title: Aminorex, a metabolite of the cocaine adulterant levamisole, exerts amphetamine like actions at monoamine transporters.
abstract: Psychostimulants such as amphetamine and cocaine are illicitly used drugs that act on neurotransmitter transporters for dopamine, serotonin or norepinephrine. These drugs can by themselves already cause severe neurotoxicity. However, an additional health threat arises from adulterant substances which are added to the illicit compound without declaration. One of the most frequently added adulterants in street drugs sold as cocaine is the anthelmintic drug levamisole. We tested the effects of levamisole on neurotransmitter transporters heterologously expressed in HEK293 cells. Levamisole was 100 and 300-fold less potent than cocaine in blocking norepinephrine and dopamine uptake, and had only very low affinity for the serotonin transporter. In addition, levamisole did not trigger any appreciable substrate efflux. Because levamisole and cocaine are frequently co-administered, we searched for possible allosteric effects; at 30μM, a concentration at which levamisole displayed already mild effects on norepinephrine transport it did not enhance the inhibitory action of cocaine. Levamisole is metabolized to aminorex, a formerly marketed anorectic drug, which is classified as an amphetamine-like substance. We examined the uptake-inhibitory and efflux-eliciting properties of aminorex and found it to exert strong effects on all three neurotransmitter transporters in a manner similar to amphetamine. We therefore conclude that while the adulterant levamisole itself has only moderate effects on neurotransmitter transporters, its metabolite aminorex may exert distinct psychostimulant effects by itself. Given that the half-time of levamisole and aminorex exceeds that of cocaine, it may be safe to conclude that after the cocaine effect "fades out" the levamisole/aminorex effect "kicks in".
authors.affiliation: Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Waehringerstrasse 13A, 1090 Vienna, Austria.
authors.forename: Tina
authors.initials: T
authors.lastname: Hofmaier
authors.affiliation: Clinical Department of Laboratory Medicine, Medical University of Vienna, Waehringer Guertel 10-20, 1090 Vienna, Austria.
authors.forename: Anton
authors.initials: A
authors.lastname: Luf
authors.affiliation: University of Vienna, Department of Medicinal Chemistry, Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Amir
authors.initials: A
authors.lastname: Seddik
authors.affiliation: Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Waehringerstrasse 13A, 1090 Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Stockner
authors.affiliation: Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Waehringerstrasse 13A, 1090 Vienna, Austria.
authors.forename: Marion
authors.initials: M
authors.lastname: Holy
authors.affiliation: Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Waehringerstrasse 13A, 1090 Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Freissmuth
authors.affiliation: University of Vienna, Department of Medicinal Chemistry, Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Gerhard F
authors.initials: GF
authors.lastname: Ecker
authors.affiliation: Clinical Department of Laboratory Medicine, Medical University of Vienna, Waehringer Guertel 10-20, 1090 Vienna, Austria.
authors.forename: Rainer
authors.initials: R
authors.lastname: Schmid
authors.affiliation: Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Waehringerstrasse 13A, 1090 Vienna, Austria. Electronic address: harald.sitte@meduniwien.ac.at.
authors.forename: Harald H
authors.initials: HH
authors.lastname: Sitte
authors.affiliation: Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Waehringerstrasse 13A, 1090 Vienna, Austria.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kudlacek
mesh_terms: D000635:Aminorex / Q000494:pharmacology*; D000661:Amphetamine / Q000494:pharmacology*; D001067:Appetite Depressants / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D003042:Cocaine / Q000737:chemistry*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D004340:Drug Contamination; D057809:HEK293 Cells; D006801:Humans; D007978:Levamisole / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects; D050493:Vesicular Monoamine Transport Proteins / Q000187:drug effects*
chemical_list: D001067:Appetite Depressants; D050483:Dopamine Plasma Membrane Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D007978:Levamisole; D000635:Aminorex; D000661:Amphetamine; D003042:Cocaine
keywords: Adulterant; Aminorex; Cocaine; Levamisole; Neurotransmitter transporter