The acute effects of monoamine reuptake inhibitors on the stimulus effects of hallucinogens.

Pretreatment with the monoamine reuptake inhibitors fluoxetine, fluvoxamine, and venlafaxine increased the discriminative stimulus effects of the hallucinogens LSD, (-)-DOM, and ibogaine in rats trained to recognize these drugs. For 5-MeO-DMT-trained rats, only fluoxetine enhanced drug-appropriate responding. The reuptake inhibitors alone sometimes produced intermediate responding, suggesting partial substitution. Further experiments with (-)-DOM showed that most combinations produced additive rather than truly potentiating effects. The findings extend earlier observations that fluoxetine augments LSD's effects to include other hallucinogens, though the mechanisms and differences between acute and chronic treatment remain unknown.

Study at a glance

Abstract

In a previous study it was observed that fluoxetine potentiates the stimulus effects of lysergic acid diethylamide (LSD). In the present investigation, stimulus control was established in groups of rats using as training drugs the hallucinogens lysergic acid diethylamide (LSD); 0.1 mg/kg), (-)-2,5-dimethoxy-4-methylamphetamine [(-)-DOM; 0.56 mg/kg], ibogaine (10 mg/kg), and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT; 3 mg/kg). A two-lever, fixed-ratio 10, positively reinforced task with saline controls was employed. The hypotheses tested were that (a) monoamine uptake inhibitors other than fluoxetine potentiate the discriminative effects of LSD, and (b) hallucinogens other than LSD are potentiated by acute pretreatment with monoamine uptake inhibitors. The effects of a range of doses of each of the training drugs were determined both alone and following pretreatment with the monoamine reuptake inhibitors fluoxetine, fluvoxamine, and venlafaxine. In LSD-trained subjects, all three reuptake inhibitors caused a significant increase in LSD-appropriate responding. Similar results were observed in rats trained with (-)-DOM and with ibogaine. In 5-MeO-DMT-trained subjects, only fluoxetine resulted in an enhancement of drug-appropriate responding. The reuptake inhibitors given alone elicited varying degrees of responses appropriate for the respective training drugs. For fluoxetine in rats trained with LSD and ibogaine, for venlafaxine in LSD trained, and for fluvoxamine in (-)-DOM trained, the degree of responding met our criterion for intermediate responding, i.e., significantly different from both training conditions. Subsequent experiments in (-)-DOM-trained subjects examined a range of doses of each of the reuptake inhibitors in combination with a fixed dose of (-)-DOM (0.1 mg/kg), which alone yielded about 50% (-)-DOM-appropriate responding. With the exception of the point obtained with the highest dose of venlafaxine, all data were compatible with additivity of effects rather than true potentiation. In summary, the present data extend our previous observation of the augmentation of the stimulus effects of LSD by fluoxetine to include other hallucinogens. The mechanisms by which these interactions arise and possible differential effects of acute and chronic treatment remain to be established.