Validity of Quinpirole Sensitization Rat Model of OCD: Linking Evidence from Animal and Clinical Studies

Abstract

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder with 1–3% prevalence. OCD is characterized by recurrent thoughts (obsessions) and repetitive behaviors (compulsions). The pathophysiology of OCD remains unclear, stressing the importance of pre-clinical studies. The aim of this article is to critically review a proposed animal model of OCD that is characterized by the induction of compulsive checking and behavioral sensitization to the D2/D3 dopamine agonist quinpirole. Changes in this model have been reported at the level of brain structures, neurotransmitter systems and other neurophysiological aspects. In this review, we consider these alterations in relation to the clinical manifestations in OCD, with the aim to discuss and evaluate axes of validity of this model. Our analysis shows that some axes of validity of quinpirole sensitization model (QSM) are strongly supported by clinical findings, such as behavioral phenomenology or roles of brain structures. Evidence on predictive validity is contradictory and ambiguous. It is concluded that this model is useful in the context of searching for the underlying pathophysiological basis of the disorder because of the relatively strong biological similarities with OCD.

From an animal model to human patients: An example of a translational study on obsessive compulsive disorder (OCD)

“…1A-G. While the incessant behavior of the quinpirole rats clearly demonstrates substantial face validity, the model was also shown to have robust construct validity but ambiguous predictive validity (for review see Stuchlik et al, 2016).…”

An Adenosine A2AReceptor Antagonist Improves Multiple Symptoms of Repeated Quinpirole-Induced Psychosis

“…Among existing experimental tools for the study of OCD, quinpirole (QNP)-induced psychosis in rats are known to be an easy-to-use tool (Stuchlik et al, 2016). After several injections of a dopamine D 2 agonist, QNP, rats show several OCD-related behaviors, e.g., robust repetitive checking behavior, which is considered to be similar to the checking compulsion in OCD patients (Szechtman et al, 1998; Stuchlik et al, 2016). However, despite the good similarity in the behavioral phenotype, limited information regarding pharmacotherapeutic response, especially for SSRI treatment, is available (Stuchlik et al, 2016).…”

“…After several injections of a dopamine D 2 agonist, QNP, rats show several OCD-related behaviors, e.g., robust repetitive checking behavior, which is considered to be similar to the checking compulsion in OCD patients (Szechtman et al, 1998; Stuchlik et al, 2016). However, despite the good similarity in the behavioral phenotype, limited information regarding pharmacotherapeutic response, especially for SSRI treatment, is available (Stuchlik et al, 2016). Considering the limited efficacy of SSRI treatment against several OCD symptoms, an assessment of both SSRI-responsive and SSRI-resistant OCD-like behaviors is beneficial for the elucidation of the pathophysiological and therapeutic mechanisms of OCD.…”

Crosstalk Between Kappa Opioid and Dopamine Systems in Compulsive Behaviors

“…At the beginning of the 90's, Szechtman and Eilam reported that along with locomotor sensitization, rats developed a stereotyped behavior, which is reinforced with each administration of quinpirole (Eilam and Szechtman, 1989;Szechtman et al, 1993). Today, quinpirole repeated administration is a validated model for OCD (Szechtman et al, 1999;Szechtman et al, 2001;Eilam and Szechtman, 2005;Stuchlik et al, 2016;Szechtman et al, 2017), based on the observation that the behavior of rats becomes increasingly structured and inflexible, reminiscent of the ritual behavior characteristic of compulsive checking behavior (Szechtman et al, 1998;Szechtman et al, 2017). Recent studies show that repeated quinpirole also induces compulsive behaviors in mice, such as compulsive checking (Sun et al, 2019), behavioral inflexibility and compulsive chewing (Asaoka et al, 2019), the latter reverted by D2Rs blockade in the striatum, further supporting that repeated D2Rs activation is needed to induce compulsive behaviors.…”

“…Indeed, the repeated activation of dopamine D2 receptors (D2Rs) is enough to induce locomotor sensitization and checking behavior in both rats and mice (Szechtman et al, 1998;Szechtman et al, 1999;Sun et al, 2019). Repeated administration of quinpirole, a D2R/D3R agonist, is an accepted model of OCD as it recapitulates face validity, through an increment of compulsive checking and stereotyped behavior, predictive validity, as seen by a decrease of compulsive behaviors after chronic treatment with serotonin reuptake inhibitors (SRI) and construct validity as brain structures involved in this model are shared with those in the pathology (Stuchlik et al, 2016;Szechtman et al, 2017). In summary, repeated activation of dopamine transmission, either by presynaptic (dopamine release) or post-synaptic (activation of D2R) m e c h a n i s m s l e a d t o l o c o m o to r s e n s i t i z a ti o n a n d compulsive behaviors.…”