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An increasing number of opioid overdose deaths have resulted from the rising availability of both prescription and nonprescription opioids. Pharmacotherapies, such as buprenorphine and methadone, are used to treat those dependent on opioids. However, these commonly used pharmacotherapies are opioid partial agonists and agonists, so the patient remains in an opioid‐dependent state throughout treatment. Treatment requires long‐term tapering with buprenorphine or methadone, during which withdrawal symptoms can occur. These limitations show a clear need for a non‐opioid pharmacotherapy. Drugs that target the NMDA receptor have been proposed as alternatives to opioid‐targeted pharmacotherapies. The NMDA receptor is involved in the maintenance of opioid dependence and its blockade may reverse the neuroadaptive changes induced by opioid dependence. Regulation of the NMDA receptor could accelerate treatment of opioid dependency (Glass, 2011). Ketamine, an NMDA antagonist, has potential as a treatment, but has associated side effects and potential for abuse. Rapastinel is a novel drug marketed as an antidepressant, and it acts as a partial agonist of the NMDA receptor complex. The negative side effects reported with ketamine have not been reported with rapastinel (Moskal et al., 2016). Since rapastinel acts as a partial agonist and has no reported side effects, it may be a more tolerable treatment option for those dependent on opioids. Male and female adolescent (between 28 and 30 days old) Sprague‐Dawley rats were injected with morphine in increasing doses twice a day for five days (5 mg/kg/day–25 mg/kg/day) to induce opioid dependency. On day six, rats were injected with naloxone (1 mg/kg) and withdrawal signs were quantified. Rats were then given either ketamine injections (1 mg/kg) twice daily (n=12), rapastinel injections (5 mg/kg) every other day (n=14), or saline injections (n=24). On day nine, rats were again administered naloxone (1 mg/kg), and withdrawal signs were quantified to measure efficacy of ketamine and rapastinel. Rapastinel treated rats exhibited significantly fewer withdrawal signs than those treated with ketamine, which did not differ from controls. These results show that rapastinel significantly enhances recovery from opioid dependence.Support or Funding InformationFunding provided by ASPET, Duke University SURPH program, and Duke University Department of Pharmacology and Cancer BiologyThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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Current antidepressant medications lack efficacy in a large fraction of patients and typically take weeks to reduce symptoms in individuals who do respond to treatment. However, the factors that govern treatment responses to various classes of antidepressants remain largely unknown. The incidence and presentation of mood and anxiety disorders are both characterized by sex differences, and sex differences in response to antidepressants have been reported for both selective serotonin reuptake inhibitors (SSRIs) and tricyclics (TCAs). As new antidepressants are developed, it will be critical to determine their efficacy in both male and female subjects to enable appropriate treatment selection. Previous research has investigated the antidepressant effects of buprenorphine, which has high affinity for mu opioid receptor (MOR), kappa opioid receptor (KOR), and some affinity for delta opioid receptor (DOR). Though previous studies have shown support for buprenorphine as an antidepressant, the effects have only been demonstrated in males. This study examined potential sex differences in the behavioral and molecular responses to acute and chronic buprenorphine administration in mice. The effects of buprenorphine were measured with the forced swim test, open field test, and light dark emergence test. In contrast to published research, acute buprenorphine showed no significant main effect of treatment in any of these behavioral tests in either sex. However, chronic treatment with buprenorphine showed a main effect of treatment in both the open field and forced swim tests, suggesting that both males and females are responsive to this drug. While gene expression analysis did show that female mice expressed higher levels of pro‐opiomelanocortin (POMC) in the striatum compared to males, no sex by drug interactions were observed. These studies show that chronic, but not acute, buprenorphine treatment has antidepressant effects, and that females do not appear to have reduced sensitivity to these effects.