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.

Research Support

This work was supported by a Foundation Grant (FDN-154312) from the Canadian Institutes of Health Research, Ottawa, Canada, to Dr. Orser.

Competing Interests

The authors declare no competing interests.

References

1.
Zurek
AA
,
Yu
J
,
Wang
DS
,
Haffey
SC
,
Bridgwater
EM
,
Penna
A
,
Lecker
I
,
Lei
G
,
Chang
T
,
Salter
EW
,
Orser
BA
:
Sustained increase in α5GABAA receptor function impairs memory after anesthesia.
J Clin Invest
2014
;
124
:
5437
41
.
2.
Wang
DS
,
Zurek
AA
,
Lecker
I
,
Yu
J
,
Abramian
AM
,
Avramescu
S
,
Davies
PA
,
Moss
SJ
,
Lu
WY
,
Orser
BA
:
Memory deficits induced by inflammation are regulated by α5-subunit-containing GABAA receptors.
Cell Rep
2012
;
2
:
488
96
.
3.
Wang
DS
,
Kaneshwaran
K
,
Lei
G
,
Mostafa
F
,
Wang
J
,
Lecker
I
,
Avramescu
S
,
Xie
YF
,
Chan
NK
,
Fernandez-Escobar
A
,
Woo
J
,
Chan
D
,
Ramsey
AJ
,
Sivak
JM
,
Lee
CJ
,
Bonin
RP
,
Orser
BA
:
Dexmedetomidine prevents excessive γ-aminobutyric acid type A receptor function after anesthesia.
Anesthesiology
2018
;
129
:
477
89
.