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

• Published in: Progress in neuro-psychopharmacology & biological psychiatry 2024-12, Vol.136, p.111238, Article 111238
• Main Authors: Dahleh, Mustafa Munir Mustafa, Muller, Sabrina Grendene, Klann, Isabella Pregardier, Marques, Luiza Souza, da Rosa, Jéssica Leandra, Fontoura, Murilo Barboza, Burger, Marilise Escobar, Nogueira, Cristina Wayne, Prigol, Marina, Boeira, Silvana Peterini, Segat, Hecson Jesser
• Format: Article
• Language: English
• Subjects: Amphetamine; Anxiety; Dopamine; Drug addiction; Psychostimulants
• ISSN: 0278-5846; 1878-4216; 1878-4216
• DOI: 10.1016/j.pnpbp.2024.111238

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. [Display omitted] •(m-CF3-PhSe)2 exhibits interactions with Dopa