[NOX1/NADPH Oxidase Facilitates Repetitive Behaviors by Enhancing D₂ Receptor-mediated Synaptic Potentiation in the...

Repetitive behavior, a form of compulsivity, is a component of several neuropsychiatric disorders, including obsessive-compulsive disorder and addiction. Dysfunction of dopaminergic modulation in the striatum is thought to be a key neural mechanism underlying compulsive behavior repetition; however, the mechanistic links between dopaminergic abnormalities and compulsivity remain unclear. This review discusses our recent work demonstrating the contribution of the NOX1 isoform of the superoxide-producing enzyme, nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), to compulsive-like repetitive behavior in mice that received repeated stimulation of D₂ receptors. Nox1 deficiency inhibited compulsive-like repetitive behaviors, as assessed by observation of spontaneous behavior patterns and perseveration in the reversal learning test. Repeated stimulation of D₂ receptors also upregulated expression of Nox1 in the central striatum (CS), and induced excitatory synaptic potentiation in CS indirect pathway medium spiny neurons. Such synaptic potentiation required recruitment of β-arrestin and was blocked by Nox1 deficiency or acute pharmacological inhibition of NOX1. Furthermore, upregulation of NOX1 in the CS contributed to accumulation of activated Src kinase following stimulation of D₂ receptors. Local inhibition of NOX1 or neuron-specific Nox1-knockdown in the CS was sufficient to reduce repetitive behavior. Collectively, these results reveal a novel role for NOX1 in D₂ receptor-mediated excitatory synaptic potentiation in the striatum, suggesting the potential of NOX1 inhibition as a treatment for compulsivity.