Chemistry to cognition: Therapeutic potential of (m-CF₃-PhSe)₂ targeting rats' striatum dopamine proteins in...

Amphetamine (AMPH) abuse represents a major global public health issue, highlighting the urgent need for effective therapeutic interventions to manage addiction caused by this psychostimulant. This study aimed to assess the potential of m-trifluoromethyl-diphenyldiselenide [(m-CF₃-PhSe)₂] in preventing the addictive effects induced by AMPH through targeting dopamine metabolism proteins. (m-CF₃-PhSe)₂ is of interest due to its demonstrated efficacy in mitigating opioid abuse, establishing it as a promising candidate for addiction treatment research. Initially, in silico studies examined the affinity of AMPH and (m-CF₃-PhSe)₂ for dopamine 1, 2, and 3 receptors (D1R, D2R, D3R), and dopamine transporter (DAT). In our experimental design, male Wistar rats were divided into four groups: I) Control; II) (m-CF₃-PhSe)₂; III) AMPH; IV) (m-CF₃-PhSe)₂ + AMPH. Animals were administered (m-CF₃-PhSe)₂ (0.1 mg/kg, by gavage) or canola oil (vehicle) 30 min before AMPH (4.0 mg/kg, i.p.) administration. Drug administration occurred for 8 days in the conditioned place preference (CPP) paradigm. Twenty-four hours after the last CPP conditioning section, preference for the drug-compartment was assessed, with anxiety-related effects and working memory were evaluated using the Y-maze test. Finally, animals were euthanized for striatal dissection to quantify D1R, D2R, D3R, and DAT levels in western blot. In silico findings suggest that (m-CF₃-PhSe)₂ may prevent AMPH activation in DAT, interacting with Asp46 and Phe319, preventing possible addictive effects of AMPH in DAT. In vivo results showed that (m-CF₃-PhSe)₂ attenuated AMPH effects, reducing preference for the drug-compartment in CPP test. Furthermore, (m-CF₃-PhSe)₂ prevented AMPH-induced anxiogenic effects in the elevated plus maze (EPM) test, similarly to light/dark test. No differences in locomotion or working memory were observed among the experimental groups in the Y-maze test. Ex vivo western blot analyses of the entire striatum indicates that (m-CF₃-PhSe)₂ prevented the AMPH-induced increase in D1R levels and decrease in D2R and DAT levels, with no changes in D3R levels. Overall, our study suggests that (m-CF₃-PhSe)₂ may interact with DAT sites similarly to AMPH, reducing drug-compartment preference and anxiogenic behaviors while maintaining dopaminergic metabolism proteins in the striatum, a key region involved in the onset and perpetuation of addiction.