Mu Opioid Receptor Activation Mediates (S)-ketamine Reinforcement in Rats: Implications for Abuse Liability

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.