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

Abstract

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.