Assessing the dose- and sex-dependent effects of oxytocin on opioid demand and reinstatement

University Of Florida, Gainesville FL

Investigators

Abstract

ABSTRACT While there are several FDA-approved medications for opioid use disorder, they are not effective at reducing opioid intake and preventing relapse in all individuals. Additional treatment options are needed. One compound that has been shown to reduce intake of multiple classes of drugs is the hormone oxytocin. Several clinical trials have found oxytocin to effectively decrease craving, withdrawal symptoms, and intake of several drugs, including heroin. However, there have been negative results in some clinical trials of oxytocin for substance use disorder (SUD), necessitating further evaluation of oxytocin’s strengths and limitations for the treatment of SUD. Oxycodone is a prescription opioid drug that has high rates of non-medical use, and contributes significantly to the number of overdoses in the U.S. SUD is a condition characterized by allocating increased resources (e.g., time, money) to drug acquisition and consumption. Studies done investigating the behavioral economics of drug- seeking in humans find that drug demand (amount of effort or resources people will allocate to obtaining drug) is predictive of future drug use and treatment success. Translational animal models provide insight into neural mechanisms of behavioral economic drug demand and allow for testing of novel treatments. Towards this goal, our preliminary data finds that in a behavioral economics model of demand for intravenous oxycodone, a mid- range dose of oxytocin (1 mg/kg IP) increases elasticity of demand and decreases the “price” (i.e. number of lever presses) at which demand for intravenous oxycodone becomes elastic in male, but not female rats. A large body of research finds no such sex differences in the ability of the same dose of oxytocin to attenuate intake and seeking of other addictive drugs such as cocaine and methamphetamine. Thus, additional research is necessary to characterize the effects of oxytocin on oxycodone seeking. Here we will generate a dose-response curve for the ability of oxytocin to increase the elasticity of demand for intravenous oxycodone in male and female rats. We observe robust spontaneous signs of withdrawal in male and female rats and greater withdrawal is associated with less elasticity of demand for oxycodone. Here we will also examine the ability of oxytocin to attenuate spontaneous withdrawal. We will also investigate the ability of oxytocin to reduce drug-seeking after a period of abstinence. Here will perform the first ever assessment of the ability of oxytocin to attenuate oxycodone seeking in male and female rats after drug abstinence, while assessing baseline blood oxytocin levels. Our hypothesis is that, as we observed for oxycodone demand, the dose-response curve for oxytocin to attenuate drug seeking after abstinence will be shifted to the right in female rats. We also hypothesize that blood oxytocin (in the absence of exogenous oxytocin administration) will be negatively correlated with oxycodone seeking. Upon determining the dose-response curve for oxytocin’s effects on oxycodone-demand and incubated seeking here, future work will interrogate neurobiological substrates and circuits involved in the ability of oxytocin to attenuate demand and incubated seeking of oxycodone in male and female subjects.