Metabolic profile and pharmaco-toxicological effects of MPA in mouse model

Methiopropamine (MPA) is a thiophene ring-based structural analog of methamphetamine that is categorized as a novel psychoactive substance. MPA acts primary as a norepinephrine-dopamine reuptake inhibitor and, secondary, as a serotonin reuptake inhibitor. In human, MPA induces stimulation, alertness and increase of focus and energy. However, important side-effects were reported after MPA administration such as tachycardia, anxiety, panic attacks, perspiration, headache and difficulty in breathing. To date, few data are available on the pharmaco-toxicological effects of MPA and on its metabolism in vivo. To this purpose we investigated the acute in vivo effects induced by MPA on visual, acoustic and tactile sensorimotor responses, body temperature, pain threshold, motor activity, cardiovascular and cardiorespiratory changes in CD-1 male mice. In vitro (from human liver microsomes preparation) and in vivo (from CD-1 male mice urine) metabolism studies were also conducted in order to characterize the phase I metabolic profile of MPA, with the aim to select both the best marker(s) of intake and the responsible of the potential behavioural effects. Systemic administration of MPA (0.01-30 mg/kg) impaired visual placing response, facilitated acoustic and tactile response, induced hypothermia, increased mechanical and thermal analgesia stimulated locomotor activity and induced motor stereotypies in mice. MPA strongly affected cardiovascular and respiratory parameters. It induced tachycardia, increased diastolic and systolic blood pressure, caused vasoconstriction. Moreover, MPA increased breath rate but it reduced SpO2 saturation. The acute administration of MPA at 10 and 30 mg/kg caused the death (~30% and ~40%, respectively) of mice. Metabolism studies show that MPA is exensively oxidated to form mainly nor-MPA, hydroxy-MPA, oxo-MPA. The best markers of intake and the compounds detected in huge amount during the behavioural tests are the MPA itself and its hydroxylated and demethylated metabolites. The experimental evidence obtained in this study demonstrates for the first time that MPA impairs sensorimotor responses, has psychostimulant effect, causes cardiovascular and respiratory alterations, thus suggesting its possible hazard for human health. This research has been funded by the Drug Policies Department, Presidency of the Council of Ministers, Italy (project: “Effects of NPS: development of a multicentric research for the information enhancement of the Early Warning System” to MM) and FIRB 2012 to FDG.