Showing papers by "David Fiorella published in 1999"

Serotonergic receptor subtypes and hallucinogen-induced stimulus control.

Abstract: More than a quarter century has passed since the demonstration that indoleamine and phenethylamine hallucinogens can function as discriminative stimuli in the rat, and that serotonergic systems are critically involved. During that period our knowledge of the physiology, pharmacology, biochemistry, and molecular biology of serotonergic receptors has increased exponentially; with each advance it has been necessary to reexamine our assumptions regarding hallucinogen-induced stimulus control. Of particular interest is the hypothesis that a drug may act, at a molecular level, upon multiple receptors to produce, at a behavioral level, a compound discriminative stimulus. The salience of the individual elements of such compound stimuli may be influenced by a variety of experimental factors including training dose, pretreatment time, the state of sensitization of the systems being acted upon, and the nature of the drugs chosen for tests of generalization. This article provides examples of experimental approaches to these complexities using selective agonists and antagonists, depletion-induced sensitization, and antagonist correlation analysis.

The Acute Effects of Monoamine Reuptake Inhibitors on the Stimulus Effects of Hallucinogens

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.

Partial generalization of (−)DOM to fluvoxamine in the rat: implications for SSRI-induced mania and psychosis

Abstract: Recent reports have implicated selective serotonin-reuptake inhibitors in the induction of psychosis and mania when SSRIs are given in combination with neuroleptics. We hypothesize that the partial substitution of fluvoxamine for the hallucinogen, (fi)DOM, in the rat provides evidence for a 5-HT # -mediated eect of fluvoxamine which may in turn account for the adverse eects observed in humans. Male Fischer-344 rats were trained with (fi)DOM (0.56 mg}kg) as a discriminative stimulus using standard operant procedures. Tests of generalization were then conducted with fluvoxamine either alone or in combination with the 5-HT "A antagonist, WAY-100635, the 5-HT # antagonist, pirenperone, and the neuroleptics, fluphenazine, chlorpromazine, thioridazine, loxapine, risperidone, and clozapine. In rats trained with (fi)DOM, fluvoxamine at a dose of 20 mg}kg yielded a maximum 58% (fi)DOM-appropriate response. This partial generalization was potentiated by treatment with WAY-100635 and antagonized by pirenperone, loxapine, risperidone, and clozapine. The present data are compatible with a 5-HT # -mediated eect of fluvoxamine which may play a role in SSRI-induced mania and psychosis. It is predicted by the results of this study that the probability of these adverse eects will be increased by the concurrent use of antagonists at 5-HT "A receptors and decreased by neuroleptics with antagonistic activity at 5-HT # receptors. Received 8 February 1999; Reviewed 29 March 1999; Revised 28 April 1999; Accepted 11 May 1999