers CJ, Van Neuten JM, Laduron PM (1982) [3H]Ketanserin (R 41 468), a selective 3H-ligand for serotonin2 receptor binding sites. Binding properties, brain distribution, and functional role. Mol Pharmacol 21:301–314

    Google Scholar 

  27. Litchfield JT, Wilcoxon F (1949) A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther 96:99–112

    CAS  Google Scholar 

  28. Marona-Lewicka D, Nichols DE (1994) Behavioral effects of the highly selective serotonin releasing agent 5-methoxy-6-methyl-2-aminoindan. Eur J Pharmacol 258:1–13

    Google Scholar 

  29. Marona-Lewicka D, Nichols DE (1997) 5-HT2A/2C receptor agonists potentiate the discriminative cue of (+)-amphetamine in the rat. Neuropharmacology 36:1471–1475

    Google Scholar 

  30. Meert TF, de Haes P, Janssen PAJ (1989) Risperidone (R 64 766), a potent and complete LSD antagonist in drug discrimination by rats. Psychopharmacology 97:206–212

    Google Scholar 

  31. Meltzer HY (1999) The role of serotonin in antipsychotic drug action. Neuropsychopharmacology 21:106S–115S

    Article  CAS  PubMed  Google Scholar 

  32. Meltzer HY, Matsubara S, Lee JC (1989) Classification of typical and atypical antipsychotic drugs on the basis of dopamine D1, D2 and serotonin2 pKi values. J Pharmacol Exp Ther 251:238–246

    CAS  PubMed  Google Scholar 

  33. Mittman SM, Geyer MA (1989) Effects of 5-HT-1A agonists on locomotor and investigatory behaviors in rats differ from those of hallucinogens. Psychopharmacology 98:729–756

    Google Scholar 

  34. Mittman SM, Geyer MA (1991) Dissociation of multiple effects of acute LSD on exploratory behavior in rats by ritanserin and propranolol. Psychopharmacology 105:69–76

    Google Scholar 

  35. Mottola DM, Kilts JD, Lewis MM, Smith HP, Walker QD, Jones SR, Booth RG, Hyslop DK, Wightman M, Lawler CP, Nichols DE, Mailman RB (2002) Functional selectivity of dihydrexidine. I. Selective activation of post-synaptic dopamine D2 receptors linked to adenylate cyclase. J Pharmacol Exp Ther 301:1166–1178

    Google Scholar 

  36. Nichols DE (2004) Hallucinogens. Pharmacol Ther 101:131–181

    Google Scholar 

  37. Schotte A, Janssen PFM, Gommeren W, Luyten WHML, Van Gompel P, Lesage AS, De Loore K, Leysen JE (1996) Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology 124:57–73

    CAS  PubMed  Google Scholar 

  38. Schreiber R, Brocco M, Millan MJ (1994) Blockade of the discriminative stimulus effects of DOI by MDL 100,907 and the “atypical” antipsychotics, clozapine and risperidone. Eur J Pharmacol 264:99–102

    Article  CAS  PubMed  Google Scholar 

  39. Seeman P (1987) Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1:133–152

    CAS  PubMed  Google Scholar 

  40. Shulgin AT, Shulgin A (1991) PIHKAL a chemical love story. Transform Press, Berkeley, CA, pp 53–56, 620–646

    Google Scholar 

  41. Shulgin AT, Shulgin A (1997) TIHKAL. The continuation. Transform Press, Berkeley CA

    Google Scholar 

  42. Watts VJ, Lawler CP, Fox DR, Neve KA, Nichols DE, Mailman RB (1995) LSD and structural analogs: pharmacological evaluation at D1 dopamine receptors. Psychopharmacology 118:401–409

    Google Scholar 

  43. Wing LL, Tapson GS, Geyer MA (1990) 5-HT-2 mediation of acute behavioral effects of hallucinogens in rats. Psychopharmacology 100:417–425

    Google Scholar 

  44. Winter JC (1994) The stimulus effects of serotonergic hallucinogens in animals. NIDA Res Monogr 146:157–182

    Google Scholar 

  45. Winter JC, Rabin RA (1988) Interactions between serotonergic agonists and antagonists in rats trained with LSD as a discriminative stimulus. Pharmacol Biochem Behav 30:617–624

    Article  Google Scholar 

  46. Winter JC, Fiorella DJ, Timineri DM, Filipink RA, Hesley SE, Rabin RA (1999) Serotonergic receptor subtypes and hallucinogen-induced stimulus control. Pharmacol Biochem Behav 64:283–293

    Google Scholar 

  47. Young R, Rosecrans JA, Glennon RA (1982) Comparative discriminative stimulus effects of 5-methoxy-N,N-dimethyltryptamine and LSD. Life Sci 30:2057–2062

    Google Scholar 

  48. Zar J (1999) Biostatistical analysis, 4th edn. Prentice-Hall, Upper Saddle River, NJ, pp 533–538 (Section 24.6)

    Google Scholar 

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Acknowledgements

These studies were supported by grant DA-02189 from NIDA.

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Correspondence to David E. Nichols.

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Marona-Lewicka, D., Thisted, R.A. & Nichols, D.E. Distinct temporal phases in the behavioral pharmacology of LSD: dopamine D2 receptor-mediated effects in the rat and implications for psychosis. Psychopharmacology 180, 427–435 (2005). https://doi.org/10.1007/s00213-005-2183-9

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Keywords

  • LSD
  • Drug discrimination
  • 5-HT2A
  • Serotonin
  • Dopamine D2
  • Schizophrenia
  • Rat