An adenosine A_2A receptor antagonist improves multiple symptoms reflecting obsessive-compulsive disorder

Abstract

Obsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by repetitive inappropriate thoughts (obsessions) and behaviors to get rid of obsessions (compulsions). Although selective serotonin reuptake inhibitors (SSRIs) are the first-choice treatment for OCD, response rates to SSRI treatment vary between symptom dimensions. In this study, to find a therapeutic target for SSRI-resilient OCD symptoms, we evaluated treatment responses of quinpirole sensitization-induced OCD-related behaviors. Chronic SSRI administration rescued the cognitive inflexibility and the hyperactivity in the lateral orbitofrontal cortex (lOFC), while repetitive behavior was not improved by SSRI. D₂ receptor signaling in the central striatum (CS) was involved in SSRI-resistant repetitive behavior. An adenosine A_2A antagonist, istradefylline rescued abnormal excitatory synaptic function in the CS indirect pathway medium spiny neurons of sensitized mice and also alleviated both of the QNP-induced OCD-related behaviors with only short-term administration. These results provide a new insight into therapeutic strategies for SSRI-resistant OCD symptoms and indicate the potential of A_2A antagonists as a rapid-acting anti-OCD drug.