Amelioration of obsessive-compulsive disorder by intracellular acidification of cortical neurons with a proton pump inhibitor.
Hikari HatakamaNozomi AsaokaKazuki NagayasuHisashi ShirakawaShuji KanekoPublished in: Translational psychiatry (2024)
Obsessive-compulsive disorder (OCD) is a highly prevalent neuropsychiatric disorder poorly controlled with pharmacological treatment because of the wide variation in symptom patterns. We analysed real-world data on adverse self-reports and insurance claims to identify a novel therapeutic target for OCD. We found that dopamine D 2 receptor (D 2 R) agonists increased the incidence of OCD-like symptoms, which were suppressed by the concomitant use of proton pump inhibitors (PPIs). Further, OCD-like repetitive and habitual behaviours were observed in mice repeatedly injected with a D 2 R agonist, quinpirole. However, these abnormalities were suppressed by short-term PPI treatment. In quinpirole-treated mice, PPI inhibited pyramidal neuron hyperactivity in the lateral orbitofrontal cortex, a region where the P-type proton pump gene Atp4a is abundantly expressed. In primary cultured cortical neurons, short-term PPI treatment lowered intracellular pH and decreased firing activity, which was mimicked by Atp4a knockdown. Our findings show that inhibition of P-type proton pumps may be a novel therapeutic strategy for OCD.
Keyphrases
- obsessive compulsive disorder
- deep brain stimulation
- emergency department
- spinal cord
- combination therapy
- risk factors
- health insurance
- machine learning
- metabolic syndrome
- spinal cord injury
- gene expression
- adverse drug
- physical activity
- reactive oxygen species
- depressive symptoms
- deep learning
- electronic health record
- functional connectivity
- data analysis
- skeletal muscle
- transcription factor
- genome wide
- insulin resistance