NOP receptors as targets for novel pharmacotherapies for cocaine use disorder in nonhuman primate models

Wake Forest University Health Sciences, Winston-Salem NC

Investigators

Abstract

Project Summary/Abstract Cocaine use disorder (CUD) remains a significant public health problem with no FDA-approved medications. Acknowledging this need, NIDA identified discovery of novel pharmacotherapies as a key component of its current strategic plan. Recent data suggest that drugs that target brain nociceptin/orphanin FQ peptide (NOP) receptors may have potential in treating CUD. For example, rodent studies indicate that NOP receptor agonists can decrease the rewarding/reinforcing effects of cocaine. Moreover, PET imaging and the novel NOP receptor radiotracer [11C]NOP-1A were used to show that NOP receptor binding was higher in individuals with CUD versus controls. While these data are encouraging, there are significant gaps in our knowledge that can be filled by using translationally relevant nonhuman primate (NHP) models of CUD and treatment. This application proposes NHP studies of long-term cocaine self-administration (SA) in combination with PET imaging to provide critical information regarding the relationships between NOP receptors and cocaine reinforcement that will help generate novel CUD treatments. Specific Aim 1 will examine how NOP receptors influence vulnerability to developing CUD. [11C]NOP-1A PET imaging will be used to determine the relationship between drug-naïve monkeys’ NOP receptor binding and sensitivity to cocaine during their initial experience with cocaine SA (acquisition and an initial dose-effect curve). Aim 2 will identify changes in brain NOP receptors with repeated [11C]NOP-1A PET scans during long-term cocaine SA. Aim 3 will assess the ability of NOP- acting drugs to decrease cocaine SA using a highly relevant model of pharmacotherapy evaluation that incorporates aspects of human CUD and treatment. Studies focus on buprenorphine analogs synthesized by Co-I Dr. Stephen Husbands that have agonist activity at mu opioid peptide (MOP) and NOP receptors (“bifunctional agonists”). These drugs lack abuse potential (i.e., they are not self-administered by NHPs) and have shown promise as medications for alcohol and opioid use disorders. Moreover, our preliminary data suggest that the ability of these drugs to decrease cocaine SA in rodent models of CUD extends to NHPs. Initial Aim 3 studies will provide detailed information regarding the pharmacodynamic profile (i.e., MOP vs. NOP receptor affinity and efficacy) for an ideal CUD medication that will be used to select candidates from the library of Dr. Husbands’ compounds for testing during chronic treatment. Throughout the studies female and male NHPs will be compared, generating novel information about potential sex differences in NOP neurobiology and the effects of NOP receptor-acting drugs; such data are nearly non-existent. Taken together, these studies will use a highly translationally relevant NHP model to provide novel information about reciprocal interactions between NOP receptors and behavioral effects of cocaine as well as specific information to aid development of novel CUD pharmacotherapies.