Obsessive compulsive disorder (OCD) is associated with disruption of sensorimotor gating, which may contribute to difficulties inhibiting intrusive thoughts and compulsive rituals. Neural mechanisms underlying these disturbances are unclear; however, striatal dopamine is implicated in regulation of sensorimotor gating and OCD pathophysiology. The goal of this study was to examine the relationships between sensorimotor gating, compulsive behavior, and striatal dopamine receptor levels in Sapap3 knockout mice (KOs), a widely used preclinical model system for OCD research. We found a trend for disruption of sensorimotor gating in Sapap3-KOs using the translational measure prepulse inhibition (PPI); however, there was significant heterogeneity in both PPI and compulsive grooming in KOs. Disruption of PPI was significantly correlated with a more severe compulsive phenotype. In addition, PPI disruption and compulsive grooming severity were associated with reduced dopamine D1 and D2/3 receptor density in the nucleus accumbens core (NAcC). Compulsive grooming progressively worsened in Sapap3-KOs tested longitudinally, but PPI disruption was first detected in high-grooming KOs at 7 months of age. Through detailed characterization of individual differences in OCD-relevant behavioral and neurochemical measures, our findings suggest that NAcC dopamine receptor changes may be involved in disruption of sensorimotor gating and compulsive behavior relevant to OCD.

Highlights• Disruption of PPI is associated with severity of compulsive grooming in Sapap3-KOs • D1 and D2/3 receptors in NAcC are negatively correlated with PPI and grooming • Chronic fluoxetine normalizes PPI and grooming • Therapeutic efficacy of fluoxetine on PPI correlates with attenuated DAT in NAc • NAc dopamine changes may underly severity of PPI in Sapap3-KOs Abbreviations CMS= centromedial striatum; DAT = Dopamine transporter; FLX= Fluoxetine; KOs = Knockout mice; NAc= nucleus accumbens; NAcC= NAc core; OCD= Obsessive compulsive disorder; PPI=prepulse inhibition; PP=prepulse; SSRI= selective serotonin reuptake inhibitor; VEH= vehicle; WT= wild-type. AbstractObsessive compulsive disorder (OCD) is associated with disruption of sensorimotor gating, which may contribute to difficulties inhibiting intrusive thoughts and compulsive rituals.Neural mechanisms underlying these disturbances are unclear; however, striatal dopamine signalling is implicated in both OCD pathophysiology and the neural regulation of sensorimotor gating. The goal of this study was to examine the relationships between sensorimotor gating, compulsive behavior, and dopamine system functioning in Sapap3 knockout mice (KOs), a widely used preclinical model system for OCD research. Using prepulse inhibition (PPI), a translational measure of sensorimotor gating, we found no differences between Sapap3-KOs and controls when comparing group means. However, there was significant heterogeneity in PPI levels across Sapap3-KOs, which was negatively correlated with severity of compulsive grooming. Disruption of PPI and compulsive grooming were associated with reduced dopamine D1 and D2/3 receptor density in the nucleus accumbens core (NAcC) measured via autoradiography. Finally, chronic treatment with a first-line pharmacotherapy for OCD, the selective serotonin reuptake inhibitor (SSRI) fluoxetine, normalized PPI; these therapeutic effects were associated with reduced density of dopamine transporter in NAcC. This is the first detailed characterization of heterogeneity across different OCD-relevant behavioral and neurochemical measures in a transgenic model system, highlighting associations between severity of compulsive behavior and sensorimotor gating disturbances. Our findings also suggest that changes in NAcC dopamine functioning may be critical for the pathology and treatment of OCD-relevant sensorimotor gating impairments.