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bioRxiv · 10.1101/2025.09.25.678598

The NMDAR positive allosteric modulator NYX-783 selectively blocks opioid withdrawal conditioned place aversion in mice.

Trinko, J. R.·Foscue, E. P.·Diaz, D. M.·Thompson, S. L.·Malison, R. T.·Sinha, R.·Taylor, J. R.·DiLeone, R. J.
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Abstract

Rates of opioid use disorder (OUD) and overdose deaths have increased dramatically in recent years. Currently approved medications for OUD include the opioid agonists methadone and buprenorphine, and the opioid antagonist naltrexone. However, relapse rates are high due to an impaired ability for addicts to control their urge to consume due to strong cravings, and the extreme severity of withdrawal symptoms. Additionally, the nature of the agonists can lead to abuse of those compounds as well. Non-opioid targets, such as glutamate receptors, are potentially ideal for developing intervention strategies with the goal of reducing OUD, relapse, and overdose death. NYX-783 is a small molecule positive allosteric modulator for the glutamate receptor NMDA. It has been shown to modulate learning and memory, both of which are impaired in drug addicts, and known play a role in relapse. Using mice, we have conducted preclinical studies to evaluate the potential for NYX-783 as a therapeutic for OUD with assessment of several outcomes: 1) respiratory depression, 2) consumption during maintenance of regular consumption as well as post-abstinence reinstatement, 3) motivation for consumption, 4) somatic withdrawals, and 5) the development of aversion to withdrawal symptoms. For respiratory depression studies, mice were pretreated 1h prior with NYX-783 and respiratory rates were monitored for 15min after each escalating dose of oxycodone. No effects were seen for any dose of NYX-783. To test for effects on drug consumption, mice were trained to orally self-administer oxycodone and then treated every two days with different doses of NYX-783 or entering an abstinence phase prior to testing with NYX-783. No effect on intake at clinically-relevant doses was observed during regular maintenance or post-abstinence intake. Additionally, we used a progressive ratio to assess the motivation self-administering mice had for reward acquisition, and no effect of NYX-783 was observed on rewards earned. We next evaluated withdrawal using two separate paradigms to test for effects of NYX-783 on, 1) for somatic withdrawal symptoms, 2) aversion to the state of withdrawal. For somatic withdrawal, using higher doses of naloxone (1 mg/kg), NYX-783 did not attenuate jumping behavior. For aversion to withdrawal, three aversion pairings were completed that consisted of oxycodone treatment, followed by NYX-783 preceding a low dose of naloxone (0.1mg/kg ip) immediately before pairing in a specific context. These alternated with neutral (saline) pairings daily. We observed a significant improvement in aversion scores in female mice treated with NYX-783, and a trending significant improvement in males. This suggests a potential therapeutic use for NYX-783 in reducing the negative state of withdrawal that can drive relapse in OUD.

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Trinko, J. R., Foscue, E. P., Diaz, D. M., Thompson, S. L., Malison, R. T., Sinha, R., Taylor, J. R., DiLeone, R. J.. 2025-09-25. The NMDAR positive allosteric modulator NYX-783 selectively blocks opioid withdrawal conditioned place aversion in mice.. https://doi.org/10.1101/2025.09.25.678598

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