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

Abstract

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.

Dorsal striatal dopamine induces fronto-cortical hypoactivity and attenuates anxiety and compulsive behaviors in rats

“…PPI of the acoustic startle response is modulated by CSTC circuit function and impaired in OCD and other neuropsychiatric disorders [ 22 – 24 ]. To assess PPI, we first tested basal acoustic startle response (SR) to different intensity sound pulses.…”

“…Self-grooming is an innate rodent behavior characterized by a sequential pattern of movements [ 43 ], which serves as a useful proxy for compulsive behavior [ 24 , 44 , 45 ]. Grooming time and frequency are under control by the efferent activity of striatal SPNs.…”

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).…”

“…Interestingly, administration of the α 1 AR antagonist prazosin or the inhibitory α 2 -autoreceptor agonist clonidine reduces tic behavior in the D1CT model of TS, which exhibit neuronal hyperactivity in the PFC that dysregulates the cortico-striato-thalamico-cortical (CSTC) loop (Godar et al, 2016; Nordstrom et al, 2015). The Sapap3−/− model of OCD, which also displays excessive grooming behavior and hyperactivity of the PFC, is associated with abnormalities in DA receptor expression in the CTSC loop (Ahmari et al, 2013; Manning et al, 2019; Manning et al, 2021). Plausibly, persistent excitation of PFC neurons by stress-induced catecholamine release may be a causal mechanism for increased repetitive behavior in patients with compulsive disorders and in animal models featuring excessive grooming as part of their phenotypes (Kasar and Yurteri, 2020; Leckman et al, 1995; McGrath et al, 1999; Zhang et al, 2013).…”

SAPAP Scaffold Proteins: From Synaptic Function to Neuropsychiatric Disorders

“…Beyond participating in glutamatergic system, SAPAPs have been implicated in modulating the monoaminergic system. Sapap3 -mutant mice display upregulation of serotonin turnover in cortical and striatal regions and dihydroxyphenylacetic acid/dopamine ratios in the OFC [ 108 ], along with alterations in dopamine receptor density within the NAc [ 109 ], indicating an important role of SAPAP proteins in glutamate–monoamine interplay, which is relevant in psychiatric disorders such as schizophrenia, mood disorders, and OCD [ 110 , 111 ]. A follow-up study revealed an anomalous excessive form of synaptic plasticity (i.e., endocannabinoid-mediated LTD) expressed at striatal excitatory synapses, requiring mGluR5 signaling in Sapap3 -mutant mice [ 99 ].…”