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

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.

Automated summary

This study found that (S)-ketamine interacts closely with opioid receptors in rats, and blocking opioid receptors can reduce (S)-ketamine self-administration and its activation of the nucleus accumbens, a key brain reward region. (S)-ketamine occupied brain mu opioid receptors (MORs) in vivo and repeated doses decreased MOR density and activity, reducing heroin reinforcement. These results suggest that the abuse liability of (S)-ketamine in humans is mediated in part by MORs in the brain.