THE EFFICACY OF THE NOVEL 5-HT1A RECEPTOR AGONIST DSP-1181 ON OBSESSIVE-COMPULSIVE DISORDER LIKE BEHAVIOR IN A MOUSE MODEL OF OPTOGENETIC NEURAL MODULATION

Abstract Background Obsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by the presence of obsessions and compulsions, leading to significant impairment in social and occupational functioning. The current first-line treatment for OCD involves the use of selective serotonin reuptake inhibitors (SSRIs). However, SSRIs typically take several weeks to show therapeutic effects in OCD patients, and they are ineffective in approximately 40% of cases. Thus, there is a need for new drugs with rapid action and high efficacy. The 5-HT1A receptor has been implicated in various psychiatric symptoms, including anxiety. Additionally, previous studies have reported the clinical efficacy of 5-HT1A receptor agonists in alleviating OCD symptoms. Therefore, we discovered a novel 5-HT1A receptor agonist called DSP-1181, which possesses a distinct profile compared to previously approved agonists of the same receptor. Aims & Objectives Our aim was to investigate whether DSP-1181 ameliorates OCD-like behavior in a mouse model using optogenetics to evaluate its potential as a novel therapeutic agent for OCD. Method We carried out the marble-burying behavior test on naï ve male ICR mice. In the test, 20 glass marbles were placed equidistant from each other on the bedding. Each animal was left for 15 minutes in a cage. At the end of the test, the number of buried marbles covered with bedding was counted. We utilized optogenetics to bilaterally activate the orbitofrontal cortex-ventromedial striatum projections in male C57BL/6J mice to create a non-clinical model (OCD mice) that reflects the neural hyperactivation observed in OCD patients. The grooming time of the mice was measured for a 5-minute period, starting 1 hour after a 5-minute stimulation session. Results In the marble-burying behavior test, the number of buried marbles significantly decreased following administration of the novel compound DSP-1181, similar to clinically effective drugs such as the SSRI escitalopram and the 5-HT1A receptor agonist buspirone. In OCD mice, the grooming time was significantly increased compared to control virus-injected mice. A single administration of DSP-1181 was sufficient to decrease the increased grooming time observed in OCD mice. In contrast, repeated administration of either escitalopram or buspirone was required to suppress the grooming time. Discussion & Conclusion This study demonstrated that DSP-1181 exerted its rapid anti-OCD effect in multiple behavioral tests including well-validated OCD mice. These findings suggest that 5-HT1A receptor agonists hold promise as a potential treatment for OCD.