Disruption of prepulse inhibition is associated with severity of compulsive behavior and nucleus accumbens dopamine receptor changes in Sapap3 knockout mice

Abstract

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.

Not only compulsivity: The SAPAP3-KO mouse reconsidered as a comorbid model expressing a spectrum of pathological repetitive behaviors

“…Taken together, we observe four distinct types of repetitive behaviours in the Sapap3 -/mouse model, two of which can unambiguously be described as of a tic-like nature. We confirm previously reported self-grooming sequences, which have been shown to adhere to a compulsive-like nature elsewhere (11,16). The in-between character of hindpaw scratching in the Sapap3 -/mouse most likely resembles hair-pulling or skin-picking described in OCD with grooming disorders or trichotillomania.…”

“…face and predictive validity suggest that the short grooming events fit with a ticlike repetitive behaviour while the long grooming events do not. Although undifferentiated into single-or multi-phase grooming events in all previous publications on the Sapap3 -/and other mouse models, self-grooming in general has been determined as compulsive-like behaviours through pharmacological characterization using the first-order treatment for obsessive-compulsive behaviours, fluoxetine, a selective serotonin reuptake inhibitor (SSRI) (11,16). Although previously never reported in the Sapap3 -/mouse model, the detection of comorbidity of tic-and compulsive-like elements in its self-grooming behaviour is in line with the numerous reports of comorbidity of tics and compulsions in OCD as well as TS patients (3).…”

“…In the Sapap3 -/mouse, cortico-striatal defects have been detailed as a postsynaptic impairment in synaptic transmission and genetically restoring Sapap3 expression in the striatum rescued both synaptic as well as behavioural aberrations in reported anxietylike and grooming behaviours (11), which has been widely accepted in the field to provoke the prominent skin lesions on the animals' necks and heads. Pharmacotherapy via selective serotonin reuptake inhibitors, which are applied as first-line therapy in OCD, or targeted deep brain stimulation, which is applied in severe, treatment-resistant OCD cases, decrease anxietylike behaviours and pathological RB in both OCD patients as well as the Sapap3 -/mouse model (11,15,16). A neurobiological core candidate in human OCD symptomatology is aberrant lateral orbito-frontal cortex (lOFC) neuroanatomy and/or activity (14,17).…”

NOX1/NADPH Oxidase Promotes Synaptic Facilitation Induced by Repeated D2Receptor Stimulation: Involvement in Behavioral Repetition

“…Clinical imaging studies revealed a reduction in D 2 receptor binding availability, which reflects low membrane expression of D 2 receptor and/or increased dopamine release, in the striatum of patients with OCD and substance use disorder (Denys et al, 2004;Fehr et al, 2008;Lee et al, 2009). Similar observations have also been reported in animal models of OCD and addiction (Nader et al, 2006;Manning et al, 2020). These observations raise the possibility that b -arrestin-mediated D 2 receptor internalization is facilitated in patients with compulsivity, supporting the present observation in QNP-sensitized mice.…”

Norepinephrine and dopamine contribute to distinct repetitive behaviors induced by novel odorant stress in male and female mice

“…Grooming is not classically considered to be a coping behavior in response to a stressor; animals will self-groom under low and/or high stress conditions (Kalueff et al, 2016;Smolinsky et al, 2009). However, animal models of obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS) demonstrate high levels of repetitive self-grooming behavior (Manning et al, 2021;Nordstrom and Burton, 2002;Welch et al, 2007), and grooming can be elicited by central infusions of ACTH or DA agonists (Guild and Dunn, 1982;Taylor et al, 2010). The ACTH-induced grooming response was prevented by drugs that block DA receptors, while grooming induced by central ACTH infusion is augmented by the DA agonist apomorphine (Guild and Dunn, 1982).…”