Therapeutic potential of psilocybin on stress-cued reinstatement

PROJECT SUMMARY Opioid use disorder (OUD) and Post-Traumatic Stress Disorder (PTSD) are highly comorbid and mutually exacerbating. There is a critical unmet need for pharmacotherapeutics targeting stress-precipitated relapse, as stress-conditioned stimuli are a major driver of relapse in comorbid patients. Classical psychedelics like psilocybin are appealing candidates as therapeutics for OUD, as they do not lead to physical dependence and demonstrate promising potential in reducing stress and addictive behaviors in humans. These effects appear to be long-lasting from one to few treatments, suggesting adaptation to neural circuits affected by chronic stress and substance use. Despite promising clinical evidence suggesting the efficacy of psychedelics in the treatment of stress and substance use disorders, there is a critical gap in the preclinical profiling of psychedelics in OUD models. Understanding the neural mechanisms underlying the therapeutic effect of these compounds is necessary for future development of novel OUD therapeutics with reduced hallucinogenic side effects. We have developed a novel mouse model for studying relapse induced by cues associated with prior stressful life events. My preliminary data from the Smith Laboratory demonstrate that the psychedelic 2,5,dimethoxy-4-iodoamphetamine (DOI) blocks stress-cued reinstatement to heroin in mice. We identified the anterior insular cortex (aIC) as a brain structure that may mediate the interaction between psychedelics, stress, and OUD, and find that DOI reduces reinstatement-induced c-Fos in the aIC. We propose that psychedelic- induced plasticity promotes lasting adaptations to circuitry affected by stress and heroin seeking, resulting in an attenuation of stress-cued heroin seeking. Aim 1 will identify the whole-brain pattern of neuronal activity and behavioral effect of psilocybin on stress-cued reinstatement to heroin. Using cell-type specific circuit manipulation via chemogenetics, we will gain valuable insight into the necessity of aIC 5HT2AR in modulating stress-cued reinstatement to heroin. Understanding the role of the 5HT2AR, which mediates hallucinogenic activity of psychedelics, in the therapeutic effects of psychedelics will provide critical information to steer drug discovery efforts aiming to treat stress and substance use disorders with serotonin agonists. Aim 2 will use fiber photometry to record aIC calcium dynamics during a stressful experience and re-exposure to stress-cue, and determine how treatment with psilocybin impacts these responses. Together, these experiments seek to elucidate circuit mechanisms underlying the effect of psilocybin on stress-induced heroin seeking behaviors. This study will be conducted at the Medical University of South Carolina, a leading center in the field of addiction neuroscience. Under the mentorship of Drs. Alexander Smith and Christopher Cowan, I will receive training in rodent intravenous drug self-administration, whole brain c-Fos mapping, chemogenetics, in vivo recording of neural activity with fiber photometry, and computational tools for data analysis.