NMDA Receptor Glycine Binding Site Modulators for Prevention and Treatment of Ketamine Use Disorder.
Yu-Chin Hsiao, Mei-Yi Lee, Ming‐huan Chan, Hwei‐hsien Chen
Pharmaceuticals May 30, 2023 DOI: 10.3390/ph16060812 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Male Sprague-Dawley rats trained to self-administer ketamine or sucrose pellets |
| Interventions | D-serine sarcosine |
| Topics | Esketamine Ketamine |
| Keywords | D-serine Breakpoint Reinstatement Sarcosine Sucrose |
| Key points | D-serine and sarcosine both significantly decreased breakpoints for ketamine self-administration and prevented reinstatement of ketamine-seeking behavior in rats, without altering sucrose-seeking, motivated behavior for sucrose pellets, or spontaneous locomotor activity. The authors conclude that targeting the glycine binding site of the NMDA receptor may be a promising approach for preventing and treating ketamine use disorder. |
Abstract
Ketamine offers a fast-acting approach to relieving treatment-resistant depression, but its abuse potential is an issue of concern. As ketamine is a noncompetitive N-methyl-D-aspartate receptor (NMDAR) ion channel blocker, modulation of NMDAR might be an effective strategy to counteract the abuse liability of ketamine and even to treat ketamine use disorder. This study evaluated whether NMDAR modulators that act on glycine binding sites can decrease motivation to obtain ketamine and reduce reinstatement to ketamine-seeking behavior. Two NMDAR modulators, D-serine and sarcosine were examined. Male Sprague-Dawley rats underwent training to acquire the ability to self-administer ketamine. The motivation to self-administer ketamine or sucrose pellets was examined under a progressive ratio (PR) schedule. The reinstatement of ketamine-seeking and sucrose pellet-seeking behaviors were assessed after extinction. The results showed that both D-serine and sarcosine significantly decreased the breakpoints for ketamine and prevented reinstatement of ketamine seeking. However, these modulators did not alter motivated behavior for sucrose pellets, the ability of the cue and sucrose pellets to reinstate sucrose-seeking behavior or spontaneous locomotor activity. These findings indicate that two NMDAR modulators can specifically reduce the measures of motivation and relapse for ketamine in rats, suggesting that targeting the glycine binding site of the NMDAR is a promising approach for preventing and treating ketamine use disorder.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 7
- The Multivariate Effect of Ketamine on PTSD: Systematic Review and Meta-Analysis Frontiers in Psychiatry March 9, 2022
- Dual action of ketamine confines addiction liability. Nature August 2022
- Efficacy of Ketamine in the Treatment of Substance Use Disorders: A Systematic Review. Frontiers in Psychiatry 2018
- The Rapidly Acting Antidepressant Ketamine and the mGlu2/3 Receptor Antagonist LY341495 Rapidly Engage Dopaminergic Mood Circuits. Journal of Pharmacology and Experimental Therapeutics July 2016
- GLYX-13 (rapastinel) ameliorates subchronic phencyclidine- and ketamine-induced declarative memory deficits in mice. Behavioural Brain Research February 15, 2016
and 2 more in the library