Abstract:
Background
(S)-ketamine is an N-methyl-D-aspartate receptor (NMDAR) antagonist, but it also binds
to and activates mu (MOR) and kappa (KOR) opioid receptors in vitro. However, the extent to which these receptors contribute to (S)-ketamine’s in vivo pharmacology is unknown.
Methods
We investigated in rats the extent to which (S)-ketamine interacts with opioid receptors
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 self-administration
without producing changes to NMDAR or KOR 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
Accepted:
December 16,
2022
Received in revised form:
December 6,
2022
Received:
September 2,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
One-Sentence Summary: (S)-ketamine binds and activates mu opioid receptors to induce desensitization and increased heroin self-administration in rats.
Identification
Copyright
© 2022 Published by Elsevier Inc on behalf of Society of Biological Psychiatry.
