Horvath Gyongyi, Plesz Szonja Bianka, Ducza Eszter, Varga Dorottya, Szucs Edina, Benyhe Sándor, Adlan Leatitia Gabriella, Braunitzer Gabor, Kekesi Gabriella
Department of Physiology, Albert Szent-Györgyi Medical School, University of Szeged, Dóm tér 10, H-6720 Szeged, Hungary.
Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, H-6720 Szeged, Hungary.
Int J Mol Sci. 2025 Jun 23;26(13):6019. doi: 10.3390/ijms26136019.
The limited efficacy of antipsychotics in treating the negative and cognitive symptoms of schizophrenia has prompted the exploration of adjuvant therapies. Several drugs developed for other indications-including caffeine, metformin, and furosemide-have shown procognitive potential. This study evaluated the effects of these agents on behavioral parameters using the reward-based Ambitus test, and on the cerebral D2 dopamine receptor (D2R) expression and binding. The drugs were administered individually and in combination in a schizophrenia-like triple-hit animal model (Lisket rats), derived from the Long Evans (LE) strain. Lisket rats received 14 days of drug treatment via drinking water; water-drinking LE rats served as the controls. The Ambitus test was conducted before treatment and on days 11-14. Caffeine enhanced activity without affecting learning or memory. Metformin and furosemide reduced exploratory behavior but improved reference memory; these effects were inhibited by caffeine co-administration. Although no statistically significant behavioral differences were found compared to water-treated Lisket rats, a trend toward reduced exploratory visits was observed in the triple-combination group. Lisket rats exhibited moderately reduced D2R binding in the cortex and increased binding in the hippocampus. Caffeine alone and in combination enhanced hippocampal D2R binding, while furosemide increased cortical D2R expression. This study is the first to highlight the behavioral and molecular effects of these non-antipsychotic agents in a schizophrenia model, supporting their potential for adjunctive use.
抗精神病药物在治疗精神分裂症阴性和认知症状方面疗效有限，这促使人们探索辅助治疗方法。几种针对其他适应症开发的药物——包括咖啡因、二甲双胍和呋塞米——已显示出有改善认知的潜力。本研究使用基于奖励的Ambitus测试评估了这些药物对行为参数的影响，以及对大脑D2多巴胺受体（D2R）表达和结合的影响。这些药物在源自Long Evans（LE）品系的精神分裂症样三重打击动物模型（Lisket大鼠）中单独给药和联合给药。Lisket大鼠通过饮水接受14天的药物治疗；饮水的LE大鼠作为对照。在治疗前以及第11 - 14天进行Ambitus测试。咖啡因增强了活动能力，但不影响学习或记忆。二甲双胍和呋塞米减少了探索行为，但改善了参考记忆；联合使用咖啡因可抑制这些作用。虽然与接受水处理的Lisket大鼠相比，未发现统计学上显著的行为差异，但在三联组合组中观察到探索性访问有减少的趋势。Lisket大鼠在皮质中表现出D2R结合适度减少，而在海马体中结合增加。单独使用咖啡因及其联合使用均可增强海马体D2R结合，而呋塞米增加皮质D2R表达。本研究首次强调了这些非抗精神病药物在精神分裂症模型中的行为和分子效应，支持了它们辅助使用的潜力。
