Acute Neurochemical and Behavioral Effects of Stereoisomers of 4-Methylaminorex in Relation to Brain Drug Concentrations

Abstract

4-Methylaminorex is a stimulant drug of abuse that exists as four stereoisomers: cis-4R,5S, cis-4S,5R, trans-4S,5S, and trans-4R,5R. These isomers have previously been shown to differ markedly in various respects. In the present study we assessed the effects of the isomers of 4-methylaminorex (2.5, 5.0, and 10 mg/kg i.p.) on extracellular dopamine and 5-hydroxytryptamine (5-HT) levels in the nucleus accumbens, as well as behavior in the rats simultaneously. The relative concentrations of the isomers in the brain were also measured. The samples were collected by in vivo microdialysis and then analyzed for neurotransmitters with highperformance liquid chromatography/electrochemical detection and for cis-and trans-4-methylaminorex with gas chromatography/mass spectrometry. The behavioral effects of the isomers were assessed from videotapes recorded during the microdialysis experiments. All isomers elevated the extracellular levels of both dopamine and 5-HT, with the exception of trans-4R,5R. The rank order of potency for elevating dopamine was trans-4S,5S Ͼ cis-4S,5R Ϸ cis-4R,5S Ͼ trans-4R,5R, and for elevating 5-HT cis-4S,5R Ͼ trans-4S,5S Ϸ cis-4R,5S Ͼ trans-4R,5R. Analysis of the behavioral data, together with the neurochemical data, suggests that behavioral effects of the isomers of 4-methylaminorex are related to drug-induced dopamine release and, in the case of higher doses of the most efficacious isomers, to 5-HT as well. The brain concentrations of the isomers did not reflect their neurochemical efficacy, which implies that their differences are pharmacodynamic rather than pharmacokinetic.

Pharmacokinetics and Tissue Distribution of the Stereoisomers of 4-Methylaminorex in the Rat

“…Unlike the other isomers, trans-4R,5R-isomer demonstrated over 3-fold longer T 1/2el and markedly better F bioav after intraperitoneal and oral administrations. These findings confirm and expand upon the results of our earlier studies, in which the concentrations of trans-4R,5R-isomer seemed to be higher than those of the other isomers in rat brain microdialysis samples, or in rat serum and brain at a single time point (Kankaanpä ä et al, 2001(Kankaanpä ä et al, , 2002. Thus, the rank order of blood and brain concentrations of the stereoisomers was trans-4R,5R-Ͼ cis-4R,5S-Ϸ cis-4S,5R-Ϸ trans-4S,5S-isomer.…”

“…Thus, the rank order of blood and brain concentrations of the stereoisomers was trans-4R,5R-Ͼ cis-4R,5S-Ϸ cis-4S,5R-Ϸ trans-4S,5S-isomer. This is clearly incompatible with the rank order of potency trans-4S,5S-Ͼ cis-4R,5S-Ϸ cis-4S,5R-Ͼ trans-4R,5R-isomer observed in previous behavioral and neurochemical studies (Glennon and Misenheimer, 1989;Batsche et al, 1994;Ashby et al, 1995;Kankaanpä ä et al, 2002). The dissociation of in vivo drug effects from pharmacokinetics is further evidenced by the observation that trans-4R,5R-isomer administered intraperitoneally or subcutaneously induced behavioral activation more slowly than the other isomers (Glennon and Misenheimer, 1989;Batsche et al, 1994;Kankaanpä ä et al, 2002), although their k ab values and T 1/2ab values are equal, indicating a similar rate of absorption.…”

“…There are, however, only limited data available on the kinetic and metabolic properties of the stereoisomers of 4-methylaminorex. Somewhat surprisingly, our previous studies show that the concentrations of the least effective isomer trans-4R,5R might be higher than those of the other isomers in rat brain dialysate or tissue samples at given time points (Kankaanpä ä et al, 2001;Kankaanpä ä et al, 2002). The published data on the metabolism of 4-methylaminorex are limited to a single study.…”

“…Trans-4S,5S-isomer is the most potent isomer followed by the equally effective cisisomers, whereas trans-4R,5R-isomer is relatively ineffective (Glennon and Misenheimer, 1989;Batsche et al, 1994;Ashby et al, 1995;Kankaanpä ä et al, 2002). The behavioral response profile of the isomers may also differ; for instance, trans-4R,5R-isomer induced behavioral activation with slower onset than the other three isomers, and cis-4S,5R-isomer elicited locomotor activity, whereas the equipotent cis-4R,5S-isomer caused mainly stereotyped behavior at a similar dose (Glennon and Misenheimer, 1989;Ashby et al, 1995;Kankaanpä ä et al, 2002).…”

“…mer being even more potent than the other isomers (Glennon and Misenheimer, 1989;Batsche et al, 1994;Ashby et al, 1995;Kankaanpä ä et al, 2002), and instructions for their synthesis are readily available (Poos et al, 1963;Klein et al, 1989), which together render them a potential alternative among drugs of abuse. Accordingly, experiences of alleged trans-4-methylaminorex intake can be found on the Internet.…”