Stimulus control by hallucinogens: SSRI interactions.

摘要

Hallucinogens are subject to widespread abuse, especially among high school and college students. The interoceptive states created by psychoactive drugs have been studied using drug discrimination techniques in animal subjects. Previous studies indicate that several selective serotonin reuptake inhibitors [SSRI's] enhance or in some cases, partially mimic hallucinogen-induced stimulus control in the rat. The objective of the project was to gain insight into the mechanism by which selective serotonin reuptake inhibitors [SSRI's] potentiate the stimulus effects of hallucinogens.; A GC-MS assay was developed to quantitate levels of the phenethylamine hallucinogen [−]-2,5-dimethoxy-4-methylamphetamine [DOM] in the rat brain in order to address potential pharmacokinetic contributions to the observed interaction. Our findings indicate that peak levels of [−]-DOM are present between 15 and 30 min following IP injection. The data indicate that fluoxetine but not citalopram significantly increased DOM brain levels.; The interaction between DOM and citalopram was examined in rats trained with DOM [0.6 mg/kg; 75 min pretreatment time] as a discriminative stimulus. Pretreatment with citalopram at a dose of 1.0 mg/kg shifted the DOM dose response relationship to the left. Unlike previously tested SSRI's, the enhancement of DOM-induced stimulus control occurred in the absence of significant partial substitution by citalopram. It is concluded that the effects of DOM as a discriminative stimulus are potentiated by the acute administration of citalopram and this effect is not mediated by additivity or pharmacokinetic mechanisms. The data suggest that the modulatory action at the 5-HT_2C receptor by citalopram mediates the pharmacodynamic potentiation of [−]-DOM-induced stimulus control in the rat.; All previously studied SSRI's enhanced to some degree the stimulus effects of hallucinogens. In order to determine if this observation was a property of all SSRI's we examined nefazodone, marketed as an agent that inhibits serotonin (5-HT) reuptake while antagonizing 5-HT₂ receptors. However, unlike (±) fluoxetine, fluvoxamine, venlafaxine, and citalopram, higher doses of nefazodone appear to reduce [−]-DOM appropriate responding. Additional experimentation suggests that (a) nefazodone acts as a partial agonist and (b) these effects are mediated by the 5-HT_2A receptor.; Observations resulting from the previously mentioned studies resulted in investigations to test the hypothesis that known metabolites of DOM are pharmacologically active. This hypothesis was tested by evaluating the ability of racemic DOM metabolites 2-O-desmethyl DOM [2-DM-DOM] and 5-O-desmethyl DOM [5-DM-DOM] to substitute for the stimulus properties of (+)lysergic acid diethylamide [LSD]. The data indicate that both metabolites are active in LSD-trained subjects and are significantly inhibited by the selective 5-HT _2A receptor antagonist M100907.