Amelioration of obsessive-compulsive disorder by intracellular acidification of cortical neurons with a proton pump inhibitor.

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 D2 receptor (D2R) 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 D2R 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.

A selective serotonin reuptake inhibitor ameliorates obsessive-compulsive disorder-like perseverative behavior by attenuating 5-HT2C receptor signaling in the orbitofrontal cortex.

Perseveration is a characteristic of patients with obsessive-compulsive disorder (OCD). Clinically, neuronal activity in the lateral orbitofrontal cortex (OFC) is increased in OCD patients. Successful treatment with selective serotonin reuptake inhibitors (SSRIs) reduces activity in the lateral OFC of OCD patients, but the precise mechanisms underlying this effect are unclear. Previously, we reported that repeated injection of the dopamine D2 receptor agonist quinpirole (QNP) resulted in OCD-like deficits, including perseveration in a reversal learning task. QNP-treated mice showed hyperactivity in lateral OFC pyramidal neurons. The present study demonstrated that 4-week administration of an SSRI increased the rate of correct choice in a reversal learning task. Using the electrophysiological approach, we revealed that an SSRI decreased the activity of lateral OFC pyramidal neurons in QNP-treated mice by potentiating inhibitory inputs. The 4-week administration of an SSRI inhibited the potentiation of neuronal activity induced by a 5-HT2C receptor agonist. Additionally, both 4-week administration of SSRI and acute application of 5-HT2C receptor antagonist prevented the QNP-induced potentiation of inhibitory inputs to fast-spiking interneurons in the lateral OFC. Administration of a 5-HT2C receptor antagonist to mice for 4 days increased the rate of correct choice in a reversal learning task. Collectively, these results indicate that chronic SSRI ameliorated perseverative behavior in QNP-treated mice by modulating inhibitory inputs in the lateral OFC. Short-term 5-HT2C receptor blockade also ameliorated QNP-induced behavioral and neurological abnormalities by, at least in part, a common mechanism with chronic SSRI.

NOX1/NADPH Oxidase Promotes Synaptic Facilitation Induced by Repeated D2 Receptor Stimulation: Involvement in Behavioral Repetition.

Repetitive behavior is a widely observed neuropsychiatric symptom. Abnormal dopaminergic signaling in the striatum is one of the factors associated with behavioral repetition; however, the molecular mechanisms underlying the induction of repetitive behavior remain unclear. Here, we demonstrated that the NOX1 isoform of the superoxide-producing enzyme NADPH oxidase regulated repetitive behavior in mice by facilitating excitatory synaptic inputs in the central striatum (CS). In male C57Bl/6J mice, repeated stimulation of D2 receptors induced abnormal behavioral repetition and perseverative behavior. Nox1 deficiency or acute pharmacological inhibition of NOX1 significantly shortened repeated D2 receptor stimulation-induced repetitive behavior without affecting motor responses to a single D2 receptor stimulation. Among brain regions, Nox1 showed enriched expression in the striatum, and repeated dopamine D2 receptor stimulation further increased Nox1 expression levels in the CS, but not in the dorsal striatum. Electrophysiological analyses revealed that repeated D2 receptor stimulation facilitated excitatory inputs in the CS indirect pathway medium spiny neurons (iMSNs), and this effect was suppressed by the genetic deletion or pharmacological inhibition of NOX1. Nox1 deficiency potentiated protein tyrosine phosphatase activity and attenuated the accumulation of activated Src kinase, which is required for the synaptic potentiation in CS iMSNs. Inhibition of NOX1 or ß-arrestin in the CS was sufficient to ameliorate repetitive behavior. Striatal-specific Nox1 knockdown also ameliorated repetitive and perseverative behavior. Collectively, these results indicate that NOX1 acts as an enhancer of synaptic facilitation in CS iMSNs and plays a key role in the molecular link between abnormal dopamine signaling and behavioral repetition and perseveration.SIGNIFICANCE STATEMENT Behavioral repetition is a form of compulsivity, which is one of the core symptoms of psychiatric disorders, such as obsessive-compulsive disorder. Perseveration is also a hallmark of such disorders. Both clinical and animal studies suggest important roles of abnormal dopaminergic signaling and striatal hyperactivity in compulsivity; however, the precise molecular link between them remains unclear. Here, we demonstrated the contribution of NOX1 to behavioral repetition induced by repeated stimulation of D2 receptors. Repeated stimulation of D2 receptors upregulated Nox1 mRNA in a striatal subregion-specific manner. The upregulated NOX1 promoted striatal synaptic facilitation in iMSNs by enhancing phosphorylation signaling. These results provide a novel mechanism for D2 receptor-mediated excitatory synaptic facilitation and indicate the therapeutic potential of NOX1 inhibition in compulsivity.

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

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.