Dr. Matthew Banks: Investigating Novel Treatment Approaches for Opioid Use Disorder in Translational Rodent Models By Paul W. Czoty, Ph.D., Animals in Research Committee Member Deaths due to opioid overdose have risen steadily for nearly two decades. Whereas early phases of this epidemic were largely attributable to heroin and “prescription opioids” such as oxycodone, the past 5 years have seen a rapid increase in deaths due to abuse of other synthetic opioids, such as the highly potent mu opioid receptor agonist fentanyl. With yearly opioid overdose deaths now eclipsing 70,000 per year, novel therapeutic approaches are needed. Laboratory animal models can aid progress in this regard, provided that their results have high translatability to the clinical condition. At Virginia Commonwealth University in Richmond, Dr. Matthew Banks and his colleagues developed a procedure in which rats could choose to receive either an intravenous injection of fentanyl or a food reward. Compared to procedures in which animals have a single response option, choice procedures better reflect the fact that drug abusers choose to allocate their time, resources and behavior towards procurement of drugs rather than other stimuli in the environment such as work, family or education. In previous attempts to study choice behavior in rodents, however, rats typically chose to respond to receive food reinforcement rather than injections of opioids. In the procedure developed by Dr. Banks and colleagues, rats responded almost exclusively for food when the simultaneously available fentanyl dose was low, but chose fentanyl more and more as the fentanyl dose increased, consistent with human laboratory and nonhuman primate choice studies. In the April 2019 issue of Neuropsychopharmacology, Dr. Banks’ group reported results that help to validate the translational utility of this model. Male and female rats chose between injections of fentanyl (0.01-0.1 mg/kg/hour) and access to liquid food. When treated with the mu opioid receptor antagonist naltrexone continuously for 7 days, choice of fentanyl decreased to a degree that was related to naltrexone dose. That the model was sensitive to naltrexone, an FDA-approved treatment for opioid use disorder, supports the contention that results from the model will translate to humans. In further support of this view, the model was sensitive to a negative control, the alpha-2 adrenergic receptor agonist clonidine. When rats were treated for 7 days with clonidine (0.0032-0.01 mg/kg/hour), fentanyl choice was increased. These data are reminiscent of results in humans because, although clonidine can reduce some somatic signs of opioid withdrawal, it has proven ineffective in preventing relapse. Having provided support for the translational utility of this model, Dr. Banks and colleagues then used it to test whether a fentanyl vaccine could reduce fentanyl choice. In non-dependent, vaccinated rats, fentanyl choice decreased and food choice increased over 15 weeks, indicating a highly effective attenuation of the reinforcing effects of fentanyl. In another experiment, the hypothesis that the vaccine would prevent withdrawal-induced increases in fentanyl choice was tested. The ability of opioid withdrawal to increase the reinforcing effects of opioids is well documented in the preclinical and clinical literature. Rats were provided access to fentanyl for 12 hours per day for 14 days under a procedure in which they received a fentanyl injection after every 5 responses. These conditions led to high fentanyl intakes and the development of dependence. When fentanyl-food choice was assessed 8 hours after the end of extended-access sessions, fentanyl choice was decreased and choice of food was increased in vaccinated rats relative to their behavior at the start of the extended-access regimen. The opposite effects (the expected withdrawal-induced increases in fentanyl choice) were observed in non-vaccinated rats. Taken together, the results present compelling evidence of the effectiveness of immunotherapies in combating the ongoing opioid epidemic. Dr. Banks is currently an Associate Professor in the Department of Pharmacology and Toxicology at Virginia Commonwealth University. He received his Pharm.D. degree from Ohio Northern University under the mentorship of Dr. Jon Sprague and received his Ph.D. from Wake Forest University working in the laboratory of Dr. Michael Nader. At both institutions, his research involved the toxic and abuse-related effects of MDMA. He subsequently completed postdoctoral fellowships at Emory University and VCU under the mentorship of Dr. Leonard Howell and Dr. Steve Negus, respectively. Dr. Banks has been regularly attending CPDD since 2004 and joined CPDD as a member-in-training in 2005. He received the CPDD Joseph Cochin Young Investigator Award in 2017. He currently is serving on the CPDD Program committee. Dr. Czoty has participated in CPDD meetings since 1998. He is currently a member of the Animals in Research Committee.
