Binding of beta-carbolines at 5-HT(2) serotonin receptors.

A series of ring-substituted (i.e., methoxy and bromo) 3,4-dihydro- and 1,2,3,4-tetrahydro-beta-carbolines was examined at 5-HT(2A) and 5-HT(2C) serotonin receptors. Whereas most of the methoxy-substituted derivatives typically displayed affinities similar to their unsubstituted parents, certain (particularly 8-substituted) bromo derivatives displayed enhanced affinity. A binding profile was obtained for selected beta-carbolines.

(+)Amphetamine-stimulus generalization to an herbal ephedrine product.

We have previously demonstrated that a (+)amphetamine stimulus generalizes both to (-)ephedrine and caffeine. Using rats trained to discriminate intraperitoneal (IP) administration of 1.0 mg/kg of (+)amphetamine (ED(50) = 0.4 mg/kg) from saline vehicle in a standard two-lever drug discrimination procedure, the present investigation shows that the (+)amphetamine stimulus generalizes to (+)amphetamine (ED(50) = 1.0 mg/kg) when administered via the intragastric (IG) route, and that (+)amphetamine appears about 2. 5-fold less potent when administered via the IG route compared to the IP route. Likewise, (-)ephedrine (ED(50) = 10.8 mg/kg) and caffeine (ED(50) = 32.9 mg/kg) are also 2.5-fold less potent when administered via the IG route compared to their potency when administered via the IP route. The (+)amphetamine stimulus also generalizes to an IG-administered herbal preparation (i.e., Herbal XTC; the herbal preparation possesses an approximate potency roughly comparable to what might have been expected on the basis of its reported ephedrine and/or caffeine content. These results demonstrate, for the first time, that an ephedrine-containing herbal preparation can produce a (+)amphetamine-like effect in animals.

(-)Ephedrine and caffeine mutually potentiate one another's amphetamine-like stimulus effects.

Using rats trained to discriminate 1 mg/kg of (+)amphetamine (ED50 = 0.4 mg/kg) from saline vehicle in a two-lever drug discrimination procedure, it was shown that (-)ephedrine (ED50 = 4.5 mg/kg), but not (+)ephedrine, substitutes for the (+)AMPH stimulus. It was also shown that caffeine (ED50 = 12.9 mg/kg) can substitute for (+)amphetamine in a dose-related fashion. Doses of (-)ephedrine and caffeine, which produced < or = 1% drug-appropriate responding when administered alone, were able to enhance each other's stimulus effects when administered in combination such that there was a twofold leftward shift in their respective dose-response curves. Furthermore, stimulus generalization occurred when a dose of caffeine that produced saline-appropriate responding when administered alone was administered in combination with (+)ephedrine. It would appear that low doses of (-)ephedrine and caffeine may mutually potentiate one another's stimulus effects in (+)AMPH-trained rats, and that a combination of caffeine and (+)ephedrine result in altered stimulus character when compared to comparable doses of either agent administered alone.

Cocaine--stimulus generalization to MDA optical isomers: a reevaluation.

It has already been demonstrated that the psychoactive agent 1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDA) produces effects that are both hallucinogen-like and amphetamine or stimulant-like in animals. Hallucinogenic activity is associated primarily with the R(-)-isomer of MDA whereas stimulant activity is primarily associated with the S(+)-isomer. Because a previous report indicates that S(+)MDA fails to substitute for cocaine in rats trained to discriminate cocaine from vehicle, and because these findings are inconsistent with the purported stimulant nature of S(+)MDA, we reinvestigated the effect of both MDA isomers in rats. In this investigation, S(+)MDA doses of 1.25 and 1.5 mg/kg were found to produce > 80% cocaine-appropriate responding in rats trained to discriminate 8 mg/kg of cocaine from saline. However, consistent with a previous report, R(-)MDA resulted only in partial generalization. These new results support the hypothesis that the optical isomers of MDA produce distinguishable stimulus effects in rats and that S(+)MDA is the more stimulant isomer of MDA.

Initial characterization of PMMA as a discriminative stimulus.

The phenylisopropylamine PMMA or N-methyl-1-(4-methoxyphenyl)-2-aminopropane, a structural hybrid of paramethoxyamphetamine (PMA) and methamphetamine, has been previously shown to unexpectedly lack amphetamine-like or hallucinogen-like stimulus properties in animals. For example, in tests of stimulus generalization, neither a (+)amphetamine stimulus nor a DOM stimulus generalized to PMMA. It has also been shown, however, that stimulus generalization does occur in animals trained to discriminate the designer drug MDMA ("Ecstasy" or N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane) from vehicle. In order to further characterize this unique agent, we trained a group of six Sprague-Dawley rats to discriminate 1.25 mg/kg of PMMA (ED50 = 0.44 mg/kg) from saline vehicle. The PMMA stimulus failed to generalize to the phenylisopropylamine stimulant (+)amphetamine, or to the phenylisopropylamine hallucinogen DOM. Stimulus generalization occurred to (+/-)MDMA (ED50 = 1.32 mg/kg) and S(+)MDMA (ED50 = 0.48 mg/kg). Partial generalization occurred with R(+)MDMA, PMA, 3.4-DMA, and fenfluramine. The PMMA stimulus also generalized to the alpha-ethyl homolog of PMMA (EH/PMMA, ED50 = 1.29 mg/kg). Taken together, the results of these studies suggest that PMMA is an MDMA-like agent that lacks the amphetamine-like stimulant character of MDMA. These findings support our previous suggestion that PMMA be considered the structural parent of the MDMA-like family of designer drugs.

Structure-activity studies on methoxy-substituted phenylisopropylamines using drug discrimination methodology.

Eighteen rats were trained to discriminate 1.0 mg/kg of (+)-amphetamine sulfate from saline in a two-lever operant procedure. Once responding was stable, these animals were administered various doses of sixteen different methoxy-substituted phenylisopropylamines in tests of stimulus generalization. Of three possible mono-methoxyphenylisopropylamines, all three produced amphetamine-appropriate responding, but none was as potent as racemic amphetamine. The amphetamine-stimulus did not completely generalize to any of the di- or tri-methoxyphenylisopropylamines.

Speculations on the mechanism of action of hallucinogenic indolealkylamines.

In this review we attempt to develop a fluid theoretical model which is being used as a strategy-base for future experimentation. The first two sections (A and B) describe how we have conducted our research, and present the perspective value of each. This is important because the research strategies developed in these laboratories over the last 5 years combine in vitro and in vivo pharmacological techniques as a means of understanding mechanisms of drug action. Sections C and D attempt to describe how we interpret our data and how we have utilized these data to formulate hypotheses concerning drug mechanisms. The last section of this review sets forth our own ideas on how we believe hallucinogenic agents produce their effects and presents some original data, which we feel, allows us to develop the overall hypotheses presented.