Program

PO4-1-84

An adenosine A2A receptor antagonist, istradefylline, improves multiple symptoms reflecting obsessive-compulsive disorder in a novel murine model

[Speaker] Nozomi Asaoka:1
[Co-author] Naoya Nishitani:1, Haruko Kinoshita:1, Yuma Nagai:1, Kazuki Nagayasu:1, Hisashi Shirakawa:1, Takayuki Nakagawa:2, Shuji Kaneko:1
1:Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan, 2:Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Japan

Background
Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder characterized by repeatedly rising concern and repetitive unwanted behaviors. Although long-term and high-dose of selective serotonin reuptake inhibitors (SSRIs) are the first-choice drug therapy for OCD, about half of OCD patients do not respond to SSRIs. While clinical studies display abnormalities in cortico-striatal pathway as one of the pathological bases of OCD, novel drug development targeting this pathway was hardly undertaken, partly due to the lack of well-validated drug screening tool. In this study, we evaluated the effects of an adenosine A2A receptor antagonist, istradefylline, which inhibits striatum indirect-pathway medium spiny neurons, on OCD-like symptoms in novel model mice.

Methods
Male C57BL/6J mice (6-12 weeks old) were received daily quinpirole injection (1 mg/kg, i.p.) and used for experiments after at least 8 injections. OCD-like behavioral, cognitive and neurological deficits were examined by monitoring of spontaneous behavior, spatial reversal learning tasks and ex vivo electrophysiological recordings, respectively.

Results
After repeated injection of quinpirole, mice showed spontaneous repetitive behavior and deficit in reversal learning. Pyramidal neurons in the lateral orbitofrontal cortex from quinpirole-injected mice showed hyperactivity, reflecting the clinical observation in OCD patients. Consistent with the limited effect of SSRI, chronic high-dose SSRI administration rescued cognitive and neurological deficits, but no therapeutic effect was observed in behavioral abnormality. Short-term administration of a 5-HT2C antagonist exhibited similar effects to chronic SSRI administration. Microinjection study and electrophysiological recordings revealed that the treatment-resistant behavioral deficit was mediated by dopamine D2 receptor signaling in the ventromedial striatum. Finally, istradefylline improved both behavioral and cognitive abnormality only by short-term administration.

Conclusions
The present results indicate that repeated quinpirole injection induced multiple OCD-like symptoms in mice. Since this mouse model also showed good predictive validity, it might become a convenient OCD model for drug-screening. Additionally, short-term administration of istradefylline improved OCD-like repetitive behavior, which was not rescued by chronic SSRI administration, providing a probability of istradefylline to be a rapid-acting and potent anti-OCD drug.

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