Preclinical Assessment of PT-150 for Opioid Use Disorder and PTSD

The overall working hypothesis of this basic science study is that selective blockade of glucocorticoid receptors (GRs) in brain with PT-150 will serve as an effective pharmacotherapy for opioid use disorder (OUD) and co-morbid post-traumatic stress disorder (PTSD). Stressful events can serve as a potent trigger for relapse among individuals who are being treated for OUD, as well as serving as basis for inducing an anxiety disorder (PTSD) that can predispose an individual to OUD. Since co-morbid OUD and PTSD is over-represented among military personnel and veterans, PT-150 may be especially beneficial for this vulnerable population. Unfortunately, there is currently a paucity of experimental data to justify a full-scale clinical trial to test this this working hypothesis. The current preclinical project will serve as the initial proof-of-principle building block to advance to the next stage of testing PT-150 as a treatment for OUD, with and without PTSD, in a human population. The basic science aims are as follows: Aim 1: Determine if PT-150 reduces stress-induced reinstatement of fentanyl seeking: This aim will use a reinstatement model of relapse. Rats will first be trained to self-inject escalating doses of the potent opioid fentanyl using a standard 2-lever operant conditioning procedure. Following this, rats will be treated daily with either PT-150 or placebo while undergoing response extinction (abstinence). Stress will then be applied either environmentally (mild footshock) or pharmacologically (yohimbine) and reinstatement of fentanyl seeking will be measured. This procedure is intended to model the use of PT-150 as a pharmacotherapeutic to prevent relapse. Endpoint: The primary endpoint for this experiment will be the number of responses on the previously active following stress. This measure will be compared to the number of responses on the last day of extinction. The primary hypothesis is that PT-150 will reduce stress-induced reinstatement of fentanyl seeking. Positive results from this experiment will form the scientific premise for determining if PT-150 blocks fentanyl craving in human participants with OUD who are abstinent. That study would be proposed by Dr. Craig Rush at the University of Kentucky, a co-I on this application. Aim 2: Determine if PT-150 reduces fentanyl self-administration in individuals with co-morbid PTSD: This aim will use two different models of stress: (1) chronic social isolation and (2) acute stress induced by restraint/swim, which have been used to model PTSD. Previous work has shown that these stressful manipulations increase drug self-administration behavior. This aim will determine if oral PT- 150 reduces the effects of chronic social isolation and acute stress, either alone or in combination, on fentanyl self-administration. Rats will be raised in either social isolation or in group housing and then will receive acute restraint/swim stress or control treatment. Plasma corticosterone will be measured immediately before and after the acute stress. On the day after the acute stress treatment, rats will be treated daily with either PT-150 or placebo and then will be trained to voluntarily self-administer i.v. fentanyl using a standard 2-lever operant conditioning procedure. Endpoint: The primary endpoint for this experiment will be the number of fentanyl infusions across sessions. A secondary measure will be plasma corticosterone levels. We expect that chronic social stress and acute stress will both increase plasma corticosterone and fentanyl self-administration. The primary hypothesis is that PT-150 will reduce the stress-induced increase in fentanyl selfadministration. If this latter result is obtained, it will form the scientific premise for conducting a clinical trial with PT-150 in patients with co-morbid OUD and PTSD.