Dopamine Receptor D1 Activation Alleviates Repeated Ketamine Exposure-Induced Cognitive Dysfunction in Mice by...

Area of Science:

• Neuroscience
• Pharmacology
• Cell Biology

Background:

• Ketamine induces neurotoxicity and cognitive deficits by triggering cellular pyroptosis via the NOD-like receptor protein 3 (NLRP3)/caspase-1 pathway.
• Dopamine receptor D1 (DRD1) activation is known to suppress NLRP3 inflammasome activation and reduce inflammation.

Purpose of the Study:

• To investigate the role of DRD1 in counteracting ketamine-induced pyroptosis and associated cognitive dysfunction.
• To explore the therapeutic potential of DRD1 activation in mitigating ketamine's adverse effects.

Main Methods:

• In vitro studies using HT22 cells to assess pyroptosis.
• In vivo experiments in mice involving DRD1 agonists and antagonists.
• Neuronal cell-specific DRD1 knockdown experiments.

Main Results:

• Ketamine induced dose-dependent pyroptosis in HT22 cells, which was reduced by NLRP3 and caspase-1 antagonists and a DRD1 agonist.
• In vivo, DRD1 activation decreased ketamine-induced pyroptosis and cognitive impairment by inhibiting NLRP3.
• DRD1 antagonism exacerbated pyroptosis and cognitive deficits, while DRD1 knockdown prevented ketamine-induced dysfunction.

Conclusions:

• Dopamine receptor D1 activation mitigates ketamine-induced cognitive dysfunction by inhibiting NLRP3/caspase-1-dependent pyroptosis.
• DRD1 activation represents a potential therapeutic strategy for ketamine-induced psychobehavioral disorders and neurotoxicity.