Neuropharmacology of levamisole and its phase I metabolites

Abstract

RATIONALE: The anthelmintic agent, levamisole, is a cocaine adulterant that causes serious adverse effects in humans. A number of hypotheses have been proposed to explain why levamisole is used as an adulterant. Here, we examined whether levamisole might enhance acute pharmacological effects of cocaine.

METHODS: Levamisole and its phase I metabolites were tested for in vitro activity at monoamine receptors and transporters. The effect of levamisole (0.1-10 µM) on cocaine-induced inhibition of [3H]dopamine uptake was examined in rat brain synaptosomes. In vivo microdialysis in nucleus accumbens of male rats was employed to determine neurochemical effects of cocaine (1-3 mg/kg, intravenous), in the absence or presence of levamisole (1:1 ratio with cocaine).

RESULTS: Levamisole displayed no measurable activity at monoamine receptors or transporters. The metabolite aminorex acted as a potent substrate at transporters for dopamine, norepinephrine and serotonin, whereas rexamino had affinity for adrenoreceptors and weak substrate activity at norepinephrine transporters. Levamisole did not alter cocaine-induced inhibition of dopamine uptake in vitro. Administration of cocaine, or cocaine plus levamisole, produced similar increases in extracellular dopamine and locomotor stimulation in vivo.

CONCLUSIONS: We found no evidence that levamisole alters the acute pharmacological effects of cocaine in male rats. The metabolite aminorex is a potent monoamine transporter substrate which could contribute to effects of levamisole under certain conditions (e.g., repeated, high-dose exposure), but most studies in human users of levamisole-adulterated cocaine have failed to detect measurable quantities of aminorex.