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


OBJECTIVE
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.


CONCLUSIONS
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.
Marona-Lewicka
Danuta
D
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, Heine Pharmacy Building, 575 Stadium Mall Dr., West Lafayette, IN 47907-2091, USA.
Thisted
Ronald A
RA
Nichols
David E
DE
D000661:Amphetamine / Q000494:pharmacology; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D003463:Cues; D004193:Discrimination Learning / Q000187:drug effects; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005464:Fluorobenzenes / Q000494:pharmacology; D006213:Hallucinogens / Q000008:administration & dosage / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D007189:Indans / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D008238:Lysergic Acid Diethylamide / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D011618:Psychotic Disorders / Q000503:physiopathology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013997:Time Factors
D000662:Amphetamines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D018765:Dopamine Uptake Inhibitors; D005464:Fluorobenzenes; D006213:Hallucinogens; D007189:Indans; D010880:Piperidines; D011804:Quinolines; D017448:Receptors, Dopamine D2; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C068879:5-methoxy-6-methyl-2-aminoindan; D008238:Lysergic Acid Diethylamide; D000661:Amphetamine; C079049:volinanserin; D006220:Haloperidol; D001058:Apomorphine; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; C047726:quinelorane
Pharmacol Biochem Behav. 1999 Oct;64(2):283-93
10515304
Life Sci. 1984 Dec 17;35(25):2505-11
6513725
Pharmacol Biochem Behav. 1986 Feb;24(2):407-15
3006090
Psychopharmacology (Berl). 1996 Mar;124(1-2):57-73
8935801
J Med Chem. 1993 Aug 20;36(17):2519-25
8355253
Eur J Pharmacol. 1983 Jul 22;91(2-3):189-96
6617740
Eur J Pharmacol. 1982 Jul 30;81(4):595-602
7117388
Life Sci. 1982 Jun 14;30(24):2057-62
7109835
J Pharmacol Exp Ther. 2002 Jun;301(3):1166-78
12023552
Neuropharmacology. 1997 Oct;36(10):1471-5
9423936
Pharmacol Biochem Behav. 1988 Jul;30(3):617-24
3211970
Psychopharmacology (Berl). 1995 Apr;118(4):401-9
7568626
Eur J Pharmacol. 1994 Jun 2;258(1-2):1-13
7925587
NIDA Res Monogr. 1994;146:157-82
8742798
Eur J Pharmacol. 1984 Jul 20;102(3-4):541-4
6489439
Pharmacol Biochem Behav. 2003 Feb;74(3):713-21
12543238
Psychopharmacology (Berl). 1982;77(2):179-85
6812137
Eur J Pharmacol. 1985 Jan 22;108(2):179-86
3156756
Psychopharmacology (Berl). 1991;105(1):69-76
1745714
Synapse. 1987;1(2):133-52
2905529
Mol Pharmacol. 1982 Mar;21(2):301-14
7099138
J Neurochem. 2001 Mar;76(5):1521-31
11238736
Pharmacol Biochem Behav. 1999 Oct;64(2):251-6
10515299
Neuropharmacology. 1978 Apr-May;17(4-5):257-63
652138
Psychopharmacology (Berl). 1989;98(3):321-9
2501811
J Pharmacol Exp Ther. 1982 Apr;221(1):206-14
7062283
Psychopharmacology (Berl). 1995 May;119(2):239-45
7659772
Eur J Pharmacol. 1994 Oct 13;264(1):99-102
7530204
Psychopharmacology (Berl). 1990;100(1):13-8
2296621
Pharmacol Biochem Behav. 1980 Oct;13(4):549-54
6107936
Pharmacol Ther. 2004 Feb;101(2):131-81
14761703
Psychopharmacology (Berl). 1982;76(2):130-5
6805022
Pharmacol Biochem Behav. 1999 Oct;64(2):353-8
10515312
J Med Chem. 1990 Jun;33(6):1756-64
1971308
J Pharmacol Exp Ther. 1949 Jun;96(2):99-113
18152921
Psychopharmacology (Berl). 1990;100(3):417-25
2138338
J Pharmacol Exp Ther. 1989 Oct;251(1):238-46
2571717
J Psychopharmacol. 1998;12(3):289-304
10958257
Neuropharmacology. 1983 Aug;22(8):1001-5
6621823
Psychopharmacology (Berl). 1989;97(2):206-12
2471220
Neuropsychopharmacology. 1999 Aug;21(2 Suppl):106S-115S
10432496
Behav Neurosci. 1985 Oct;99(5):881-900
3843306
Biosci Rep. 2001 Dec;21(6):691-710
12166820