HBK-15 rescues recognition memory in MK-801- and stress-induced cognitive impairments in female mice

Depression affects 30 million people worldwide, and women are diagnosed with this condition nearly twice as often as men. Cognitive impairments that develop during depression contribute to poor therapeutic outcomes and reduced quality of life. Recognizing the significance of sex as a variable in depression research, we investigated the procognitive properties of a multimodal compound- HBK-15 in female mice using two models of cognitive impairments: induced by NMDA receptor blockade or stress. We employed the object recognition test to assess intermediate recognition memory. We used MK-801 (NMDA receptor antagonist) or the unpredictable chronic mild stress (UCMS) to induce memory impairments. The sucrose preference test evaluated the anhedonic state in the UCMS model. HBK-15, at doses of 0.625, 1.25, and 2.5 mg/kg, effectively protected against MK-801-induced recognition memory impairment in naïve mice after a single administration. In the UCMS model, HBK-15 (2.5 mg/kg) administered for 14 days rescued recognition memory. Notably, only HBK-15 (0.625 mg/kg) exhibited antianhedonic properties by increasing the sucrose preference. Our findings demonstrate that HBK-15 mitigates memory impairments induced by acute NMDA receptor blockade or chronic stress. In the depression model, the procognitive effect was observed at a higher dose than that exerting antianhedonic effects, suggesting distinct mechanisms underlying these two domains of the compound’s activity. This study has been conducted as part of a research project financed by the National Science Centre, Poland (grant number 2019/34/E/NZ7/00454).