Effects of 5-HT 2A Receptor Activation on Oxycodone Demand after Short and Long Access Self-Administration in Male and Female Rats

Introduction: Oxycodone is a necessary analgesic medication but carries abuse potential. There is an urgent need to develop therapeutics to reduce abuse potential. Psychedelic compounds may be a viable option, but the behavioral and pharmacological mechanism of action is undefined. Methods: Male and female Sprague–Dawley rats were implanted with indwelling jugular catheters and allowed to self-administer oxycodone (0.1 mg/kg/infusion). Rats were tested in the low-price twice within-session threshold self-administration procedure to quantify oxycodone reinforcement value before and after Short (ShA) or Long (LgA) access oxycodone self-administration sessions. Rats were pretreated with 2,5-dimethoxy-4-iodoamphetamine (DOI), volinanserin (VOL), and/or SB242084 to determine the therapeutic contribution of the 5-HT 2A R to reduce oxycodone self-administration. Data were analyzed with an exponentiated demand equation to yield the demand parameters demand intensity (Q 0 ) and demand elasticity (α), which summarize consumption across a range of prices. Results: Biological sex did not alter the acquisition of oxycodone self-administration. ShA rats maintained stable oxycodone self-administration. LgA rats escalated their oxycodone intake across training sessions. In ShA male and female rats, DOI dose dependently reduced oxycodone demand by increasing α and decreasing Q 0 . After LgA procedures, the lowest doses of DOI reduced demand in male and female rats, while the highest doses of DOI enhanced oxycodone reinforcement. Most but not all effects of DOI (0.1 mg/kg) were blocked by volinanserin. Interestingly, volinanserin reduced oxycodone demand in LgA male and female rats. SB242084 did not block any effects of DOI on oxycodone demand but showed additive effects with DOI. Conclusion: Regardless of access condition, the hallucinogenic compound, DOI, dose and sex-dependently reduced oxycodone demand by decreasing consumption at near-free prices and/or increasing the elasticity of oxycodone as a reinforcer, an effect driven mostly by the 5-HT 2A R. Notably, the receptor mediating these effects depended on the ShA/LgA condition because selective antagonists differentially blocked the effects. To conclude, while 5-HT 2A R activation maintains its therapeutic efficacy, nonselective phenethylamine hallucinogens that simultaneously activate and block multiple receptors may prove to be beneficial in reducing opioid use disorder by capitalizing on the functional status of various 5-HT 2 Rs.