Comparison of the action of the stereoisomers of the psychostimulant 4‐methylaminorex (4‐MAX) on midbrain dopamine cells in the rat: An extracellular single unit study

Abstract

In this study, we examined and characterized the action of the stereoisomers of 2-amino-4-methyl-delta 2-5-phenyl-oxazoline (4-methylaminorex, 4-MAX) on spontaneously active dopamine (DA) neurons in the substantia nigra pars compacta (SNC or A9) and ventral tegmental area (VTA or A10) in anesthetized male rats. This was accomplished using the technique of extracellular single unit recording. The intravenous (i.v.) administration of the stereoisomers of 4-MAX (0.1-6.4 mg/kg) produced a dose-dependent suppression of the basal firing rate of A10 DA cells with the following rank order of potency: trans 4S,5S > cis 4R,5S approximately cis 4S,5R >> trans 4S,5S 4-MAX. The rank order of potency of the isomers of 4-MAX to suppress the firing of A9 DA cells was trans 4S,5S = cis 4R,5S = cis 4S,5R >> trans 4R,5R. The trans 4S,5S isomer was 5-fold more potent in suppressing DA cell firing in the A10 compared to the A9 area. The suppressant action of the isomers on A9 and A10 DA cells was reversed by the i.v. administration of haloperidol and the D2/D3 receptor antagonists (-)-sulpiride and (-)-eticlopride but not by the D1 receptor antagonists SCH 23390 and SCH 39166. In addition, the suppressant action of the trans 4S,5S isomer on A10 DA cells was not antagonized or reversed by the i.v. administration of the receptor antagonists granisetron (5-HT3), ritanserin (5-HT2A,C), idazoxan (alpha 2), phentolamine (peripheral alpha 1), (+/-)-pindolol (5-HT1A,B beta) or prazosin (alpha 1). The pretreatment of animals with either alpha-methyl-p-tyrosine (AMPT) or reserpine, but not p-chlorophenylalanine (PCPA), (+/-)-fluoxetine or tomoxetine, significantly attenuated the suppression of A10 DA cell firing produced by trans 4S,5S 4-MAX. Overall, our results suggest that the suppressant action of 4-MAX on midbrain DA cell firing may be mediated by the release of DA, which subsequently interacts with D2/D3 receptors.

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

“…The rank order for elevating 5-HT was cis-4S,5R Ͼ trans-4S,5S Ϸ cis-4R,5S Ͼ trans-4R,5R, whereas the corresponding order for elevating extracellular dopamine was trans-4S,5S Ͼ cis-4S,5R Ϸ cis-4R,5S Ͼ trans-4R,5R. The latter is consistent with the preliminary microdialysis report by Eberle et al (1992) and also with observations concerning the potential of the isomers in substituting for S-amphetamine (Glennon and Misenheimer, 1990), inducing locomotor activity and stereotypes (Batsche et al, 1994) and suppressing the basal firing rate of A10 dopamine cells (Ashby et al, 1995). As remarked by Glennon and Misenheimer (1990), similar rank order can be predicted from the established structure-activity relationships for central stimulant and discriminative stimulus properties of phenylisopropylamines.…”

“…This rank order is also identical to that observed when measuring dopaminergic parameters (Eberle et al, 1992;Ashby et al, 1995; this study), which suggests that the behavioral effects of moderate doses of 4-methylaminorex are mediated by its effect on dopamine. Furthermore, dopaminergic manipulations were shown to attenuate locomotor activity induced by trans-4S,5S-4-methylaminorex (Batsche et al, 1994) and the ability of the same isomer to suppress basal firing rates of A10 dopamine cells (Ashby et al, 1995).…”

“…A similar phenomenon may also underlie the changes observed in both cis-isomers and the isomer trans-4S,5S. Such dual mechanisms are supported by observations of Ashby et al (1995) who showed that the suppressant effects of trans-4S,5S-4-methylaminorex on A10 dopamine cells are attenuated by pretreating animals with ␣-methyl-p-tyrosine or reserpine, which depletes newly synthesized cytoplasmic dopamine and vesicular stores of monoamines, respectively (Garattini and Samanin, 1981). Taken together, it seems that both cytoplasmic and vesicular dopamine mediate the effects of trans-4S, 5S-, cis-4S,5R-, and cis-4R,5S-4-methylaminorex, which implies an action mechanism involving both dopamine release and uptake inhibition.…”

“…Published reports concerning the effects of the 4-methylaminorex stereoisomers include evaluation of the isomers' ability to substitute for S-amphetamine in drug discrimination paradigms (Glennon and Misenheimer, 1990), to induce locomotor activity or stereotyped behavior (Batsche et al, 1994), and to suppress the basal firing rate of A10 dopamine cells in an extracellular single unit study (Ashby et al, 1995). In all these studies, the rank order of potencies of the isomers was trans-4S,5S Ͼ cis-4S,5R Ϸ cis-4R,5S Ͼ trans-4R,5R.…”

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

“…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.…”