Complex discriminative stimulus properties of (+)lysergic acid diethylamide (LSD) in C57Bl/6J mice.
BACKGROUND
The drug discrimination procedure is the most frequently used in vivo model of hallucinogen activity. Historically, most drug discrimination studies have been conducted in the rat. With the development of genetically modified mice, a powerful new tool has become available for investigating the mechanisms of drug-induced behavior. The current paper is part of an ongoing effort to determine the utility of the drug discrimination technique for evaluating hallucinogenic drugs in mice.


OBJECTIVE
To establish the training procedures and characterize the stimulus properties of (+)lysergic acid diethylamide (LSD) in mice.


METHODS
Using a two-lever drug discrimination procedure, C57Bl/6J mice were trained to discriminate 0.45 mg/kg LSD vs saline on a VI30 sec schedule of reinforcement, with vanilla-flavored Ensure serving as the reinforcer.


RESULTS
As in rats, acquisition was orderly, but the training dose was nearly five-fold higher for mice than rats. LSD lever selection was dose-dependent. Time-course studies revealed a rapid loss of the LSD stimulus effects. The 5-HT(2A/2C) receptor agonist, 2,5-dimethoxy-4-bromoamphetamine [(-)DOB] (1.0 mg/kg), substituted fully for LSD and the 5-HT(1A) receptor agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) (1.6 mg/kg), substituted partially for LSD. Pretreatment with the 5-HT(2A) receptor-selective antagonist, MDL 100907, or the 5-HT(1A)-selective antagonist WAY 100635, showed that each antagonist only partially blocked LSD discrimination. Substitution of 1.0 mg/kg (-)DOB for LSD was fully blocked by pretreatment with MDL 100907 but unaltered by WAY 100635 pretreatment.


CONCLUSIONS
These data suggest that in mice the stimulus effects of LSD have both a 5-HT(2A) receptor and a 5-HT(1A) receptor component.
Benneyworth
Michael A
MA
Department of Pharmacology, Vanderbilt University School of Medicine, 8148 MRB III, Nashville, TN 37232, USA.
Smith
Randy L
RL
Barrett
Robert J
RJ
Sanders-Bush
Elaine
E
D004290:DOM 2,5-Dimethoxy-4-Methylamphetamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D003463:Cues; D004193:Discrimination Learning; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005464:Fluorobenzenes / Q000494:pharmacology; D005502:Food; D006213:Hallucinogens / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008238:Lysergic Acid Diethylamide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010880:Piperidines / Q000494:pharmacology; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology; D012702:Serotonin Antagonists / Q000494:pharmacology
D005464:Fluorobenzenes; D006213:Hallucinogens; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D012702:Serotonin Antagonists; D004290:DOM 2,5-Dimethoxy-4-Methylamphetamine; C003943:2,5-dimethoxy-4-bromoamphetamine; D008238:Lysergic Acid Diethylamide; C079049:volinanserin