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eNeuro. 2019 Feb 27;6(1). pii: ENEURO.0366-18.2019. doi: 10.1523/ENEURO.0366-18.2019. eCollection 2019 Jan-Feb.

An Adenosine A2A Receptor Antagonist Improves Multiple Symptoms of Repeated Quinpirole-Induced Psychosis.

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Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan.


Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder characterized by the repeated rise of concerns (obsessions) and repetitive unwanted behavior (compulsions). Although selective serotonin reuptake inhibitors (SSRIs) is the first-choice drug, 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 (QNP) sensitization-induced OCD-related behaviors in mice. SSRI administration rescued the cognitive inflexibility, as well as hyperactivity in the lateral orbitofrontal cortex (lOFC), while no improvement was observed for the repetitive behavior. D2 receptor signaling in the central striatum (CS) was involved in SSRI-resistant repetitive behavior. An adenosine A2A antagonist, istradefylline, which rescued abnormal excitatory synaptic function in the CS indirect pathway medium spiny neurons (MSNs) of sensitized mice, alleviated both of the QNP-induced abnormal 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 A2A antagonists as a rapid-acting anti-OCD drug.


D2 receptor; obsessive-compulsive disorder

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