Dose-Dependent Effects of the Serotonergic Psychedelic (R)-DOI are Contingent on Prior Coping Strategies to an Escapable Social Stress

Limitations of current medications for anxious and depressive mood disorders have generated interest in finding new pharmacotherapies that are more effective and produce fewer side effects. A resurgence of research into serotonergic psychedelics has recently demonstrated these drugs may have extremely valuable therapeutic potential. While serotonergic psychedelics produce temporary changes in sensory processing and behavior, psilocybin has been found to produce rapid and long-lasting (6-8 months) anti-depressive effects with single or few administrations in treatment resistant and terminally ill patients - populations particularly insensitive to current therapies. However, little is known about how psychedelics can generate such immediate and long-lasting therapeutic effects, and whether these properties are shared among other serotonergic psychedelics.Here, the therapeutic efficacy of the serotonergic psychedelic (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI] was investigated in a preclinical model of repeated social stress. (R)-DOI can enhance neuronal dendrite and spine growth, but also has potent anti-inflammatory properties at extremely low doses, both of which depend on (R)-DOI binding to the 5-Hydroxytryptamine-2A-Receptor (5-HT2A). These properties may mediate potential therapeutic effects for stress-related mood disorders, as enhanced inflammatory responses and atrophy of neurons in specific stress-related brain regions have been observed in both humans and rodents displaying stress-induced dysfunctional behavior. To assess the behavioral impacts of (R)-DOI, mice were exposed to the Stress Alternatives Model (SAM), a 4-day social stress paradigm that offers the option of escape from an aggressive conspecific. By the end of day 2, animals establish either active (Escape) or passive (Stay) coping strategies in response to social stress, which generally remain unchanged for days 3 and 4 of the SAM without intervention. Immediately following day 2 of the SAM, mice were injected subcutaneously with (R)-DOI (0.3, 0.03, or 0.015 mg/kg) or saline. Results show (R)-DOI produces dose-dependent effects on stress behaviors that differ based on prior coping strategy