Obsessive-compulsive disorder (OCD) is a psychiatric syndrome accompanied with inadequate repetitive and/or habitual actions, which often appears as an adverse effect of dopamine receptor stimulants. In this study, to find a new therapeutic target for OCD, we analyzed human real-world data including adverse events self-reports and insurance claims and found that concomitant use of proton pump inhibitors suppressed the incidence of OCD symptoms induced by the use of pramipexole or ropinirole. In an in vivo validation of the hypothesis, OCD-like abnormalities, such as spontaneous repetitive behavior and facilitation of habit formation were observed in mice received repetitive injections of quinpirole (QNP; a dopamine D₂ receptor agonist; 1 mg/kg; 8 days). In this OCD model, a systemic vonoprazan (Vpz; a proton pump inhibitor; 100 mg/kg i.p.) or an i.c.v. injection of Vpz (3 µg) suppressed the QNP-induced OCD-like behaviors. In ex vivo cortical slices prepared from OCD model mice, an increase in the firing rate was observed in pyramidal neurons of lateral orbitofrontal area, which was reduced in the presence of Vpz (10 µM) or by intracellular acidification from pH 7.3 to 7.0. In primary cultured cortical neurons in which Atp4a gene (encoding proton pump) was knocked down, a decrease in pH by Vpz was mitigated in parallel with a reduction of firing rate. These results demonstrate that regulation of acid-base balance of orbitofrontal neurons will be a novel therapeutic target for OCD.