title: Role of the 5-HT₂A receptor in the locomotor hyperactivity produced by phenylalkylamine hallucinogens in mice.
abstract: The 5-HT₂A receptor mediates the effects of serotonergic hallucinogens and may play a role in the pathophysiology of certain psychiatric disorders, including schizophrenia. Given these findings, there is a need for animal models to assess the behavioral effects of 5-HT₂A receptor activation. Our previous studies demonstrated that the phenylalkylamine hallucinogen and 5-HT₂A/₂C agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) produces dose-dependent effects on locomotor activity in C57BL/6J mice, increasing activity at low to moderate doses and reducing activity at high doses. DOI did not increase locomotor activity in 5-HT₂A knockout mice, indicating the effect is a consequence of 5-HT₂A receptor activation. Here, we tested a series of phenylalkylamine hallucinogens in C57BL/6J mice using the Behavioral Pattern Monitor (BPM) to determine whether these compounds increase locomotor activity by activating the 5-HT₂A receptor. Low doses of mescaline, 2,5-dimethoxy-4-ethylamphetamine (DOET), 2,5-dimethoxy-4-propylamphetamine (DOPR), 2,4,5-trimethoxyamphetamine (TMA-2), and the conformationally restricted phenethylamine (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine (TCB-2) increased locomotor activity. By contrast, the non-hallucinogenic phenylalkylamine 2,5-dimethoxy-4-tert-butylamphetamine (DOTB) did not alter locomotor activity at any dose tested (0.1-10 mg/kg i.p.). The selective 5-HT₂A antagonist M100907 blocked the locomotor hyperactivity induced by mescaline and TCB-2. Similarly, mescaline and TCB-2 did not increase locomotor activity in 5-HT₂A knockout mice. These results confirm that phenylalkylamine hallucinogens increase locomotor activity in mice and demonstrate that this effect is mediated by 5-HT₂A receptor activation. Thus, locomotor hyperactivity in mice can be used to assess phenylalkylamines for 5-HT₂A agonist activity and hallucinogen-like behavioral effects. These studies provide additional support for the link between 5-HT₂A activation and hallucinogenesis.
authors: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0804, USA. ahalbers@ucsd.edu
authors: Adam L
authors: AL
authors: Halberstadt
authors: Susan B
authors: SB
authors: Powell
authors: Mark A
authors: MA
authors: Geyer
mesh_terms: D000814:Aniline Compounds / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005464:Fluorobenzenes / Q000494:pharmacology; D006213:Hallucinogens / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006948:Hyperkinesis / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010880:Piperidines / Q000494:pharmacology; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000502:physiology*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; D005464:Fluorobenzenes; D006213:Hallucinogens; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; C079049:volinanserin
references: Psychiatr Genet. 2008 Oct;18(5):213-8
references: 18797395
references: Neuroimage. 2008 Aug 1;42(1):306-14
references: 18511303
references: J Med Chem. 1990 Mar;33(3):1032-6
references: 2308135
references: J Psychopharmacol. 2011 Nov;25(11):1548-61
references: 21148021
references: Neuron. 2007 Feb 1;53(3):439-52
references: 17270739
references: Neuropsychopharmacology. 2009 Jul;34(8):1958-67
references: 19322172
references: Neurosci Lett. 2011 Aug 21;501(1):20-4
references: 21741447
references: Psychopharmacology (Berl). 1988;94(2):213-6
references: 3127847
references: Mol Psychiatry. 1998 Jan;3(1):61-6
references: 9491814
references: Neurosci Biobehav Rev. 1982 Winter;6(4):489-97
references: 6757811
references: Pharmacogenomics J. 2009 Feb;9(1):61-70
references: 18253134
references: J Med Chem. 2006 Sep 21;49(19):5794-803
references: 16970404
references: J Cogn Neurosci. 2005 Oct;17(10):1497-508
references: 16269092
references: Psychopharmacology (Berl). 2011 May;215(1):81-92
references: 21153406
references: Life Sci. 1984 Dec 17;35(25):2505-11
references: 6513725
references: Psychopharmacology (Berl). 1995 Oct;121(3):347-56
references: 8584617
references: Am J Hum Genet. 2006 May;78(5):804-814
references: 16642436
references: Eur J Pharmacol. 1975 Jun-Jul;32(02):156-62
references: 1149803
references: J Med Chem. 1997 Sep 12;40(19):2997-3008
references: 9301661
references: Eur J Pharmacol. 1984 Jun 15;102(1):23-9
references: 6479216
references: J Anxiety Disord. 2008 Dec;22(8):1529-34
references: 18436425
references: J Pharmacol Exp Ther. 1995 Apr;273(1):101-12
references: 7714755
references: J Med Chem. 1975 Dec;18(12):1201-4
references: 1195275
references: Biol Psychiatry. 1973 Apr;6(2):177-80
references: 4709133
references: Mol Pharmacol. 1998 Jul;54(1):94-104
references: 9658194
references: Prog Neuropsychopharmacol Biol Psychiatry. 1985;9(2):121-32
references: 3858911
references: Med Res Rev. 1983 Jul-Sep;3(3):289-340
references: 6350763
references: Neuropharmacology. 2011 Sep;61(3):364-81
references: 21256140
references: Brain Res. 2006 Jan 5;1067(1):164-9
references: 16360124
references: J Pharmacol Exp Ther. 2010 Dec;335(3):728-34
references: 20858706
references: Pharmacol Biochem Behav. 1990 Aug;36(4):901-6
references: 2145593
references: Neuromolecular Med. 2010 Sep;12(3):237-42
references: 19937159
references: Neuroreport. 1998 Dec 1;9(17):3897-902
references: 9875725
references: Behav Brain Res. 1993 Feb 26;53(1-2):11-20
references: 8466655
references: Neuropsychopharmacology. 2006 Nov;31(11):2349-58
references: 16855533
references: Experientia. 1975 Jan 15;31(1):93-5
references: 234850
references: Psychopharmacology (Berl). 2011 Feb;213(2-3):583-92
references: 20614105
references: Psychopharmacology (Berl). 2007 Dec;195(3):415-24
references: 17874073
references: Pharmacol Biochem Behav. 1982 Apr;16(4):557-9
references: 7071089
references: Psychiatry Res. 2007 Oct 31;153(2):103-9
references: 17629952
references: Physiol Behav. 1996 Dec;60(6):1495-500
references: 8946497
references: Pharmacol Ther. 2004 Feb;101(2):131-81
references: 14761703
references: Behav Brain Res. 2008 Dec 16;195(1):198-213
references: 18571247
references: Eur Addict Res. 2008;14(1):47-52
references: 18182772
references: Neuropsychopharmacology. 1998 May;18(5):339-51
references: 9536447
references: Psychopharmacology (Berl). 2009 Aug;205(2):285-92
references: 19387614
references: Psychopharmacology (Berl). 1989;98(4):495-9
references: 2505289
references: Schizophr Res. 2011 Jul;129(2-3):183-90
references: 21550210
references: Psychopharmacology (Berl). 2010 Sep;212(1):13-23
references: 19823806
references: J Pharmacol Exp Ther. 2007 Jun;321(3):1054-61
references: 17337633
references: Pharmacol Biochem Behav. 2005 Aug;81(4):830-7
references: 16005500
references: Pharmacol Biochem Behav. 2009 Nov;94(1):194-203
references: 19698737
references: J Med Chem. 2006 Jul 13;49(14):4269-74
references: 16821786
references: NIDA Res Monogr. 1992;119:131-5
references: 1435968
references: J Pharmacol Exp Ther. 2003 Jan;304(1):229-37
references: 12490596
references: Psychopharmacology (Berl). 1990;100(3):417-25
references: 2138338
references: Psychopharmacology (Berl). 2003 Feb;166(1):61-8
references: 12474110