Nicotinamide Adenine Dinucleotide (NAD) Attenuates the Rate-Decreasing Effects of Oxycodone Withdrawal in Rats with No Apparent Abuse Liability

Abstract ID 56040 Poster Board 2 Background: Two current treatments for opioid use disorder (OUD) are the chronic administration of buprenorphine (partial opioid receptor agonist) or methadone (full opioid receptor agonist), as both of these agonists can alleviate withdrawal symptoms. However, neither of these drugs transition individuals with OUD to abstinence, and they both have an abuse liability. We examined whether the intravenous administration of the small molecule NAD+ could effectively attenuate withdrawal and transition individuals to abstinence (Experiment 1) while also having no abuse liability (Experiment 2). Methods: In Experiment 1, prior to establishing oxycodone dependence, seven Long-Evans rats (4 male and 3 female) were trained to lever press under a fixed-ratio 30 schedule for food reinforcers. When responding stabilized, subjects were administered an increasing chronic regimen of oxycodone (i.e., 3.2 mg/kg of oxycodone once daily, 3.2 mg/kg twice daily, and 10-18 mg/kg twice daily) until both spontaneous and precipitated withdrawal were reflected by disruptions in overall response rate (responses/second) and pre-ratio pausing (seconds). Precipitated withdrawal was demonstrated by administering increasing cumulative doses of naltrexone i.p. (0.32-3.2 mg/kg). After disruption of behavioral responding (withdrawal) was demonstrated consistently, indicating dependence, surgery was performed to implant a catheter and port. Twenty-four hours following catheterization, the chronic oxycodone regimen was restarted for the recovery period from surgery and for reestablishing responding under the operant schedule. When responding stabilized, the chronic regimen of oxycodone was permanently discontinued, and subjects were infused i.v. with either saline or 180 mg/kg of NAD+ each night for 10 hours per day for 10 consecutive days. Subjects responded under the operant task every afternoon during the 10 days to assess the disruptions in behavior. In Experiment 2, four male Sprague-Dawley rats were trained to respond under a fixed-ratio 10 schedule of oxycodone reinforcement after catheterization. During these sessions, overall response rate and pre-ratio pausing (PRP) were recorded. After self administration was established for an oxycodone training dose of 0.032 mg/kg/infusion, saline or NAD+ (1.57 or 3.2 mg/kg/infusion) was substituted for oxycodone until one of three criteria were met. Results: In Experiment 1, precipitated and spontaneous withdrawa