Performance of compulsive behavior in rats is not a unitary phenomenon - validation of separate functional components in compulsive checking behavior.

Mark C Tucci,Jane Foster,Henry Szechtman,Arnav Agarwal,Leena Taji,Paul Cheon,Anna Dvorkin‐Gheva,Eric Johnson

doi:10.1111/ejn.12652

Abstract

A previous analysis of the quinpirole sensitisation rat model of obsessive-compulsive disorder revealed that the behavioral phenotype of compulsive checking consists of three constitutive components – vigor of checking performance, focus on the task of checking, and satiety following a bout of checking. As confirmation of this analysis, the aim of the present study was to reconstitute, without quinpirole treatment, each of the putative components, with the expectation that these would self-assemble into compulsive checking. To reconstitute vigor and satiety, the employed treatment was a bilateral lesion of the nucleus accumbens core (NAc), as this treatment was shown previously to exaggerate these components. To reconstitute focus, the employed treatment was a low dose of the serotonin-1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin hydrochloride (DPAT) (0.0625 mg/kg), as high doses of this drug induce compulsive behavior and exacerbate focus. Results showed that injection of DPAT to NAc lesion rats did yield compulsive checking. Neither the drug alone nor the NAc lesion by itself produced compulsive checking. The demonstrated synthesis of compulsive checking by the combined treatment of low-dose DPAT and NAc lesion strengthened the previous fractionation of the model obsessive-compulsive disorder phenotype into three constitutive components, and suggested a role for serotonin-1A receptors outside the NAc in enhanced focus on the task of checking.

Highlights

There is a general consensus that the neurobiological substrate underlying obsessive-compulsive disorder (OCD) stems at least in part from a dysfunction that results in persistent neural activity within a series of cascading cortical-basal ganglia-thalamo-cortical loops (Wise & Rapoport, 1989; Saxena et al, 1998; Graybiel & Rauch, 2000; Stein, 2002; Aouizerate et al, 2004; Huey et al, 2008; Szechtman et al, 2014), probably involving alterations in serotonin (5-HT) and dopamine (DA) signaling (Goodman et al, 1990; Zohar et al, 2000; Westenberg et al, 2007; Nikolaus et al, 2010)
Animal models of psychopathology can be useful preparations to discover the psychological components of a psychiatric disorder and their underlying neurobiology (Szechtman & Eilam, 2005)
This approach of ‘analysis followed by synthesis’ underlies the rationale for the current study where we aimed to synthesise compulsive checking behavior from the components identified in a previous analysis (Dvorkin et al, 2010)

Summary

Introduction

There is a general consensus that the neurobiological substrate underlying obsessive-compulsive disorder (OCD) stems at least in part from a dysfunction that results in persistent neural activity within a series of cascading cortical-basal ganglia-thalamo-cortical loops (Wise & Rapoport, 1989; Saxena et al, 1998; Graybiel & Rauch, 2000; Stein, 2002; Aouizerate et al, 2004; Huey et al, 2008; Szechtman et al, 2014), probably involving alterations in serotonin (5-HT) and dopamine (DA) signaling (Goodman et al, 1990; Zohar et al, 2000; Westenberg et al, 2007; Nikolaus et al, 2010). Relatively little is known about the specific behavioral process, or processes, that is altered in this neurocircuit to yield OCD, and more generally, whether the OCD phenotype is the manifestation of a unitary functional system or a collection of constitutive components To address this question, a recent study employed the quinpirole sensitisation rat model of OCD (Szechtman et al, 1998; Eilam & Szechtman, 2005), and revealed that quinpiroleinduced compulsive checking behavior is not a unitary phenomenon. The rationale for the choice of this compound was as follows

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