piperidines and 2-5-dimethoxy-4-bromoamphetamine

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

Topics: Animals; Cues; Discrimination Learning; Discrimination, Psychological; DOM 2,5-Dimethoxy-4-Methylamphetamine; Dose-Response Relationship, Drug; Fluorobenzenes; Food; Hallucinogens; Lysergic Acid Diethylamide; Male; Mice; Mice, Inbred C57BL; Piperidines; Receptor, Serotonin, 5-HT2A; Reinforcement Schedule; Reinforcement, Psychology; Serotonin Antagonists

The drug discrimination procedure has proven to be a valuable tool for studying the mechanism of action of psychoactive drugs. Recently, mice with targeted gene mutations have been developed that may also prove useful in evaluating the role of specific receptors in mediating the actions of drugs. We were interested in studying the effects of hallucinogens in genetically modified mice using the drug discrimination procedure.. To establish the training procedures and characterize the stimulus properties of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(+/-)DOI] versus saline in wild-type mice.. Using a two-lever drug discrimination procedure, C57BL/6J mice were trained to discriminate (+/-)DOI (2.5 mg/kg) from saline on a VI 30-s schedule of reinforcement.. The acquisition function was orderly and similar to that found previously with rats, although the training dose required for the mice was four times higher (2.5 versus 0.75 mg/kg). The dose-response relationship indicated that percent drug lever responding was dose-dependent. Two other hallucinogens, LSD and (-)DOB, substituted fully for (+/-)DOI. Mice were tested for their ability to discriminate (+/-)DOI following pretreatment with the 5-HT(2A) receptor antagonist MDL 100,907, or with 5-HT(2C) selective antagonists, SB 206,553 or SB 242,084. A dose of 0.25 mg/kg MDL 100,907 essentially completely blocked the discriminative stimulus effects of 2.5 mg/kg (+/-)DOI. Surprisingly, both SB 206,553 and SB 242,084 also attenuated the effect of 2.5 mg/kg (+/-)DOI. The effect of SB 206,553 was surmountable at 5.0 mg/kg (+/-)DOI.. These data agree with the results from studies with rats indicating a prominent role for the 5-HT(2A) receptors in mediating the discriminative stimulus effects of (+/-)DOI but in addition, suggest a small but significant role for the 5-HT(2C) receptor in mice.

Topics: Aminopyridines; Animals; Conditioning, Operant; Discrimination Learning; DOM 2,5-Dimethoxy-4-Methylamphetamine; Dose-Response Relationship, Drug; Fluorobenzenes; Indoles; Indophenol; Lysergic Acid Diethylamide; Male; Mice; Mice, Inbred C57BL; Piperazines; Piperidines; Pyridines; Reaction Time; Reinforcement Schedule; Serotonin Antagonists; Serotonin Receptor Agonists