Characterization of 4,4’-DMAR, a synthetic psychostimulant designer drug

Introduction: The new psychoactive drugs (NPS) are a wide series of new substances that have been designed to mimicking the psychotropic effect of traditional illicit drugs. The poor knowledge about these emerging NPS represents a serious problem for public health. In this study we evaluated the pharmacological profile, the brain penetration and the motivational propertiesof 4-methyl-5-(4-methylphenyl)-4,5-dihydrooxazol-2-amine (4,4’-DMAR) a synthetic derivative of 4-methylaminorex and aminorex, both of which are stimulants and controlled under the 1971 United Nations Convention on Psychotropic Substances. Methods: Independent groups of naïve male Wistar rats were used in all experiments. The doses of 4,4’-DMAR to be tested were selected on the basis of the primary observation Irwin test. Pharmacokinetics of 4,4’-DMAR was evaluated by HPLC-MS/MS. Alterations in locomotor activity after 4,4’-DMAR administration were measured in activity cages equipped with photobeams, while rewarding properties of the drug were assessed in an unbiased conditioned place preference (CPP) paradigm. Results: Pharmacokinetics studies found that the peak in plasma and brain is around 1 hr after the administration. The acute and chronic administration of 4,4’-DMAR (3-10 mg/kg i.p.) produced a dose-dependent increase in locomotor activity with a sort of sensitization after 14 day treatment that is maintained also after a 48 hr wash-out. 4,4’-DMAR 10 mg/kg i.p., but not 1 and 3 mg/kg, induces CPP that was similar to the one induced by cocaine (10 mg/kg i.p.). Conclusion: These data demonstrate that 4,4’-DMAR is a potent psychostimulant drug eliciting positive motivational properties.