de la Peña Ike, Figueroa Johnny, Shi Wei-Xing
Department of Pharmaceutical and Administrative Sciences, Loma Linda University School of Pharmacy, Loma Linda, CA 92350, USA.
Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Physiology Division, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
Brain Sci. 2025 Aug 25;15(9):913. doi: 10.3390/brainsci15090913.
Obesity is a complex disorder with both metabolic and neurocognitive consequences, including impairments in prefrontal cortex (PFC)-dependent learning and memory. Combination pharmacotherapy may offer a more effective approach for addressing obesity-induced cognitive deficits. This study evaluated the effects of 30-day co-administration of lorcaserin (5-HTC agonist) and betahistine (H agonist/H antagonist) in reversing cognitive deficits in a diet-induced obesity (DIO) rat model. Male Lewis rats were subjected to DIO and administered lorcaserin (2 mg/kg) and betahistine (5 mg/kg), either alone or in combination, via intraperitoneally implanted osmotic minipumps for 30 days. Y-maze, novel object recognition, and object-in-place (OIP) tests were used to assess cognitive functions. In vivo electrophysiological recordings were employed to examine effects of the combination treatment on ventral tegmental area (VTA) dopaminergic neuron activity. Obese Western-diet-fed rats showed lower discrimination scores in the OIP task, a behavioral test that engages PFC functions, while their performance in the Y-maze and novel object recognition tasks was similar to that of non-obese Control-diet-fed rats. Combination treatment with lorcaserin and betahistine significantly improved the OIP scores of obese rats. However, the combination treatment did not reduce body weight or obesity-associated morphometrical parameters. Electrophysiological recordings revealed a reduction in the number of spontaneously active dopaminergic neurons in the VTA of obese rats. Lorcaserin and betahistine co-treatment significantly increased the number of spontaneously active dopaminergic neurons of obese animals. These results demonstrate the potential of combination lorcaserin-betahistine treatment to reverse obesity-related cognitive deficits, possibly through enhancement of mesocortical dopaminergic neuron activity.
肥胖是一种复杂的病症，会产生代谢和神经认知方面的后果，包括前额叶皮质（PFC）依赖的学习和记忆受损。联合药物治疗可能为解决肥胖引起的认知缺陷提供一种更有效的方法。本研究评估了30天联合使用洛卡塞林（5-羟色胺能激动剂）和倍他司汀（组胺激动剂/组胺拮抗剂）对饮食诱导肥胖（DIO）大鼠模型认知缺陷的逆转作用。雄性Lewis大鼠被诱导形成饮食性肥胖，并通过腹腔内植入的渗透微型泵单独或联合给予洛卡塞林（2mg/kg）和倍他司汀（5mg/kg），持续30天。采用Y迷宫、新物体识别和物体定位（OIP）测试来评估认知功能。采用体内电生理记录来检查联合治疗对腹侧被盖区（VTA）多巴胺能神经元活动的影响。喂食西方饮食的肥胖大鼠在OIP任务（一种涉及PFC功能的行为测试）中的辨别分数较低，而它们在Y迷宫和新物体识别任务中的表现与喂食对照饮食的非肥胖大鼠相似。洛卡塞林和倍他司汀联合治疗显著提高了肥胖大鼠的OIP分数。然而，联合治疗并未降低体重或与肥胖相关的形态学参数。电生理记录显示肥胖大鼠VTA中自发活动的多巴胺能神经元数量减少。洛卡塞林和倍他司汀联合治疗显著增加了肥胖动物自发活动的多巴胺能神经元数量。这些结果表明，洛卡塞林-倍他司汀联合治疗有可能逆转肥胖相关的认知缺陷，可能是通过增强中脑皮质多巴胺能神经元的活动来实现的。
