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  • Introduction Amphetamine AMPH methamphetamine MA and ethylen


    Introduction Amphetamine (AMPH), methamphetamine (MA), and 3,4-ethylenedioxymethamphetamine (MDMA) are widely abused psychoactive substances, with the basic chemical structure of phenylethylamine [1]. The abuse of these drugs is associated with psychostimulant, anorectic and hallucinogenic properties [2]. Furthermore, amphetamine analogs (AMPHs) exhibited significant toxic effects on the central nervous system, could cause long-term damage to nigrostriatal dopaminergic system [[3], [4], [5], [6]]. Indeed, compelling evidence suggested that MA [[7], [8], [9], [10], [11], [12], [13], [14]] and AMPHs (i.e., para-methoxymethamphetamine [15], and 3-fluoromethamphetamine [16]), induce neurotoxicity associated with oxidative stress, microglial activation, and pro-apoptotic changes. These neurotoxic potentials might be, at least in part, due to the excessive release of dopamine, followed by activation of dopamine receptors, and consistent degeneration of dopaminergic system [17]. Moreover, converging evidence indicated that either pharmacological antagonism [7,8,[18], [19], [20], [21]] or genetic inhibition of dopamine D1 or D2 FK-228 [18,22] protects from nigrostriatal dopaminergic neurotoxicity induced by MA, suggesting that dopamine receptors are critical mediators for the dopaminergic neurotoxicity. The use of novel psychoactive substances has been increasing substantially in many countries, and being used as recreational drugs in recent years [23]. The methiopropamine [MPA, 1-(2-thienyl)- 2-(methylamino)propane] is a MA analogue in which benzene ring has been replaced by a thiophene ring [24]. It was first synthesized in 1942 [25], and first appeared on internet selling as “legal highs” in 2010 [26]. MPA was first detected for the prevalence of synthetic drug in Europe in 2011 [27]. MPA is still legally available in Germany, but it became a controlled drug in Switzerland in 2012 [26]. In addition, there has been a growing evidence of MPA use in the United Kingdom (UK) in 2012 [28,29]. Administration of MPA encompasses a wide range of adverse effects including tachycardia, anxiety, insomnia, perspirations, and hallucinations [30]. A recent finding indicated that dopamine D2 receptor mediates behavioral sensitization exerted by MPA [31]. There are two reported cases on the significant acute toxicity induced by MPA [24], and even death in Australia [30], which are attributed to human MPA abuse. Moreover, three cases of fatal intoxication were reported in UK, and Sweden when MPA is consumed in conjunction with other drugs [30,32]. However, up to date, little is known about the neurotoxicity induced by MPA.
    Materials and methods
    Discussion We observed in this study that MPA treatment significantly induces initial oxidative burdens, followed by M1 phenotype-dependent microglial activation, and pro-apoptotic changes. Moreover, treatment with MPA resulted in significant impairments in dopaminergic system, and in behavioral activity. Both dopamine D1 receptor antagonist SCH23390 and D2 receptor antagonist sulpiride consistently and significantly attenuated dopaminergic toxicity induced by MPA, suggesting that activation of both dopamine D1 and D2 receptors contributes to MPA-induced dopaminergic neurotoxicity (Fig. 10). In addition, we propose here that Iba-1-labeled microglia, but not GFAP-labeled astroglia, may be the neurotoxic target for the activation of dopamine D1 and D2 receptors induced by MPA. Converging evidence indicated a possible connection between hyperthermic and neurotoxic responses of AMPHs [[52], [53], [54]]. Earlier reports suggested that MA-induced hyperthermia may be important for striatal dopamine depletion [52], formation of dopamine quinones [55], and thereby production of free radicals [56]. In addition, earlier reports suggested that inhibition of hyperthermia, at least in part, exhibits the protective effects on MA-dependent neurotoxicity [57,58]. Consistently, genetic or pharmacological inhibition of dopamine D1 or D2 receptor attenuated hyperthermic responses induced by AMPHs [8,16,22,59]. Similarly, we observed that MPA-induced hyperthermia requires activation of both dopamine D1 and D2 receptors.