Dopamine Receptor D1 Activation Alleviates Repeated Ketamine Exposure-Induced Cognitive Dysfunction in Mice by Inhibiting NLRP3/Caspase-1-Dependent Pyroptosis.
Ying Pan, Jia-Yu Zhang, Ang Li, Xiu-Mei Zhu, Peng Lv, Feng-Tong Zhang, Yang Bai, Yang Li, Jia-Yi Wei, Jun Yao
Schizophrenia Bulletin April 1, 2026 DOI: 10.1093/schbul/sbag063 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal and in vitro study Peer reviewed |
|---|---|
| Population | Mice (in vivo) and HT22 mouse hippocampal neuronal cells (in vitro) |
| Interventions | Ketamine DRD1 agonist DRD1 antagonist caspase-1 antagonist |
| Topics | Ketamine Esketamine |
| Keywords | Animals Mice, inbred c57bl Disease models, animal Caspase 1 Receptors, dopamine d1 Dopamine agonists Behavior, animal Male Pyroptosis Cognitive dysfunction Cognitive impairment Nlrp3 Drd1 |
| Key findings | Ketamine induced dose-dependent pyroptosis via the NLRP3/caspase-1 pathway in HT22 cells and mice, and DRD1 activation reduced this pyroptosis and ameliorated ketamine-induced cognitive impairment, while a DRD1 antagonist worsened pyroptosis and replicated behavioral deficits. The authors conclude that DRD1 activation mitigates ketamine-induced cognitive dysfunction by inhibiting NLRP3/caspase-1-dependent pyroptosis. |
Abstract
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.
Citations in the library
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