Progress in Neuro-Psychopharmacology and Biological Psychiatry
Current animal models of obsessive compulsive disorder: A critical review
Introduction
During the last 30 years there have been many attempts to develop animal models of obsessive compulsive disorder (OCD), and these have been reviewed quite extensively (e.g., Insel et al., 1994, Man et al., 2004, Pitman, 1989, Ricciardi and Hurley, 1990, Stein et al., 1994, Winslow and Insel, 1991). Most of these animal models have been abandoned during the years, and others have emerged. The aim of the present paper is to provide a critical review of currently used animal models of OCD. To this end, some features of OCD will be shortly described (these features are reviewed extensively in other papers in this issue); the criteria for validating animal models of psychopathology in general will be discussed, and several points which are specific to the modeling of OCD will be highlighted; on this basis, current animal models of OCD, divided according to the method used to induce ‘compulsive’ behavior (i.e., genetic, pharmacological, or behavioral manipulation) will be reviewed, and their validity evaluated.
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; American Psychiatric Association, 1994), the essential features of OCD are recurrent obsessions 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 (see Bartz and Hollander, this issue).
Several neural systems have been implicated in the pathophysiology of OCD. Dysregulation of the serotonergic (5-HT) system has been suggested primarily on the basis of the effectiveness of serotonin reuptake inhibitors (SRIs) 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 (DA) system have also been implicated in the pathophysiology of OCD (see a paper by Blier, this issue), based on surplus therapeutic benefits obtained with co-administration of SRIs and DA 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, 1987). In parallel, the results of neuroimaging studies in OCD patients have implicated most consistently the orbitofrontal cortex, the cingulate cortex and the basal ganglia in the pathophysiology of obsessions and compulsions (for review see Saxena et al., 1998, Stein, 2000). These regions are interconnected and are densely innervated by dopaminergic and serotonergic terminals. However, the nature of the dysfunction of these regions or the relation between their malfunction and the disturbance in the neurotransmitter systems postulated to be involved in OCD is still unknown.
For obvious reasons, 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. Before reviewing animal models of OCD that are currently in use, we discuss the criteria for the validation and evaluation of animal models.
Section snippets
Assessing the validity 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,
Assessing the validity of animal models of OCD
Several points should be raised with respect to the assessment of predictive validity in animal models of OCD. First, although SRIs are, to date, the only effective pharmacological treatment of OCD, they are effective in several other psychiatric disorders, including depression, generalized anxiety disorder, panic disorder and social phobia (for recent reviews, see Argyropoulos et al., 2000, Vaswani et al., 2003). Animal models of OCD should therefore demonstrate both sensitivity to SRIs and
Genetic models
Under this heading there are currently four mice models of OCD. It is important to note that the four models are not genetic models in the sense alluded to by Matthysse (1986), that is, they were not created on the basis of a known mutation in humans that was found to be related to OCD. Rather, these models are based on behavioral similarity, that is, the behavior of genetically modified mice was found to be similar in specific respects to that of OCD patients, and this is the main basis for
Pharmacological models
Pharmacological models of OCD are based on drug-induced behavioral alterations which bear similarity to some specific characteristics of the behavior of humans diagnosed with OCD, such as perseveration and indecision (Yadin et al., 1991), or compulsive checking (Eilam and Szechtman, 1995, Szechtman et al., 1998, Szechtman et al., 2001). In addition to behavioral similarity, in both models the relevant behavior is induced by manipulations of a neurotransmitter system whose dysfunction has been
Behavioral models
Most early animal models of OCD can be grouped under this heading. These include naturally occurring repetitive or stereotypic behaviors, such as tail chasing, fur chewing and weaving (for review see Insel et al., 1994, Stein et al., 1994, Winslow and Insel, 1991); innate motor behaviors that occur during periods of conflict, frustration or stress (displacement behaviors) such as grooming, cleaning and pecking (for review see Insel et al., 1994, Pitman, 1991, Ricciardi and Hurley, 1990, Winslow
Conclusions
Each of the models surveyed above has strengths and limitations (Table 1) which are important for choosing 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
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