Review
Animal models of obsessive-compulsive disorder: Exploring pharmacology and neural substrates

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Abstract

During the last 30 years there have been many attempts to develop animal models of obsessive-compulsive disorder (OCD). Most models have not been studied further following the original publication, and in the past few years, most papers present studies employing a few established animal models, exploring the neural basis of compulsive behavior and developing new treatment strategies. Here we summarize findings from the five most studied animal models of OCD: 8-OHDPAT (8-hydroxy-2-(di-n-propylamino)-tetralin hydrobromide) induced decreased alternation, quinpirole-induced compulsive checking, marble burying, signal attenuation and spontaneous stereotypy in deer mice. We evaluate each model's face validity, derived from similarity between the behavior in the model and the specific symptoms of the human condition, predictive validity, derived from similarity in response to treatment (pharmacological or other), and construct validity, derived from similarity in the mechanism (physiological or psychological) that induces behavioral symptoms and in the neural systems involved. We present ideas regarding future clinical research based on each model's findings, and on this basis, also emphasize possible new approaches for the treatment of OCD.

Highlights

► There have been many attempts to develop animal models of obsessive-compulsive disorder. ► Lately, studies employ established animal models of OCD in order to study the disorder. ► We summarize the results obtained in these models. ► We evaluate the validity of each model. ► We describe new approaches for the treatment of OCD.

Introduction

During the last 30 years there have been many attempts to develop animal models of obsessive-compulsive disorder (OCD, for review see Insel et al., 1994, Joel, 2006a, Korff and Harvey, 2006, Man et al., 2004, Pitman, 1989, Ricciardi and Hurley, 1990, Stein et al., 1994, Wang et al., 2009, Winslow and Insel, 1991). Yet most of these models have not been studied further following the original publication. The past few years have seen a change in the field. Although new models have been presented (Andersen et al., 2010, Hill et al., 2007, Korff et al., 2008, Korff et al., 2009, Shmelkov et al., 2010, Tsaltas et al., 2005, Welch et al., 2007), most papers reported studies aiming to develop new treatment strategies and to study the neural basis of compulsive behavior using a few established animal models of OCD. The primary aim of the present review is to review the most studied animal models of OCD and evaluate their validity, and the secondary aim is to provide some ideas regarding future clinical research based on current findings.

We start by shortly describing some features of OCD (for extensive reviews see, Chamberlain et al., 2005, Greist and Jefferson, 2007, Lochner and Stein, 2003) and criteria for the validation and evaluation of animal models of psychiatric disorders in general and of OCD in particular. Next we review the five most studied animal models of OCD, namely, 8-OHDPAT (8-hydroxy-2-(di-n-propylamino)-tetralin hydrobromide) induced decreased alternation, quinpirole-induced compulsive checking, marble burying, signal attenuation and spontaneous stereotypy in deer mice. For each model we shortly describe the manipulation used to induce compulsive behavior and estimate the model's pharmacological predictive validity. We next summarize new data on the model's pharmacology and neural substrates, and on the basis of these data assess the model's validity and summarize possible implications for clinical research. The final section of the review summarizes the findings obtained in the different models, with special emphasis on possible new approaches for the treatment of OCD.

OCD is a psychiatric affliction with a lifetime prevalence of 1–3% (Rasmussen and Eisen, 1992, Sasson et al., 1997). According to the Diagnostic and Statistical Manual of Mental Disorders (4th ed; DSM IV), the essential features of OCD are recurrent obsessions and/or compulsions (e.g., doubting, checking, washing) that are time consuming (i.e., they take more than 1 h a day) or cause marked distress or significant impairment. To date, the most effective treatments for OCD are pharmacological treatment, using serotonin reuptake inhibitors (SRIs, e.g., Masand and Gupta, 1999, Piccinelli et al., 1995, Pigott and Seay, 1999, Stein et al., 1995, Zohar et al., 1992), and behavioral treatment, using the response exposure and prevention technique (e.g., Simpson et al., 2004). Yet, around 30% of the patients are refractory to pharmaco- and behavioral therapy (Eddy et al., 2004). Some of these treatment-resistant patients are treated by lesions to structures and pathways within basal ganglia-thalamo-cortical circuits (for review see, Lopes et al., 2004) as well as by high frequency stimulation (HFS) of the ventral striatum region (Aouizerate et al., 2004, Aouizerate et al., 2005, Greenberg et al., 2006, Greenberg et al., 2008, Rauch et al., 2006, Sturm et al., 2003) the subthalamic nucleus (Mallet et al., 2008), and the thalamic reticular nucleus and the inferior thalamic peduncles (Jimenez et al., 2007, Jimenez-Ponce et al., 2009).

Several neural systems have been implicated in the pathophysiology of OCD: The results of neuroimaging studies in OCD patients have implicated most consistently the orbitofrontal cortex, the cingulate cortex and the basal ganglia, and more recently also regions within the parietal lobe, in the pathophysiology of obsessions and compulsions (for review see Menzies et al., 2008, Rotge et al., 2009, Saxena et al., 1998, Stein, 2000). Dysregulation of the serotonergic (5-HT) system has been suggested primarily on the basis of the effectiveness of SRI's and selective serotonin reuptake inhibitors (SSRI's) in alleviating obsessions and compulsions in patients (Zohar and Insel, 1987, Zohar et al., 1992), and has received further support from neurobiological, pharmacological and more recently genetic data (for review see Murphy et al., 2001, Ozaki et al., 2003, Sasson and Zohar, 1996, Stein, 2000, but see Baumgarten and Grozdanovic, 1998). Abnormalities of the dopaminergic system have also been implicated in the pathophysiology of OCD, based on surplus therapeutic benefits obtained with co-administration of SSRI's and dopamine blockers (McDougle et al., 1990, McDougle et al., 1994, Sasson and Zohar, 1996) as well as on clinical observations of obsessions and compulsions in basal ganglia-related disorders, such as Tourette's syndrome (Frankel et al., 1986, Grad et al., 1987, Pitman et al., 1987). More recently, an increasing body of evidence points also to the involvement of the glutamatergic system in OCD (for review, see Pittenger et al., 2006), including association of certain polymorphisms in the NMDA receptor gene with susceptibility to OCD (Arnold et al., 2004); elevated glutamate levels in the cerebro-spinal fluid of drug-naïve patients (Chakrabarty et al., 2005); correlations between symptom severity and the level of several glutamatergic metabolites (Starck et al., 2008); improvement of symptoms following treatment with d-cycloserine (DCS), a partial NMDA agonist (blinded controlled trials, Kushner et al., 2007, Wilhelm et al., 2008), riluzole, a glutamatergic antagonist (open-label trials, Coric et al., 2005, Grant et al., 2007), and memantine, a non-competitive NMDA antagonist (an open-label trial, Aboujaoude et al., 2009). There is also some evidence suggesting the involvement of nitric oxide (NO) in OCD. Atmaca et al. (2005) found that OCD patients have higher NO levels in their plasma compared to healthy subjects and that these levels are positively correlated with the severity of OC symptoms. The possibility that high NO levels are related to OC symptoms is supported by the fact that SSRI's, anti-dopaminergic drugs and the NMDA antagonist memantine, all used to treat OCD patients, inhibit the synthesis of NO (Almeida et al., 2006, Park and West, 2009, Zhang et al., 2010). Reports that life events related to the female hormonal cycle may trigger or exacerbate OCD in women patients (Abramowitz et al., 2003, Labad et al., 2005, Maina et al., 1999) suggest that ovarian hormones play a modulatory role in OCD (Uguz et al., 2007). Indeed, gonadotropine-releasing hormone (GnRH) agonists were reported to ameliorate OC symptoms in OCD patients (Casas et al., 1986, Eriksson, 2000).

The understanding and treatment of diseases such as OCD must rely heavily on appropriate animal models that closely mimic their behavioral and if possible their neural manifestations. This is especially true for OCD as its neuropathological mechanisms are still largely unknown, and many patients are either treatment-resistant or experience only partial alleviation of symptoms. Before reviewing animal models of OCD that are currently in use, we discuss the criteria for the validation and evaluation of animal models.

Animal models are “experimental preparations developed in one species for the purpose of studying phenomena occurring in another species” (McKinney, 1988, p. 20). Although there has been an expansion in the development and use of animal models in psychiatry, and several papers aiming at providing a conceptual framework for guiding the development of this field have been published (Geyer and Markou, 1995, Matthysse, 1986, McKinney, 1988, McKinney and Bunney, 1969, Willner, 1984, Willner, 1986, Willner, 1991), there is still a lack of clarity regarding the terminology and classification of animal models and their validation criteria (for review see Joel, 2006a).

In the present paper we treat phenomenological similarity between the behavior in the animal model and the specific symptoms of the human condition as contributing to the face validity of a model; similarity in the mechanism (physiological or psychological) that induces behavioral symptoms and in the neural systems involved, as contributing to construct validity; and similarity in response to treatment (pharmacological or other) as contributing to the predictive validity of the model and to its construct validity (for a comprehensive discussion of the criteria for the validation and evaluation of animal models of psychopathology see Joel, 2006a).

In the field of animal models of OCD, a model's face validity is typically based on the induction of behaviors that are similar to compulsions, that is, that are repetitive, excessive and inappropriate. There are also a few animal models that mimic other aspects typical of OCD, such as perseveration. Most notable of these is the 8-OHDPAT model reviewed below, but perseveration in additional tasks has also been suggested to provide a model of OCD (e.g., the stop-signal reaction time task, Boulougouris et al., 2009; the 5-choice serial reaction time task, Chudasama et al., 2003; reversal learning, Boulougouris et al., 2007, Clarke et al., 2007). Of these, only 8-OHDPAT-induced perseveration has been shown to have pharmacological similarity to OCD (see below). Because perseveration is common in neurological and psychiatric conditions other than OCD (e.g., Parkinson's disease, schizophrenia, depression and bipolar disorder, ADHD, Hozumi et al., 2000, Waford and Lewine, 2010), we chose not to discuss tasks in which the predictive validity of perseveration has not been demonstrated. Finally, we would like to note that animal models of OCD can model only abnormal behaviors typical of OCD patients, but cannot model one of the main symptoms of OCD, namely, obsessional ideation.

A model's predictive validity should be established by a demonstration of selective alleviation of symptoms by SRI's and SSRI's, as well as by demonstrating the efficacy of HFS of the subthalamic nucleus and ventral striatum in the model. We would like to emphasize three points with respect to the establishment of predictive validity on the basis of pharmacological similarity. First, it is critical to demonstrate both sensitivity to S/SRI's and insensitivity to other classes of drugs (e.g., non-serotonergic antidepressants such as desipramine, anxiolytic agents such as diazepam), which are not effective in OCD but are effective in other conditions which are responsive to S/SRI treatment, such as depression, generalized anxiety disorder, panic disorder and social phobia (for reviews see Argyropoulos et al., 2000, Vaswani et al., 2003). Second, because S/SRI's are not effective in all OCD patients, a lack of effect of S/SRI's in a model may suggest that it is a model of compulsive behavior in the subgroup of OCD patients that do not respond to S/SRI treatment, rather than demonstrate that it is not a model of OCD. Yet, such a model should still demonstrate insensitivity to other types of pharmacological treatment, because there is currently no other effective monotherapy for this subgroup of OCD patients. The third point concerns the issue of acute versus chronic drug administration. In OCD patients S/SRI's are effective only after several weeks of repeated administration. Although several authors pointed to some difficulties with the notion of delayed drug effects in psychiatric disorders (e.g., Agid et al., 2003, Matthysse, 1986), this notion raises a question regarding the predictive validity of animal models that show beneficial effects after acute drug administration. As a model's predictive validity is relevant first and foremost for its ability to differentiate between effective and non-effective treatments, we view this ability as critical for establishing a model's predictive validity, regardless of the regimen of drug administration (for a similar view see Willner, 1991). In practice, although this issue is relevant for animal models of many psychiatric disorders (in which response to pharmacological treatment is evident only after several weeks of treatment), whether emphasis is placed on treatment regime greatly depends on the psychopathology that is being modeled. In the field of animal models of OCD some models used chronic (3–5 weeks of daily injections) or sub-chronic (3 injections over 24 h) regimen of drug administration to establish predictive validity (e.g., the 8-OHDPAT and quinpirole models), whereas others have mainly used acute administration (e.g., marble burying and signal attenuation).

As the physiological and/or psychological causes of OCD are currently unknown, construct validity can be established by demonstrating involvement of the orbitofrontal cortex, cingulate cortex and basal ganglia, as well as of ovarian hormones and the serotonergic, dopaminergic and glutamatergic systems. As discussed above, evidence supporting the predictive validity of a model (e.g., a similar response to treatment) also strengthens its construct validity by demonstrating similarity in the neural systems involved. A more indirect way to strengthen a model's construct validity is to demonstrate in the model cognitive deficits typical of OCD using equivalent tasks for humans and animals. Possible candidates for such an assessment could be the stop-signal reaction time and the intradimensional–extradimensional shift tasks, in which OCD patients are impaired (Chamberlain et al., 2006, Menzies et al., 2008). Unfortunately, performance in these tasks was not assessed in any of the models reviewed here.

In the sections below we first present for each animal model the evidence relevant to establishing its pharmacological predictive validity, on the basis of only response to S/SRI's and prescription drugs known not to be effective in OCD. We then review data acquired using the model, and on the basis of these data evaluate the model's face, construct and predictive validity and describe possible implications for clinical research. Regarding the latter we would like to emphasize that findings obtained in animals are not easily translated into clinical practice. At best, such findings suggest the possible value of certain directions for clinical research in humans. The likelihood that data obtained in animal models may be translated into clinical practice is greater when several models point in the same direction. In the last section of the paper we summarize the results obtained in the different models and discuss areas of convergence.

Section snippets

8-OHDPAT-induced decrease in spontaneous alternation

Spontaneous alternation refers to the natural tendency of rats to explore novel places sequentially and in succession. Yadin et al. (1991) were the first to suggest that pharmacologically induced decrease in spontaneous alternation may serve to model a specific aspect of OCD, namely, perseveration and indecision. The most common version of this model uses acute administration of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin hydrobromide (8-OHDPAT) to decrease spontaneous

Conclusions

Each of the models surveyed above has strengths and limitations, which dictate the aim(s) it can serve. In the context of screening for anti-compulsive activity, the most critical features of a model are its predictive validity and its cost-effectiveness. With regard to predictive validity, it is important to reiterate that about half of OCD patients do not respond to an SSRI monotherapy, yet, there is currently no other monotherapy that is effective in these patients. Therefore a demonstration

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