Preclinical Investigation of 2,5-dimethoxy-4-iodoamphetamine (DOI) on Fearful and Anxious Behaviors

Current antidepressants have many limitations, including high dependency, low effectiveness, and long administration periods. However, research suggests serotonergic psychedelic compounds may effectively treat depressive disorders without these limitations. The use of serotonergic psychedelics to treat mood disorders have found long-lasting (6-8 months) and rapid anti-depressive behavioral effects within 1-3 administrations, and do not produce dependence or have addictive properties. It is currently unknown whether these antidepressive effects are shared amongst all serotonergic psychedelics or how they are generated. The serotonergic psychedelic studied here was (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI], a partial agonist for 5-Hydroxytryptamine-2-Receptor subtypes (5-HT2A,/2B,/2C) that is most selective for 5-HT2A. Serotonergic psychedelics produce their primary behavioral effects by binding to the 5-HT2A receptor in rodents and humans and promote dendritic spine growth in the prefrontal cortex through this mechanism. However, (R)-DOI has also been shown to have potent anti-inflammatory properties at extremely low doses by binding to the 5-HT2A receptor. Since inflammatory responses and atrophy of neurons in specific brain regions have been seen in humans and rodents displaying stress-induced behaviors, (R)-DOI may mediate therapeutic effects on fearful and anxious behaviors. The Stress Alternatives Model (SAM) was used here to test the behavioral impacts of (R)-DOI. The SAM is 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. Subjects were also put through a Social Interaction/Preference (SIP) Test. Administration of (R)-DOI impacted several stress-related behaviors in the SAM. Additionally, Stay animals showed susceptibility to social stress in SIP whereas (R)-DOI treated animals showed no phenotypic difference in susceptibility. These results suggest a single administration of (R)-DOI can produce changes in several behavioral measures of anxiety and fear in an animal model