Distinct temporal phases in the behavioral pharmacology of LSD: dopamine D2 receptor-mediated effects in the rat and implications for psychosis
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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.
We decided to investigate this phenomenon from the perspective that the pharmacology might have relevance to the neurochemical mechanisms underlying psychosis.
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.
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.
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.
KeywordsLSD Drug discrimination 5-HT2A Serotonin Dopamine D2 Schizophrenia Rat
These studies were supported by grant DA-02189 from NIDA.
- Adams LM, Geyer MA (1982) LSD-induced alterations of locomotor patterns and exploration in rats. Psychopharmacology 77:179–185Google Scholar
- Adams LM, Geyer MA (1985) A proposed animal model for hallucinogens based on patterns of exploration in rats. Psychopharmacologia 77:179–185Google Scholar
- Arnt J (1986) Effects of neuroleptics on the amphetamine and LSD cue in rats. Psychopharmacology 89:S44Google Scholar
- Bennett MR (1998) Monoaminergic synapses and schizophrenia: 45 years of neuroleptics. J Psychopharmacol 12:289–304Google Scholar
- 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 33:1756–1764Google Scholar
- Callahan PM, Appel JB (1990) Differentiation between the stimulus effects of (+)-lysergic acid diethylamide and lisuride using a three-choice, drug discrimination procedure. Psychopharmacology 100:13–18Google Scholar
- Carlsson A (2001) A half-century of neurotransmitter research: Impact on neurology and psychiatry. Nobel lecture. Biosci Rep 21:691–710Google Scholar
- Colpaert FC (1984) Cross generalization with LSD and yohimbine in the rat. Eur J Pharmacol 102:541–544Google Scholar
- Colpaert FC, Janssen PA (1983) A characterization of LSD-antagonist effects of pirenperone in the rat. Neuropharmacology 22:1001–1005Google Scholar
- 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 221:206–214Google Scholar
- Cunningham KA, Callahan PM, Appel JB (1985) Differentiation between the stimulus effects of 1-5-hydroxytryptophan and LSD. Eur J Pharmacol 108:179–186Google Scholar
- Doat MM, Rabin RA, Winter JC (2003) Characterization of the discriminative stimulus properties of centrally administered (−)-DOM and LSD. Pharmacol Biochem Behav 74:713–721Google Scholar
- 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 119:239–245Google Scholar
- 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 203–226Google Scholar
- Freedman DX (1986) Hallucinogenic drug research—if so, so what?: symposium summary and commentary. Pharmacol Biochem Behav 24:407–415Google Scholar
- Glennon RA (1999) Arylalkylamine drugs of abuse: an overview on drug discrimination studies. Pharmacol Biochem Behav 64:251–256Google Scholar
- Glennon RA, Titeler M, McKenney JD (1984) Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sci 35:2505–2511Google Scholar
- 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
- 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 76:1521–1531CrossRefPubMedGoogle Scholar
- Jarbe TUC (1980) LSD-25 as a discriminative stimulus for response selection by pigeons. Pharmacol Biochem Behav 13:549–554Google Scholar
- Koerner J, Appel JB (1982) Psilocybin as a discriminative stimulus: lack of specificity in an animal behavior model for “hallucinogens”. Psychopharmacology 76:130–135Google Scholar
- Kuhn DM, White FJ, Appel JB (1978) The discriminative stimulus properties of LSD: mechanism of action. Neuropharmacology 17:257–263Google Scholar
- 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 21:301–314Google Scholar
- Litchfield JT, Wilcoxon F (1949) A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther 96:99–112Google Scholar
- Marona-Lewicka D, Nichols DE (1994) Behavioral effects of the highly selective serotonin releasing agent 5-methoxy-6-methyl-2-aminoindan. Eur J Pharmacol 258:1–13Google Scholar
- Marona-Lewicka D, Nichols DE (1997) 5-HT2A/2C receptor agonists potentiate the discriminative cue of (+)-amphetamine in the rat. Neuropharmacology 36:1471–1475Google Scholar
- Meert TF, de Haes P, Janssen PAJ (1989) Risperidone (R 64 766), a potent and complete LSD antagonist in drug discrimination by rats. Psychopharmacology 97:206–212Google Scholar
- Mittman SM, Geyer MA (1989) Effects of 5-HT-1A agonists on locomotor and investigatory behaviors in rats differ from those of hallucinogens. Psychopharmacology 98:729–756Google Scholar
- Mittman SM, Geyer MA (1991) Dissociation of multiple effects of acute LSD on exploratory behavior in rats by ritanserin and propranolol. Psychopharmacology 105:69–76Google Scholar
- 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 301:1166–1178Google Scholar
- Nichols DE (2004) Hallucinogens. Pharmacol Ther 101:131–181Google Scholar
- Shulgin AT, Shulgin A (1991) PIHKAL a chemical love story. Transform Press, Berkeley, CA, pp 53–56, 620–646Google Scholar
- Shulgin AT, Shulgin A (1997) TIHKAL. The continuation. Transform Press, Berkeley CAGoogle Scholar
- Watts VJ, Lawler CP, Fox DR, Neve KA, Nichols DE, Mailman RB (1995) LSD and structural analogs: pharmacological evaluation at D1 dopamine receptors. Psychopharmacology 118:401–409Google Scholar
- Wing LL, Tapson GS, Geyer MA (1990) 5-HT-2 mediation of acute behavioral effects of hallucinogens in rats. Psychopharmacology 100:417–425Google Scholar
- Winter JC (1994) The stimulus effects of serotonergic hallucinogens in animals. NIDA Res Monogr 146:157–182Google Scholar
- Winter JC, Fiorella DJ, Timineri DM, Filipink RA, Hesley SE, Rabin RA (1999) Serotonergic receptor subtypes and hallucinogen-induced stimulus control. Pharmacol Biochem Behav 64:283–293Google Scholar
- Young R, Rosecrans JA, Glennon RA (1982) Comparative discriminative stimulus effects of 5-methoxy-N,N-dimethyltryptamine and LSD. Life Sci 30:2057–2062Google Scholar
- Zar J (1999) Biostatistical analysis, 4th edn. Prentice-Hall, Upper Saddle River, NJ, pp 533–538 (Section 24.6)Google Scholar