Dopamine Receptor D1 Activation Alleviates Repeated Ketamine Exposure-Induced Cognitive Dysfunction in Mice by Inhibiting NLRP3/Caspase-1-Dependent Pyroptosis

BACKGROUND AND HYPOTHESIS: Ketamine triggers cellular pyroptosis through an NOD-like receptor protein 3 (NLRP3)/caspase-1 pathway, leading to neurotoxicity and cognitive deficits. Dopamine receptor D1 (DRD1) activation, however, suppresses NLRP3 inflammasome activation, thereby curbing inflammation. We hypothesized that ketamine induces pyroptosis through the NLRP3/caspase-1 pathway, resulting in neurotoxicity and cognitive dysfunction, and that DRD1 activation could counteract these effects. STUDY DESIGN: To investigate the relationship between DRD1 and ketamine-induced pyroptosis and behavioral changes in mice, we conducted both in vivo and in vitro experiments. STUDY RESULTS: Our findings reveal that ketamine induces dose-dependent pyroptosis in HT22 cells, which is alleviated by NLRP3 and caspase-1 antagonists. Furthermore, a DRD1 agonist effectively reduces ketamine-induced pyroptosis in these cells. In vivo, DRD1 activation decreases ketamine-induced NLRP3/caspase-1-dependent neuronal pyroptosis and ameliorates cognitive impairment in mice by inhibiting NLRP3. Conversely, a DRD1 antagonist enhances NLRP3/caspase-1-mediated pyroptosis, replicating the behavioral deficits seen with ketamine exposure. Moreover, DRD1-specific knockdown in neuronal cells prevents ketamine-induced cognitive dysfunction and reduces pyroptosis. CONCLUSIONS: Dopamine receptor D1 activation mitigates ketamine-induced cognitive dysfunction in mice by inhibiting NLRP3/caspase-1-dependent pyroptosis. These findings offer new insights into the psychobehavioral disorders and cytotoxicity associated with ketamine.