Evaluation of Multi-target Drugs on the Cocaine-induced Locomotor Sensitization in Rats

Abstract Purpose — Cocaine use disorder (CUD) is a complex disease. Some suggest that multi-target drugs could be useful in the treatment of cocaine use disorder. Several studies have shown the efficacy of various multi-target-target drugs used in clinical studies to treat CUD; which integrate into their pharmacological profile the simultaneous NE or 5-HT receptors antagonism or agonism. However, the results of these studies have not shown results consistently. Thus, this study aimed to compare the efficacy of various multi-target drugs on cocaine-induced behavioral effects in rats. Methods — Male Wistar rats received cocaine (10 mg/Kg; i.p.) during the induction and expression of locomotor sensitization. The MIR, PIN, FLX, RIS, TRZ, ZRP, OND, YOH, or PRZ were administered 30 minutes before cocaine. After each treatment, the locomotor activity was recorded for 30 minutes. In experiments 5 and 6, the animals were sacrificed after treatment administration. Dopamine levels were determined in the ventral striatum, the prefrontal cortex (PFc), and the ventral tegmental area (VTA) by high-performance liquid chromatographic (HPLC) in animals treated with mirtazapine and cocaine. The quantification of c-fos immunoreactive cells was carried out by stereology analysis. Results — In this study, we found mirtazapine generated a decrease in cocaine-induced locomotor activity of greater magnitude and duration compared to the other drugs evaluated. Also, at the optimal doses used the PIN, FLX, RIS, TRZ, ZRP, OND, YOH, or PRZfailed to attenuate long-term cocaine locomotor activation. In addition, mirtazapine decreased in the striatum, prefrontal cortex (PFc), and ventral-tegmental area (VTA) the amount of cocaine-induced extracellular dopamine and the number of cells immunoreactive to the Fos protein. Conclusion — At the optimal doses of drugs evaluated, mirtazapine was the multi-target drug that showed the greatest long-term effects on cocaine-induced behavioral effects compared to other multi-target drugs.