Abstract
Background
(S)-ketamine is an NMDA receptor antagonist, but it also binds to and activates mu opioid
receptors (MORs) and kappa opioid receptors in vitro. However, the extent to which
these receptors contribute to (S)-ketamine’s in vivo pharmacology is unknown.
Methods
We investigated the extent to which (S)-ketamine interacts with opioid receptors in rats by combining in vitro and in vivo
pharmacological approaches, in vivo molecular and functional imaging, and behavioral
procedures relevant to human abuse liability.
Results
We found that the preferential opioid receptor antagonist naltrexone decreased (S)-ketamine self-administration and (S)-ketamine–induced activation of the nucleus accumbens, a key brain reward region.
A single reinforcing dose of (S)-ketamine occupied brain MORs in vivo, and repeated doses decreased MOR density and
activity and decreased heroin reinforcement without producing changes in NMDA receptor
or kappa opioid receptor density.
Conclusions
These results suggest that (S)-ketamine’s abuse liability in humans is mediated in part by brain MORs.
Keywords
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Article info
Publication history
Published online: December 24, 2022
Accepted:
December 16,
2022
Received in revised form:
December 6,
2022
Received:
September 2,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
Published by Elsevier Inc on behalf of Society of Biological Psychiatry.
