Discriminative Stimulus Effects of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM), Ketanserin, and (R)-(+)-{alpha}-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-pipidinemethanol (MDL100907) in Rats

Overview

Journal J Pharmacol Exp Ther

Specialty Pharmacology

Date 2009 Aug 19

PMID 19687292

Citations 9

Authors

Jun-Xu Li

Alison Unzeitig

Martin A Javors

Kenner C Rice

Wouter Koek

Charles P France

Affiliations

Soon will be listed here.

Abstract

Very little is known about constitutive activity in vivo. This study examined whether constitutive activity and inverse agonism contribute to discriminative stimulus effects of drugs acting at serotonin (5-HT)(2A) receptors. Rats were trained to discriminate between saline and either 0.56 mg/kg 5-HT(2) receptor agonist 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM), 1.0 mg/kg 5-HT(2A) receptor antagonist ketanserin, or 0.1 mg/kg purported 5-HT(2A) receptor inverse agonist (R)-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-pipidinemethanol (MDL100907). Discriminative control was established with each drug after 33 to 35 sessions. MDL100907 and ketanserin did not occasion DOM lever responding but attenuated the discriminative stimulus effects of DOM. DOM did not occasion responding on the drug-associated lever in rats discriminating MDL100907 or ketanserin, but attenuated the discriminative stimulus effects of both drugs. Ketanserin and ritanserin occasioned MDL100907-lever responding, whereas rats discriminating ketanserin responded only partially on the drug-associated lever after receiving MDL100907, ritanserin, or the alpha(1)-adrenergic antagonist prazosin. Combining prazosin with MDL100907 or ritanserin resulted in near-complete ketanserin-lever responding, indicating that the ketanserin stimulus involves both 5-HT(2A) and alpha(1)-adrenergic receptors. Administration of p-chlorophenylalanine methyl ester, then fenfluramine, significantly decreased cortical 5-HT, enhanced sensitivity to the discriminative stimulus effects of DOM, and occasioned partial MDL100907-lever responding. Collectively, these results show that DOM and MDL100907 discriminative stimulus effects are mediated by 5-HT(2A) receptors and that ketanserin discriminative stimulus effects involve both 5-HT(2A) and alpha(1)-adrenergic receptors. Results in 5-HT-depleted rats further suggest that the discriminative stimulus effects of MDL100907 might involve antagonism of endogenous 5-HT and/or inverse agonism at 5-HT(2A) receptors.

Citing Articles

Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action.

Canal C Handb Exp Pharmacol. 2018; 252:227-260.

PMID: 29532180 PMC: 6136989. DOI: 10.1007/164_2018_107.

Mechanisms of imidazoline I receptor agonist-induced antinociception in rats: involvement of monoaminergic neurotransmission.

Siemian J, Wang K, Zhang Y, Li J Br J Pharmacol. 2018; 175(9):1519-1534.

PMID: 29451703 PMC: 5900992. DOI: 10.1111/bph.14161.

Role of 5-HT and 5-HT Serotonin Receptors, and Protein Kinases C and A on Taurine Transport in Lymphocytes of Rats Treated with Fluoxetine.

Colmenares-Aguilar M, Lima L Adv Exp Med Biol. 2017; 975 Pt 2:1129-1140.

PMID: 28849528 DOI: 10.1007/978-94-024-1079-2_90.

Role of intracellular Ca signaling in the antinociceptive and discriminative stimulus effects of the imidazoline I receptor agonist 2-BFI in rats.

Siemian J, Qiu Y, Zhang Y, Li J Psychopharmacology (Berl). 2017; 234(22):3299-3307.

PMID: 28825118 PMC: 5660937. DOI: 10.1007/s00213-017-4719-1.

Tolerance and cross-tolerance to the antinociceptive effects of oxycodone and the imidazoline I receptor agonist phenyzoline in adult male rats.

Thorn D, Zhang Y, Li J Psychopharmacology (Berl). 2017; 234(12):1871-1880.

PMID: 28314949 PMC: 5451304. DOI: 10.1007/s00213-017-4599-4.

References

Orallo F, Rosa E, Campos-Toimil M, Cadavid M, Loza M . Cardiovascular effects of ketanserin on normotensive rats in vivo and in vitro. Gen Pharmacol. 2001; 35(2):95-105. DOI: 10.1016/s0306-3623(01)00099-4. View

Glennon R, Young R, ROSECRANS J . Antagonism of the effects of the hallucinogen DOM and the purported 5-HT agonist quipazine by 5-HT2 antagonists. Eur J Pharmacol. 1983; 91(2-3):189-96. DOI: 10.1016/0014-2999(83)90464-8. View

Silverman P, Ho B . The discriminative stimulus properties of 2,5-dimethoxy-4-methylamphetamine (DOM): differentiation from amphetamine. Psychopharmacology (Berl). 1980; 68(3):209-15. DOI: 10.1007/BF00428105. View

White F, Simmons M, West K, Holohean A, Appel J . The effect of serotonin depletion on the discriminability of LSD. Pharmacol Biochem Behav. 1980; 13(4):569-74. DOI: 10.1016/0091-3057(80)90282-8. View

Dekeyne A, Iob L, Hautefaye P, Millan M . The selective serotonin(2A) receptor antagonist, MDL100,907, elicits a specific interoceptive cue in rats. Neuropsychopharmacology. 2002; 26(4):552-6. DOI: 10.1016/S0893-133X(01)00389-X. View

Parra S, Bond R . Inverse agonism: from curiosity to accepted dogma, but is it clinically relevant?. Curr Opin Pharmacol. 2007; 7(2):146-50. DOI: 10.1016/j.coph.2006.10.005. View

Fiorella D, Helsley S, Lorrain D, Rabin R, Winter J . 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. Psychopharmacology (Berl). 1995; 121(3):364-72. DOI: 10.1007/BF02246076. View

Walker E, Kohut S, Hass R, Brown Jr E, Prabandham A, Lefever T . Selective and nonselective serotonin antagonists block the aversive stimulus properties of MK212 and m-chlorophenylpiperazine (mCPP) in mice. Neuropharmacology. 2005; 49(8):1210-9. DOI: 10.1016/j.neuropharm.2005.07.015. View

Li J, Rice K, France C . Behavioral effects of dipropyltryptamine in rats: evidence for 5-HT1A and 5-HT2A agonist activity. Behav Pharmacol. 2007; 18(4):283-8. DOI: 10.1097/FBP.0b013e3281f19ca0. View

10.

Kenakin T . The classification of seven transmembrane receptors in recombinant expression systems. Pharmacol Rev. 1996; 48(3):413-63. View

11.

Berg K, Stout B, Cropper J, Maayani S, Clarke W . Novel actions of inverse agonists on 5-HT2C receptor systems. Mol Pharmacol. 1999; 55(5):863-72. View

12.

Strange P . Agonist binding to G-protein coupled receptors. Br J Pharmacol. 2000; 129(4):820-1. PMC: 1571878. DOI: 10.1038/sj.bjp.0702991. View

13.

Ullrich T, Rice K . A practical synthesis of the serotonin 5-HT2A receptor antagonist MDL 100907, its enantiomer and their 3-phenolic derivatives as precursors for [11C]labeled PET ligands. Bioorg Med Chem. 2000; 8(10):2427-32. DOI: 10.1016/s0968-0896(00)00175-9. View

14.

Negus S . Some implications of receptor theory for in vivo assessment of agonists, antagonists and inverse agonists. Biochem Pharmacol. 2006; 71(12):1663-70. PMC: 1866283. DOI: 10.1016/j.bcp.2005.12.038. View

15.

Alhaider A, Ageel A, Ginawi O . The quipazine- and TFMPP-increased conditioned avoidance response in rats: role of 5HT1C/5-HT2 receptors. Neuropharmacology. 1993; 32(12):1427-32. DOI: 10.1016/0028-3908(93)90040-a. View

16.

Li J, Rice K, France C . Discriminative stimulus effects of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane in rhesus monkeys. J Pharmacol Exp Ther. 2007; 324(2):827-33. DOI: 10.1124/jpet.107.130625. View

17.

Costa T, Herz A . Antagonists with negative intrinsic activity at delta opioid receptors coupled to GTP-binding proteins. Proc Natl Acad Sci U S A. 1989; 86(19):7321-5. PMC: 298053. DOI: 10.1073/pnas.86.19.7321. View

18.

Welsh S, Romano A, Harvey J . Effects of serotonin 5-HT(2A/2C) antagonists on associative learning in the rabbit. Psychopharmacology (Berl). 1998; 137(2):157-63. DOI: 10.1007/s002130050605. View

19.

Barker E, WESTPHAL R, Schmidt D, Sanders-Bush E . Constitutively active 5-hydroxytryptamine2C receptors reveal novel inverse agonist activity of receptor ligands. J Biol Chem. 1994; 269(16):11687-90. View

20.

Glennon R, Young R, ROSECRANS J . Discriminative stimulus properties of DOM and several molecular modifications. Pharmacol Biochem Behav. 1982; 16(4):553-6. DOI: 10.1016/0091-3057(82)90413-0. View