Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens.
Serotonergic hallucinogens produce profound changes in perception, mood, and cognition. These drugs include phenylalkylamines such as mescaline and 2,5-dimethoxy-4-methylamphetamine (DOM), and indoleamines such as (+)-lysergic acid diethylamide (LSD) and psilocybin. Despite their differences in chemical structure, the two classes of hallucinogens produce remarkably similar subjective effects in humans, and induce cross-tolerance. The phenylalkylamine hallucinogens are selective 5-HT(2) receptor agonists, whereas the indoleamines are relatively non-selective for serotonin (5-HT) receptors. There is extensive evidence, from both animal and human studies, that the characteristic effects of hallucinogens are mediated by interactions with the 5-HT(2A) receptor. Nevertheless, there is also evidence that interactions with other receptor sites contribute to the psychopharmacological and behavioral effects of the indoleamine hallucinogens. This article reviews the evidence demonstrating that the effects of indoleamine hallucinogens in a variety of animal behavioral paradigms are mediated by both 5-HT(2) and non-5-HT(2) receptors.
Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States. ahalbers@ucsd.edu
Adam L
AL
Halberstadt
Mark A
MA
Geyer
D000818:Animals; D001519:Behavior / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D006213:Hallucinogens / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D008238:Lysergic Acid Diethylamide / Q000737:chemistry / Q000633:toxicity; D009419:Nerve Tissue Proteins / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D010627:Phenethylamines / Q000737:chemistry / Q000633:toxicity; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D011562:Psilocybin / Q000737:chemistry / Q000633:toxicity; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000737:chemistry / Q000633:toxicity*; D020230:Serotonin Syndrome / Q000139:chemically induced / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000633:toxicity; D009435:Synaptic Transmission / Q000187:drug effects
D006213:Hallucinogens; D008238:Lysergic Acid Diethylamide; D009419:Nerve Tissue Proteins; D010627:Phenethylamines; D011562:Psilocybin; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors
Science. 1981 May 15;212(4496):827-9
7221567
Eur J Pharmacol. 1984 Nov 13;106(2):271-82
6241568
Pharmacol Biochem Behav. 1996 Sep;55(1):1-10
8870031
Brain Res. 1981 Jun 29;215(1-2):275-93
6114779
Neuropharmacology. 1979 Dec;18(12):981-9
530379
Eur J Pharmacol. 1989 Feb 14;161(1):45-51
2524390
J Med Chem. 2006 Sep 21;49(19):5794-803
16970404
J Cogn Neurosci. 2005 Oct;17(10):1497-508
16269092
J Med Chem. 1995 Mar 17;38(6):958-66
7699712
J Neurochem. 2010 Sep;114(6):1701-10
20584103
Biol Psychiatry. 1992 Dec 1;32(11):976-91
1467389
Int J Neuropharmacol. 1963 Dec;2:273-7
14119487
Psychopharmacology (Berl). 2002 Oct;164(1):93-107
12373423
Life Sci. 1984 Dec 17;35(25):2505-11
6513725
Nature. 2009 Nov 12;462(7270):175-81
19881490
Pharmacol Biochem Behav. 1988 Jul;30(3):617-24
3211970
Neuropharmacology. 1977 Nov;16(11):771-4
593537
Psychopharmacology (Berl). 2005 Jun;179(4):854-62
15645221
Pharmacol Biochem Behav. 1986 Dec;25(6):1207-10
3809222
Neuropsychopharmacology. 1991 Feb;4(2):131-44
2025379
J Pharmacol Exp Ther. 1988 Sep;246(3):924-8
2843634
Pharmacol Biochem Behav. 1986 Jul;25(1):277-88
2875472
J Pharmacol Exp Ther. 2008 Feb;324(2):827-33
17993605
Psychopharmacologia. 1964 Feb 12;5:217-27
14138757
Pharmacol Biochem Behav. 2008 Jan;88(3):358-65
17905422
Psychopharmacology (Berl). 2010 Apr;209(2):163-74
20165943
J Pharm Pharmacol. 1976 Jun;28(6):516-8
7653
Psychopharmacologia. 1975 May 28;42(2):163-71
1080571
J Neurochem. 1971 Jun;18(6):1053-66
4254940
Behav Brain Res. 1996;73(1-2):121-4
8788488
Neuropsychopharmacology. 1996 Oct;15(4):349-60
8887989
Psychopharmacology (Berl). 1995 Oct;121(3):347-56
8584617
J Med Chem. 2000 Nov 30;43(24):4701-10
11101361
Eur J Pharmacol. 1975 Jun-Jul;32(02):156-62
1149803
Br J Pharmacol Chemother. 1963 Feb;20:106-20
14023050
Eur J Pharmacol. 1984 May 18;101(1-2):57-68
6745319
Neuropharmacology. 1980 Oct;19(10):1005-7
7422071
Brain Res Dev Brain Res. 1994 Jul 15;80(1-2):1-6
7955334
Psychopharmacol Commun. 1975;1(6):619-29
1063421
Pharmacol Biochem Behav. 1994 Mar;47(3):667-73
8208787
Neuropsychopharmacology. 1990 Apr;3(2):137-48
1969270
Eur J Pharmacol. 1986 Sep 23;129(1-2):123-30
2876903
Eur J Pharmacol. 1983 Jul 22;91(2-3):189-96
6617740
Neuropsychopharmacology. 1992 Aug;7(1):15-31
1355968
J Pharmacol Exp Ther. 1995 Apr;273(1):101-12
7714755
Psychopharmacology (Berl). 1987;91(1):25-9
2881318
Behav Neurosci. 1985 Oct;99(5):881-900
3843306
Br J Pharmacol. 2009 Nov;158(6):1477-85
19845681
Pharmacol Biochem Behav. 1995 Dec;52(4):649-54
8587900
Pharmacol Biochem Behav. 1989 Aug;33(4):821-7
2533357
Proc Natl Acad Sci U S A. 1954 Apr;40(4):228-31
16589461
Biol Psychiatry. 1973 Apr;6(2):177-80
4709133
J Pharmacol Exp Ther. 1974 Mar;188(3):688-99
4593245
Behav Pharmacol. 1998 Nov;9(7):561-6
9862081
Nat Rev Neurosci. 2010 Sep;11(9):642-51
20717121
Prog Neuropsychopharmacol Biol Psychiatry. 1985;9(2):121-32
3858911
Med Res Rev. 1983 Jul-Sep;3(3):289-340
6350763
J Pharmacol Exp Ther. 1999 Feb;288(2):643-52
9918570
Neurosci Res. 2006 May;55(1):96-104
16580757
Psychopharmacology (Berl). 1985;86(1-2):45-54
2862659
Br J Pharmacol. 1999 Sep;128(1):13-20
10498829
Pharmacol Biochem Behav. 2007 Oct;87(4):472-80
17688928
Trends Pharmacol Sci. 1988 Mar;9(3):89-94
3072739
Psychopharmacology (Berl). 1989;97(1):118-22
2540505
Psychopharmacology (Berl). 1999 Jun;144(3):248-54
10435391
Behav Pharmacol. 2008 Sep;19(5-6):548-61
18690109
Psychopharmacology (Berl). 1987;93(2):158-66
3122248
Psychopharmacology (Berl). 1998 Oct;139(4):383-90
9809859
Toxicol Lett. 2007 Apr 5;170(1):75-82
17382495
Life Sci. 1979 Mar 12;24(11):993-7
286864
Eur J Pharmacol. 1987 Mar 31;135(3):279-87
3495447
J Neurochem. 1986 Aug;47(2):529-40
2942638
Pharmacol Biochem Behav. 1988 Jan;29(1):193-5
2895479
J Pharmacol Exp Ther. 2007 Jan;320(1):486-96
17038512
Psychopharmacology (Berl). 2004 Mar;172(2):233-40
14598016
Biochem Pharmacol. 1991 Jun 1;41(11):1739-44
1828347
J Pharmacol Exp Ther. 1990 Aug;254(2):456-64
1974635
Eur J Pharmacol. 1985 Jul 31;113(3):463-4
2931289
J Pharmacol Exp Ther. 2010 Dec;335(3):728-34
20858706
J Pharmacol Exp Ther. 1993 May;265(2):572-9
8496807
Pharmacol Biochem Behav. 1990 Aug;36(4):901-6
2145593
Naunyn Schmiedebergs Arch Pharmacol. 1999 Jan;359(1):1-6
9933142
Psychopharmacology (Berl). 1992;108(1-2):85-92
1357711
Synapse. 1993 Aug;14(4):297-304
8248853
J Med Chem. 1992 Feb 21;35(4):734-40
1542100
Mol Pharmacol. 1992 Jun;41(6):1066-72
1352034
J Neurochem. 1988 May;50(5):1624-31
3361315
J Pharmacol Exp Ther. 1991 Feb;256(2):795-800
1847213
Ann N Y Acad Sci. 1998 Dec 15;861:79-84
9928242
NIDA Res Monogr. 1992;124:203-35
1470213
Eur J Pharmacol. 1985 Mar 12;109(3):421-5
3987809
Science. 1968 Aug 16;161(3842):706-8
4874578
Psychopharmacologia. 1971;22(1):64-71
5119576
Synapse. 2009 Aug;63(8):698-704
19391150
Psychopharmacologia. 1972;23(1):75-85
5018979
Neuropsychopharmacology. 2000 Jun;22(6):650-9
10788764
Psychopharmacology (Berl). 1979 Sep;65(1):35-40
116288
Pharmacopsychiatry. 1998 Jul;31 Suppl 2:85-91
9754839
Eur J Pharmacol. 1996 Nov 21;315(3):245-54
8982661
Pharmacol Biochem Behav. 2001 Jul-Aug;69(3-4):643-52
11509227
Psychopharmacology (Berl). 2005 Sep;181(3):496-503
15983786
Psychopharmacologia. 1969;14(1):62-73
5351858
J Psychopharmacol. 2011 Nov;25(11):1548-61
21148021
Psychopharmacology (Berl). 1998 Apr;136(4):409-14
9600588
Psychopharmacology (Berl). 2006 Dec;189(3):319-29
17013638
Neuropsychopharmacology. 2007 Sep;32(9):1876-87
17299516
Pharmacol Biochem Behav. 1992 Sep;43(1):131-7
1409796
J Pharmacol Exp Ther. 1997 Aug;282(2):699-706
9262333
Eur J Pharmacol. 1994 Oct 13;264(1):99-102
7530204
Neuroreport. 1998 Dec 1;9(17):3897-902
9875725
Pharmacol Biochem Behav. 2006 Jan;83(1):122-9
16460788
Psychopharmacology (Berl). 2006 Aug;187(3):268-83; discussion 284-92
16826400
J Pharmacol Exp Ther. 1994 Sep;270(3):1345-58
7932189
Trends Pharmacol Sci. 2008 Sep;29(9):445-53
19086254
Synapse. 1987;1(1):3-9
3505364
J Pharmacol Exp Ther. 1988 Nov;247(2):547-55
2903234
Psychopharmacology (Berl). 1989;99(1):40-7
2571175
Science. 1967 Nov 3;158(3801):669-70
4860952
Pharmacol Biochem Behav. 1979 Feb;10(2):293-8
450941
Pharmacol Biochem Behav. 1986 Feb;24(2):351-7
3952126
J Pharmacol Exp Ther. 2002 Nov;303(2):791-804
12388666
J Psychopharmacol. 2007 May;21(3):312-20
17591658
Psychopharmacology (Berl). 2009 Apr;203(2):265-77
18604600
J Pharmacol Exp Ther. 1970 Feb;171(2):178-87
5459056
Neuron. 2007 Feb 1;53(3):439-52
17270739
Psychopharmacology (Berl). 2002 Dec;165(1):18-28
12474114
Psychopharmacologia. 1959;1:29-38
14405870
J Med Chem. 1994 Jun 24;37(13):1929-35
8027974
Eur J Pharmacol. 1986 Apr 2;122(3):373-7
3709659
Arch Int Pharmacodyn Ther. 1978 Sep;235(1):86-92
736694
J Neurochem. 1996 Dec;67(6):2521-31
8931486
Neuropsychopharmacology. 2009 Jul;34(8):1958-67
19322172
Neuropsychopharmacology. 1997 May;16(5):357-72
9109107
Eur J Pharmacol. 1987 Jan 6;133(1):47-56
2881789
Mol Pharmacol. 1979 Nov;16(3):687-99
530254
J Med Chem. 1998 Dec 17;41(26):5148-9
9857084
Psychopharmacology (Berl). 2008 Jan;196(1):51-62
17922234
Pharmacol Biochem Behav. 1990 Sep;37(1):95-9
2263671
J Pharmacol Exp Ther. 1997 Aug;282(2):747-59
9262338
Psychopharmacologia. 1963 Oct 24;5:1-15
14085622
Psychopharmacology (Berl). 1994 Jan;113(3-4):429-37
7862855
Pharmacol Biochem Behav. 1998 Nov;61(3):323-30
9768567
Behav Pharmacol. 1995 Dec;6(8):839-842
11224388
Psychopharmacology (Berl). 2008 Nov;201(1):55-66
18604652
Brain Res. 1997 Jun 27;761(1):97-104
9247071
Pharmacology. 2005 Jul;74(4):193-9
15886504
J Pharmacol Exp Ther. 2007 Feb;320(2):662-9
17077317
J Neural Transm (Vienna). 1998;105(6-7):635-43
9826108
Mol Pharmacol. 1988 Feb;33(2):178-86
2828913
Behav Pharmacol. 1996 Nov;7(6):551-559
11224452
J Pharmacol Exp Ther. 1998 Aug;286(2):913-24
9694950
J Pharmacol Exp Ther. 1991 Sep;258(3):891-6
1679849
Pharmacol Biochem Behav. 2000 Jan 1;65(1):75-82
10638639
J Med Chem. 1988 Apr;31(4):867-70
2965244
Neurosci Biobehav Rev. 1992 Spring;16(1):95-105
1553110
J Neurosci. 2002 Nov 1;22(21):9604-11
12417685
Neuropharmacology. 1977 Oct;16(10):663-70
304190
Pharmacol Biochem Behav. 1985 Sep;23(3):461-8
4048241
Psychopharmacology (Berl). 1988;94(2):213-6
3127847
Psychopharmacologia. 1963 Apr 16;4:139-47
14050419
Psychopharmacology (Berl). 1999 Feb;142(1):41-50
10102781
Obesity (Silver Spring). 2009 Mar;17(3):494-503
19057523
Brain Res. 1977 Jan 7;119(2):291-303
264274
Behav Pharmacol. 2007 Jul;18(4):283-8
17551320
Neuropsychopharmacology. 2008 Oct;33(11):2648-56
18075489
Psychopharmacology (Berl). 1995 Apr;118(4):401-9
7568626
J Clin Psychiatry. 2006 Nov;67(11):1735-40
17196053
Neuropsychopharmacology. 2006 Nov;31(11):2349-58
16855533
Neuropsychopharmacology. 2001 Oct;25(4):565-75
11557170
Psychopharmacologia. 1961;2:147-59
13717955
Histochem J. 1996 Nov;28(11):747-58
8968727
Psychopharmacol Bull. 1986;22(3):953-8
3025916
Psychopharmacol Commun. 1976;2(2):149-64
136010
J Pharmacol Exp Ther. 1984 Jan;228(1):133-9
6694097
Ann N Y Acad Sci. 1992 Jul 1;658:223-55
1497260
Pharmacol Biochem Behav. 2010 Sep;96(3):260-5
20493209
J Neural Transm (Vienna). 2009 Dec;116(12):1591-9
19756361
Psychopharmacology (Berl). 1995 Jan;117(1):41-8
7724701
Pharmacol Biochem Behav. 1980 Oct;13(4):549-54
6107936
AMA Arch Gen Psychiatry. 1959 Sep;1:279-82
13796178
Behav Brain Res. 2007 Dec 11;185(1):65-7
17727968
Commun Psychopharmacol. 1979;3(3):173-8
574070
Psychopharmacology (Berl). 1989;98(3):321-9
2501811
Neuropharmacology. 1991 Jun;30(6):629-36
1922682
Neuropsychopharmacology. 1990 Oct-Dec;3(5-6):509-17
2078284
Science. 2009 Feb 13;323(5916):934-7
19213917
Life Sci. 1979 May 28;24(22):2053-61
459700
Psychopharmacology (Berl). 2007 Dec;195(3):415-24
17874073
Nature. 1997 May 15;387(6630):303-8
9153397
Psychopharmacol Bull. 1986;22(3):959-67
3797596
J Pharmacol Exp Ther. 1994 Jul;270(1):198-208
8035316
J Neurosci. 1992 Feb;12(2):440-53
1531498
Pharmacol Toxicol. 1989 Feb;64(2):165-72
2526950
J Med Chem. 1988 Jan;31(1):5-7
3336031
Psychopharmacology (Berl). 1991;105(1):69-76
1745714
Neuropsychopharmacology. 1989 Mar;2(1):81-7
2803482
Psychopharmacology (Berl). 1995 Aug;120(4):384-91
8539318
Commun Psychopharmacol. 1980;4(6):501-6
7297054
Psychopharmacologia. 1967;11(1):65-78
5302272
Psychopharmacology (Berl). 2005 Oct;182(2):197-204
16025319
Psychopharmacology (Berl). 1995 Oct;121(3):357-63
8584618
Psychopharmacology (Berl). 1995 Dec;122(3):237-43
8748393
Neuropharmacology. 1990 Mar;29(3):193-8
2139186
J Recept Res. 1988;8(1-4):59-81
3290473
Arch Gen Psychiatry. 1994 Feb;51(2):98-108
8297217
Pharmacol Biochem Behav. 1986 Jul;25(1):135-9
2944129
Pharmacol Ther. 2004 Feb;101(2):131-81
14761703
Neuropharmacology. 2009 Sep;57(3):259-67
19501602
Neurosci Lett. 1986 Sep 12;69(3):269-74
3763057
Science. 1979 Aug 3;205(4405):515-8
451617
Pharmacol Biochem Behav. 1986 Jun;24(6):1513-9
2942947
Neuropsychopharmacology. 1998 May;18(5):339-51
9536447
Neuropsychopharmacology. 1993 May;8(3):201-11
8099482
Brain Res. 1985 Nov 4;346(2):205-30
4052776
NIDA Res Monogr. 1994;146:203-13
8742800
Psychopharmacology (Berl). 1989;97(2):206-12
2471220
Mol Pharmacol. 1982 Mar;21(2):301-14
7099138
Eur J Pharmacol. 1984 Nov 27;106(3):539-46
6519175
Pharmacol Biochem Behav. 1987 Nov;28(3):393-9
3685075
Psychopharmacology (Berl). 1995 Nov;122(1):15-26
8711060
Eur J Pharmacol. 1985 Oct 29;117(1):15-24
2935408
Arch Gen Psychiatry. 2011 Jan;68(1):71-8
20819978
Psychopharmacology (Berl). 1989;98(4):495-9
2505289
Eur J Pharmacol. 1973 Jan;21(1):53-60
4709205
J Med Chem. 1998 Dec 3;41(25):5084-93
9836624
J Med Chem. 1993 Aug 20;36(17):2519-25
8355253
J Neuropsychiatr. 1960 Jul-Aug;1:283-92
13827606
J Pharmacol Exp Ther. 2009 Mar;328(3):976-81
19098164
J Pharmacol Exp Ther. 1975 Jun;193(3):785-95
168347
J Pharmacol Exp Ther. 1982 Apr;221(1):206-14
7062283
Biochem Pharmacol. 1993 Jan 26;45(2):375-83
8382063
Psychopharmacology (Berl). 2010 Sep;212(1):13-23
19823806
Eur J Pharmacol. 1994 Oct 3;263(3):315-8
7843270
Arch Int Pharmacodyn Ther. 1968 Jun;173(2):316-26
5684262
Neuropharmacology. 1984 Dec;23(12B):1511-20
6396527
Pharmacol Biochem Behav. 2005 Aug;81(4):830-7
16005500
J Pharmacol Exp Ther. 1978 Aug;206(2):339-47
682117
J Med Chem. 2002 Sep 12;45(19):4344-9
12213075
Neuropsychopharmacology. 1990 Oct-Dec;3(5-6):361-9
2078272
NIDA Res Monogr. 1992;119:131-5
1435968
Neuropharmacology. 1994 Mar-Apr;33(3-4):441-8
7984282
Headache. 1977 May;17(2):54-60
324950
Psychopharmacology (Berl). 2005 Jul;180(3):427-35
15723230
Arch Gen Psychiatry. 1994 Feb;51(2):85-97
8297216
Neuropharmacology. 1978 Apr-May;17(4-5):257-63
652138
Psychopharmacologia. 1962;3:219-23
14007905
Life Sci. 1979 Apr 2;24(14):1289-97
470543
Eur J Pharmacol. 1984 Jul 20;102(3-4):541-4
6489439
Eur J Pharmacol. 2007 Mar 22;559(2-3):132-7
17223101
J Neurosci. 1985 Dec;5(12):3178-83
4078623
Arch Int Pharmacodyn Ther. 1960 Apr 1;125:1-20
13809586
Pharmacol Biochem Behav. 2007 Oct;87(4):453-61
17618679
J Pharmacol Exp Ther. 1992 Nov;263(2):486-93
1432685
J Clin Psychopharmacol. 1990 Jun;10(3 Suppl):13S-20S
1973935
Prog Neuropsychopharmacol Biol Psychiatry. 1996 Aug;20(6):951-65
8888103
N Engl J Med. 2010 Jul 15;363(3):245-56
20647200
Pharmacol Biochem Behav. 1999 Oct;64(2):353-8
10515312
NIDA Res Monogr. 1991;(116):25-44
1369672
Psychopharmacologia. 1962 Mar 12;3:1-14
14007904
J Pharmacol Exp Ther. 1992 Nov;263(2):682-9
1359109
Eur J Pharmacol. 1989 Apr 12;163(1):145-9
2545460
Neuropharmacology. 1983 Aug;22(8):1001-5
6621823
Psychopharmacology (Berl). 1990;100(3):417-25
2138338
Psychopharmacology (Berl). 2003 Feb;166(1):61-8
12474110
Mol Pharmacol. 2006 Sep;70(3):1013-21
16772521
J Pharmacol Exp Ther. 1986 Jul;238(1):248-53
2941565
Psychopharmacology (Berl). 2010 Feb;208(2):179-89
19937319
Pharmacopsychiatry. 2005 Nov;38(6):301-11
16342002