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Published on: June 12, 2018
Dopamine Receptor D1 Activation Alleviates Repeated Ketamine Exposure-Induced Cognitive Dysfunction in Mice by
Ying Pan1,2,3,4, Jia-Yu Zhang5, Ang Li1,2,3
1Department of Forensic Genetics and Biology, School of Forensic Medicine, China Medical University, Shenyang, Liaoning, 110122, P.R. China.
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.
