Assessment of liability to substance use disorder induced by two emerging stimulants, 4,4'-dimethylaminorex and escaline, in mice.

Background: The emergence of new psychoactive substances (NPSs) poses a serious global health threat. Although various groups of psychostimulants exist, this study specifically investigated two lesser-studied substances, 4,4'-dimethylaminorex (4,4'-DMAR) and escaline.Objective: To assess liability to substance use disorder (SUD), as evidenced via preclinical models, of the two psychostimulants.Methods: 4,4'-DMAR and escaline were evaluated, in mice, for their potential to exhibit rewarding and reinforcing effects, and for causing central dopaminergic activity. The climbing behavior test investigated whether the substances acted as dopaminergic agents and to determine the dose range for further evaluation. The rewarding and reinforcing effects of these substances were evaluated via the conditioned place preference (CPP) and self-administration (SA) tests.Results: The results showed that both test substances significantly increased climbing behavior at 1 mg/kg (p < .01). Mice treated with 0.1 and 1 mg/kg 4,4'-DMAR (p < .05) and with 1 mg/kg escaline (p < .01) exhibited increased duration of time spent in the substance-paired compartment in the CPP test compared to those treated with vehicle. Further, the frequency of infusions from the 5th to 7th sessions was significantly increased at 1 mg/kg/infusion of 4,4'-DMAR (p < .001) and at 0.01 and 0.1 mg/kg/infusion of escaline (p < .01) compared to controls.Conclusion: The findings suggest that 4,4'-DMAR and escaline have dopaminergic activity, exert reinforcing and rewarding effects, and may cause SUD. The findings can inform relevant authorities about the need to regulate these two new compounds.