An Avoidance-Based Rodent Model of Exposure With Response Prevention Therapy for Obsessive-Compulsive Disorder

doi:10.1016/j.biopsych.2016.02.012

Biological Psychiatry

Volume 80, Issue 7, 1 October 2016, Pages 534-540

https://doi.org/10.1016/j.biopsych.2016.02.012 Get rights and content

Abstract

Background

Obsessive-compulsive disorder is treated with exposure with response prevention (ERP) therapy, in which patients are repeatedly exposed to compulsive triggers but prevented from expressing their compulsions. Many compulsions are an attempt to avoid perceived dangers, and the intent of ERP is to extinguish compulsions. Patients failing ERP therapy are candidates for deep brain stimulation (DBS) of the ventral capsule/ventral striatum, which facilitates patients’ response to ERP therapy. An animal model of ERP would be useful for understanding the neural mechanisms of extinction in obsessive-compulsive disorder.

Methods

Using a platform-mediated signaled avoidance task, we developed a rodent model of ERP called extinction with response prevention (Ext-RP), in which avoidance-conditioned rats are given extinction trials while blocking access to the avoidance platform. Following 3 days of Ext-RP, rats were tested with the platform unblocked to evaluate persistent avoidance. We then assessed if pharmacologic inactivation of lateral orbitofrontal cortex (lOFC) or DBS of the ventral striatum reduced persistent avoidance.

Results

Following Ext-RP training, most rats showed reduced avoidance at test (Ext-RP success), but a subset persisted in their avoidance (Ext-RP failure). Pharmacologic inactivation of lOFC eliminated persistent avoidance, as did DBS applied to the ventral striatum during Ext-RP.

Conclusions

DBS of ventral striatum has been previously shown to inhibit lOFC activity. Thus, activity in lOFC, which is known to be hyperactive in obsessive-compulsive disorder, may be responsible for impairing patients’ response to ERP therapy.

Section snippets

Subjects

One hundred ten male Sprague Dawley rats (~325 g; Harlan Laboratories, Indianapolis, IN) were housed and handled as previously described (18). Rats were fed standard rat chow in a restricted manner (18 g/day) to facilitate pressing a bar for food on a variable-interval schedule of reinforcement (variable interval 30 seconds). All procedures were approved by the Institutional Animal Care and Use Committee of the University of Puerto Rico School of Medicine in compliance with the National

Extinction With Response Prevention Training Reduces Avoidance and Freezing

The Ext-RP task (Figure 1A) was a modification of the platform-mediated avoidance, in which rats avoid a tone-signaled shock by stepping onto a nearby platform (17). Following 10 days of avoidance training, access to the platform was blocked with a transparent Plexiglas barrier, and rats were given 3 days of extinction (tone, no shock). The following day (day 14), the barrier to the platform was removed and rats were tested for avoidance. The time spent avoiding at test (percent tone on

Discussion

We developed an avoidance-based rodent model of ERP therapy in which signaled avoidance behaviors are reduced following extinction of tone-shock associations. Ext-RP training reduced avoidance in the majority of rats; however, 25% persisted in their avoidance following Ext-RP. Persistent avoidance could be eliminated by inactivating lOFC or by delivering DBS to the VS.

It is estimated that 26% of OCD patients suffer from the harm-avoidant type of OCD, because they believe that their compulsions

Acknowledgments and Disclosures

This work was supported by the Silvio O. Conte Center for Research in OCD (Grant Nos. P50-MH086400 to BDG, SAR, and GJQ); R37 MH058883 and R01 MH081975 to GJQ; R36 MH105039 to JR-R; and the University of Puerto Rico President’s Office.

We thank Ricardo Rodríguez-Colón and Estefanía González-Araya for help with behavioral experiments and Carlos Rodríguez and Zarkalys Quintero for technical assistance.

The authors reported no biomedical financial interests or potential conflicts of interest. The

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Archival ReportAn Avoidance-Based Rodent Model of Exposure With Response Prevention Therapy for Obsessive-Compulsive Disorder

Abstract

Background

Methods

Results

Conclusions

Section snippets

Subjects

Extinction With Response Prevention Training Reduces Avoidance and Freezing

Discussion

Acknowledgments and Disclosures

Behav Res Ther

Neurosci Biobehav Rev

Trends Cogn Sci

Biol Psychiatry

Biol Psychiatry

Compr Psychiatry

Behav Res Ther

Biol Psychiatry

J Psychiatr Res

Curr Opin Neurobiol

Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication

Arch Gen Psychiatry

Treatment of obsessive compulsive disorder

Annu Rev Clin Psychol

Randomized, placebo-controlled trial of exposure and ritual prevention, clomipramine, and their combination in the treatment of obsessive-compulsive disorder

Am J Psychiatry

A randomized, controlled trial of cognitive-behavioral therapy for augmenting pharmacotherapy in obsessive-compulsive disorder

Am J Psychiatry

Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: Worldwide experience

Mol Psychiatry

Deep brain stimulation of the nucleus accumbens for treatment-refractory obsessive-compulsive disorder

Arch Gen Psychiatry

Cognitive-behavioural therapy augments the effects of deep brain stimulation in obsessive-compulsive disorder

Psychol Med

Brain mediation of obsessive-compulsive disorder symptoms: Evidence From functional brain imaging studies in the human and nonhuman primate

Semin Clin Neuropsychiatry

Probing compulsive and impulsive behaviors, from animal models to endophenotypes: A narrative review

Neuropsychopharmacology

Archival Report
An Avoidance-Based Rodent Model of Exposure With Response Prevention Therapy for Obsessive-Compulsive Disorder