Abstract
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 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 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.
Significance statement Clinical studies show distinct therapeutic efficacies for SSRIs between subtypes of OCD symptoms. While abnormal activity in the cortico-striatal pathway is critically involved in the pathophysiology of OCD, the neurological mechanisms and therapeutic strategies for SSRI-resistant symptoms remain unclear. In this study, we showed that repeated injection of dopamine D2 receptor agonist, quinpirole elicited two distinct OCD-related behaviors; cognitive inflexibility (SSRI-responsive) and repetitive behavior (SSRI-resistant). While SSRI treatment normalized hyperactivity of the orbitofrontal cortex, we also demonstrated the imbalanced excitatory inputs in the central striatum of quinpirole-treated mice and the therapeutic potential of an A2A antagonist as a modulator of indirect pathway medium spiny neurons (MSNs).
Footnotes
Authors report no conflict of interest.
Japanese Society for the Promotion of Science (JSPS) [16H05091]; Japan Agency for Medical Research and Development (AMED) [18ak0101088h0001]
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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