Compulsive-Like Responding for Opioid Analgesics in Rats with Extended Access

Neuropsychopharmacology (2015) 40, 421–428 & 2015 American College of Neuropsychopharmacology. All rights reserved 0893-133X/15 www.neuropsychopharmacology.org Compulsive-Like Responding for Opioid Analgesics in Rats with Extended Access Carrie L Wade*,1, Leandro F Vendruscolo1, Joel E Schlosburg1, Daniel O Hernandez1 and George F Koob1 1 Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA The abuse of prescription opioids that are used for the treatment of chronic pain is a major public health concern, costing B$53.4 billion annually in lost wages, health-care costs, and criminal costs. Although opioids remain a first-line therapy for the treatment of severe chronic pain, practitioners remain cautious because of the potential for abuse and addiction. Opioids such as heroin are considered very rewarding and reinforcing, but direct and systematic comparisons of compulsive intake between commonly prescribed opioids and heroin in animal models have not yet been performed. In the present study, we evaluated the potential for compulsive-like drug seeking and taking, using intravenous self-administration of oxycodone, fentanyl, and buprenorphine in rats allowed long access sessions (12 h). We measured compulsive-like intake using an established escalation model and responding on a progressive ratio schedule of reinforcement. We compared the potential for compulsive-like self-administration of these prescription opioids and heroin, which has been previously established to induce increasing intake that models the transition to addiction in humans. We found that animals that self-administered oxycodone, fentanyl, or heroin, but not buprenorphine had similar profiles of escalation and increases in breakpoints. The use of extended access models of prescription opioid intake will help better understand the biological factors that underlie opioid dependence. Neuropsychopharmacology (2015) 40, 421–428; doi:10.1038/npp.2014.188; published online 20 August 2014 INTRODUCTION A growing problem in the field of drug abuse is prescription opioid abuse and dependence, which has reached epidemiclike proportions. Overdose deaths that involve opioid pain relievers, also known as opioid analgesics, have increased and now exceed deaths that involve the use of heroin and cocaine combined (Centers for Disease Control and Prevention, 2011). A prominent contributor to this trend is the intake of oxycodone, which can be insufflated, injected, or smoked. As of 2012, nearly 14 million people aged 12 or older had used oxycodone for nonmedical reasons at least once during their lifetime (Substance Abuse and Mental Health Services Administration, 2008, 2012); the average age of patients enrolled in treatment programs for heroin users is significantly higher than for prescription opioid users. Therefore, the identification of opioids with increased efficacy for pain treatment and reduced potential to cause dependence is a critical goal for preclinical research. Opioid addiction is a chronically relapsing disorder characterized by a compulsion to seek and take opioids, *Correspondence: Dr CL Wade, Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, 10550 North Torrey Pines Road, SP30-2400, La Jolla, CA 92037, USA, Tel: +1 858 784 8030, Fax: +1 858 784 7405, E-mail: Received 12 February 2014; revised 14 July 2014; accepted 15 July 2014; accepted article preview online 25 July 2014 loss of control in limiting its intake, and emergence of a profound negative emotional state during withdrawal (Koob et al, 2013). Multiple sources of reinforcement have been identified in the course of the opioid addiction syndrome (American Psychiatric Association, 2013; World Health Organization, 1992), and animal models can reproduce many features of opioid dependence that resemble the human condition (Barbier et al, 2013; Vendruscolo et al, 2011). Animal models of self-administration include the escalation of self-administration of the drug and increased motivation for the drug under conditions of increased workload, defined here as increases in breakpoints under a progressive ratio (PR) schedule of reinforcement (Ahmed et al, 2000; Koob, 2009; Koob et al, 2004; Piazza et al, 2000). Rats allowed extended access to intravenous heroin selfadministration rapidly escalate their drug intake and demonstrate signs of physical and motivational aspects of opioid dependence, including tolerance, physical withdrawal signs, increased drug intake, and increased motivation to take the drug in the face of adverse consequences (Ahmed et al, 2000; Bozarth and Wise, 1985; Chen et al, 2006; Negus, 2006; Vendruscolo et al, 2011). The epidemic-like spread of the abuse of oxycodone and other opioids used to treat chronic pain indicates that these drugs have a high abuse potential. Opioids such as heroin and morphine have been shown to induce conditioned rewards and are reinforcing in animals, reflected by behavioral measures of conditioned place preference (Prus et al, 2009) and intravenous self-administration Compulsive opioid intake in rats CL Wade et al 422 (Ko et al, 2002), respectively. The effects are dose dependent, particularly via the intravenous route of administration, in which the time to onset is immediate (Edwards and Koob, 2012). However, few studies have examined the differences in the potential of different opioid drugs to induce escalations in self-administration and increases in breakpoints. Evaluating the behavioral patterns of the self-administration of clinically relevant drugs, such as oxycodone, fentanyl, and buprenorphine, will provide an animal model with which to elucidate the neurobiological bases of their abuse potential. In the present study, we used the intravenous self-administration paradigm with extended access to systematically compare the potential for escalation of self-administration and drug seeking and intake under conditions of increased cost of opioids that are commonly used for the treatment of chronic pain (ie, oxycodone, fentanyl, and buprenorphine). These drugs were compared with the illicit drug heroin, which as a m-opioid receptor (MOR) agonist has been extensively studied in rodent models of self-administration. In the first experiment, we allowed separate groups of rats to self-administer several doses of oxycodone, fentanyl, and buprenorphine under both limited access (short access (ShA)) and extended access (long access (LgA)) conditions. In the second experiment, we examined the reinforcing strength of these drugs using a PR schedule of reinforcement. MATERIALS AND METHODS Subjects Adult male Wistar rats (n ¼ 144 (6/group); Charles River, Raleigh, NC, USA), weighing 225–275 g at the beginning of the experiments, were housed in groups of 2–3 per cage in a temperature-controlled (22 1C) vivarium on a 12-h/12-h light/dark cycle (lights on at 1800 hours) with ad libitum access to food and water. The anim (...truncated)