Innovative Therapeutic Intervention For Opioid Use Disorder

The United States is in the grip of an opioid misuse and overdose crisis. Progression from misuse to opioid use disorder (OUD) is marked by compulsive drug-taking and clinically significant impairment. Behavioral interventions along with treatment with OUD pharmacotherapeutics, such as buprenorphine, mitigates withdrawal, reduces mortality, opioid intake, and opioid-seeking behaviors, as well as improves psychosocial functioning (Volkow et al, 2014). Medication-assisted treatment is an important adjunct to the proper management of OUD patients, yet additional opportunities exist to enhance the probability of extended abstinence and recovery from OUD.

Dysregulation of the limbic-corticostriatal circuitry that subserves reward and adaptive behaviors contributes to OUD development as well as the vulnerability to relapse during abstinence. Serotonin (5-HT) neurotransmission confers modulatory control over this circuitry, particularly through the 5-HT_2C receptor (5-HT_2CR) (for review) (Cunningham and Anastasio, 2014). Selective 5-HT_2CR agonists, which lack intrinsic abuse liability, curb self-administration of psychostimulants (eg, cocaine, nicotine) as well as associated sensitivity to drug-associated cues and impulsivity in preclinical studies (for review) (Cunningham and Anastasio, 2014). These data sparked a clinical trial that demonstrated that the FDA-approved anti-obesity medication and first-in-class 5-HT_2CR agonist lorcaserin (Belviq) increased abstinence from smoking (Shanahan et al, 2016). Furthermore, the efficacy and safety of lorcaserin for cocaine use disorder is presently under study (https://clinicaltrials.gov/ct2/show/NCT03007394). We have recently demonstrated the efficacy of lorcaserin to suppress intake of the semisynthetic opioid oxycodone as well as associated cue reactivity in both abstinence and extinction-reinstatement paradigms, effects which were blocked by the selective 5-HT_2CR antagonist SB242084 (Neelakantan et al, 2017). Lorcaserin pretreatment also decreases opioid-induced behavioral sensitization and the physical signs of naloxone-precipitated withdrawal following chronic opioid exposure in mice (Wu et al, 2015). Thus, the non-opioid medication lorcaserin acts as a 5-HT_2CR agonist to influence aspects of opioid-evoked behaviors, suggesting that the 5-HT_2CR system may play a key role in the shared mechanisms for addiction and relapse vulnerability across psychostimulant and opioid drug classes.

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