Reduction of OCD by intracellular acidification of cortical neurons

A new study was published in the beginning of this year titled “Amelioration of obsessive-compulsive disorder by intracellular acidification of cortical neurons with a proton pump inhibitor”.

Highlights of the study

• Dopamine D2 receptor agonists increased the incidence of OCD-like symptoms.
• These symptoms were suppressed by proton pump inhibitors (PPIs).
• Quinpirole - a D2R agonist - induced OCD-like repetitive and habitual behaviours.
• PPI attenuated hyperactivity in the lateral orbitofrontal cortex pyramidal neurons induced by repeated D2R stimulation
• PPI reduced neuronal activity through intracellular acidification of primary cultured cortex neurons

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. (R1)

Knock-down of ATP4a

neuron-specific Atp4a KD significantly decreased the intracellular pH (Fig. 5H) and significantly inhibited the current-induced firing responses without altering the resting membrane potential (R1)

Agonism of D2R could be the cause of OCD

We have confirmed this hypothesis through chronological analysis. OCD-like symptoms induced by D2R agonists have been reported in patients with Parkinson’s disease, restless legs syndrome, and hyperprolactinemia.

D2R abnormalities occur in psychiatric patients with obsession and compulsion (e.g. OCD, eating disorder, and substance abuse). Our findings demonstrated that repeated stimulation of D2R causes OCD-like symptoms regardless of the primary disease. (R1)

Hyperactivity in the OFC is related to OCD-like symptoms. In patients with OCD, there is a positive correlation between neural activity in the lateral OFC and symptom severity.

Moreover, chronic administration of SSRIs normalises the lateral OFC activity only in SSRI-responsive patients with OCD.

Consistent with these reports, we previously found that QNP-treated mice exhibit hyperactivity in the lateral OFC pyramidal neurons, which was suppressed by the 4-week administration of SSRI.

In this study, a single administration of vonoprazan successfully decreased the neural activity of lateral OFC pyramidal neurons. (R1)