Most commonly used intravenous and inhaled general anesthetic drugs have two distinct effects on γ-aminobutyric acid type A (GABAA) receptors. First, the drugs act as positive allosteric modulators of both synaptic and extrasynaptic GABAA receptors. This action enhances the ability of endogenous γ-aminobutyric acid (GABA) to activate the opening of integral ion channels. The resulting increase in chloride (Cl–) influx causes neuronal inhibition and the profound neurodepressive state, which allows patients to tolerate surgery. Second, exposure to the anesthetic drugs triggers an overexpression of extrasynaptic GABAA receptors on the surface of neurons in the postanesthetic period.1 These overexpressed GABAA receptors are activated by low ambient concentrations of endogenous GABA, which causes a low-grade persistent increase in chloride influx in neurons. This sustained increase in extrasynaptic GABAA receptor function causes subtle cognitive deficits in laboratory animals that persist long after the drugs have been eliminated.1 The excessive cell-surface expression of extrasynaptic GABAA receptors is also induced by proinflammatory cytokines that are released during surgery.2 Both mechanisms may contribute to subtle neurocognitive disorders that occur in patients after surgery, such as postoperative delirium. Dexmedetomidine activates α2 adrenergic receptors in astrocytes and stimulates the release of brain-derived neurotrophic factor (BDNF), which in turn acts as a paracrine factor to prevent overexpression of extrasynaptic GABAA receptors in neurons.3 Dexmedetomidine thereby mitigates cognitive disorders in animal models. Similar mechanisms may account for the cognition-sparing properties of dexmedetomidine in patients.
This work was supported by a Foundation Grant (FDN-154312) from the Canadian Institutes of Health Research, Ottawa, Canada, to Dr. Orser.
The authors declare no competing interests.