R‐(‐)2,5‐dimethoxy‐4‐iodoamphetamine (DOI) Blunts the Discriminative Stimulus Properties of Oxycodone

Abstract

AimsA record ~100,000 fatalities due to drug overdoses was reported in the U.S. for the twelve months preceding April 2021. Opioids account for most deaths, and recurrent opioid use may lead to the development of opioid use disorder (OUD), a debilitating chronic disorder. Current medication‐assisted OUD treatment (e.g., buprenorphine) mitigates withdrawal, reduces mortality, and reduces intake of abused opioids. Still, the opioid epidemic crystalized the need to identify novel non‐opioid therapeutics to improve the odds of successful OUD recovery. In the last decade, there has been a resurgence of interest in serotonergic psychedelics for the treatment of psychiatric disorders, including substance use disorders. Psychedelic compounds act through agonist actions at the serotonin (5‐HT) 5‐HT2A receptor (5‐HT2AR) and there is some literature to suggest functional interactions between 5‐HT2AR and opioids. We tested the hypothesis that the psychedelic 5‐HT2AR agonist R‐(‐)2,5‐dimethoxy‐4‐iodoamphetamine (DOI) will disrupt the discriminative stimulus properties of the commonly misused prescription opioid oxycodone. The drug discrimination paradigm is a rigorous laboratory procedure for modeling the interoceptive effects of drugs and is widely recognized as useful in establishing ligand potency and effectiveness in vivo, as well as interrogating abuse liability.MethodsMale, Sprague‐Dawley rats (n = 13) were trained to discriminate an injection (s.c.) of oxycodone (1 mg/kg) from saline (1 ml/kg) in a two‐lever, water‐reinforced paradigm. Pharmacological testing began upon establishment of the stable oxycodone vs. saline discrimination. Substitution tests with DOI (0‐0.2 mg/kg; s.c.) and combination tests with DOI plus oxycodone were conducted interspersed with maintenance sessions. Percent oxycodone‐lever responding, response rates and latency to the first response were analyzed with an experimentwise error rate of α=0.05.ResultsAll rats acquired the oxycodone vs. saline discrimination to stability. Substitution tests indicated that all DOI doses resulted in percent oxycodone‐lever responding significantly different from the training dose of oxycodone (p< 0.05). Pretreatment with DOI (0.1, 0.2 mg/kg) significantly reduced the percent oxycodone‐lever responding (0.5 mg/kg), relative to pretreatment with vehicle (p < 0.05). The selective 5‐HT2AR antagonist M100907 prevented DOI‐induced suppression of oxycodone‐lever responding (p < 0.05).ConclusionsThe current studies reveal that the psychedelic DOI does not substitute for oxycodone, but does suppress the stimulus effects of oxycodone, an effect which is reversed by the 5‐HT2AR antagonist M100907. Taken together, these studies provide support for expanded interrogation of the efficacy of 5‐HT2AR agonists in counteracting the behavioral effects of opioids.