In this study, we evaluated the preventive effect of mazindol on the development of obesity and sought to elucidate the drug's effects on the reward system. In mice, body weight gain and hyperphagia induced by high-fat diet (HFD) were decreased by 38.6% and 13.9%, respectively, by subcutaneous infusion of mazindol (1.5 mg/kg/day) for 28 days. A single intraperitoneal administration of mazindol (1.5 mg/kg) significantly reduced lipid preference, as assessed using the two-bottle preference paradigm (vehicle, 89.98 ± 1.66%; mazindol, 75.65 ± 5.47%; p < 0.05). In addition, the conditioned place preference (CPP) test demonstrated that mazindol (1.5 mg/kg) significantly decreased CPP score for HFD as compared with vehicle (vehicle, 330.44 ± 58.61 s; mazindol, 144.72 ± 43.02 s; p < 0.05). Moreover, at the dose required for these effects, mazindol did not elicit abuse potential or induce psychostimulant-like behavior. These results confirm that mazindol prevents diet-induced obesity without addictive behavior and demonstrate that its action is mediated at least in part via the reward system, advancing our understanding of mazindol in clinical practice.
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