Sex differences in oral oxycodone self‐administration and stress‐primed reinstatement in rats

• Published in: Addiction biology Vol. 25; no. 6; pp. e12822 - n/a
• Main Authors: Fulenwider, Hannah D., Nennig, Sadie E., Hafeez, Hiba, Price, Michaela E., Baruffaldi, Federico, Pravetoni, Marco, Cheng, Kejun, Rice, Kenner C., Manvich, Daniel F., Schank, Jesse R.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.11.2020
• Subjects: Analgesics, Opioid - administration & dosage; Analgesics, Opioid - blood; Animals; Cocaine; Drug-Seeking Behavior - drug effects; Estrous Cycle - drug effects; Extinction, Psychological - drug effects; Female; Females; Gender differences; Male; Naloxone - administration & dosage; Narcotics; Neurokinin; Neurokinin-1 Receptor Antagonists - pharmacology; Operant conditioning; opiate; Opioid receptors (type mu); Oral administration; Oxycodone; Oxycodone - administration & dosage; Oxycodone - blood; Prescription Drug Misuse; Public health; Rats; Rats, Wistar; Receptors, Neurokinin-1 - physiology; Receptors, Opioid, mu - antagonists & inhibitors; Reinstatement; Self Administration; Sex differences; reinstatement; self-administration; opiate
• ISSN: 1355-6215; 1369-1600; 1369-1600
• DOI: 10.1111/adb.12822

The opioid epidemic has become a severe public health problem, with approximately 130 opioid‐induced deaths occurring each day in the United States. Prescription opioids are responsible for approximately 40% of these deaths. Oxycodone is one of the most commonly abused prescription opioids, but despite its prevalent misuse, the number of preclinical studies investigating oxycodone‐seeking behaviors is relatively limited. Furthermore, preclinical oxycodone studies that include female subjects are even more scarce, and it is critical that future work includes both sexes. Additionally, the oral route of administration is one of the most common routes for recreational users, especially in the early stages of drug experimentation. However, currently, only two studies have been published investigating operant oral oxycodone self‐administration in rodents. Therefore, the primary goal of the present study was to establish an oral oxycodone operant self‐administration model in adult male and female rats, as well as to examine a potential mechanism of stress‐primed reinstatement. We found that females consumed significantly more oral oxycodone than males in operant self‐administration sessions. We also found that active oxycodone self‐administration was reduced by mu opioid receptor antagonism and by substitution of water for oxycodone solution. Lastly, we induced stress‐primed reinstatement and found that this behavior was significantly attenuated by antagonism of the neurokinin‐1 receptor, consistent with our prior work examining stress‐induced reinstatement of alcohol‐ and cocaine‐seeking. In a model of oral operant selfadministration of oxycodone, it was found that female rats self‐administer significantly more drug than males. Self‐administration rates in female rats were not affected by estrous cycle. After extinction, reinstatement of oxycodone seeking was induced by footshock stress, and this behavior was sensitive to antagonism of the neurokinin‐1 receptor.