Translational approaches to obsessive‐compulsive disorder: from animal models to clinical treatment

Abstract

Obsessive-compulsive disorder (OCD) is characterized by obsessions (intrusive thoughts) and compulsions (repetitive ritualistic behaviours) leading to functional impairment. Accumulating evidence links these conditions with underlying dysregulation of fronto-striatal circuitry and monoamine systems. These abnormalities represent key targets for existing and novel treatment interventions. However, the brain bases of these conditions and treatment mechanisms are still not fully elucidated. Animal models simulating the behavioural and clinical manifestations of the disorder show great potential for augmenting our understanding of the pathophysiology and treatment of OCD. This paper provides an overview of what is known about OCD from several perspectives. We begin by describing the clinical features of OCD and the criteria used to assess the validity of animal models of symptomatology; namely, face validity (phenomenological similarity between inducing conditions and specific symptoms of the human phenomenon), predictive validity (similarity in response to treatment) and construct validity (similarity in underlying physiological or psychological mechanisms). We then survey animal models of OC spectrum conditions within this framework, focusing on (i) ethological models; (ii) genetic and pharmacological models; and (iii) neurobehavioural models. We also discuss their advantages and shortcomings in relation to their capacity to identify potentially efficacious new compounds. It is of interest that there has been rather little evidence of 'false alarms' for therapeutic drug effects in OCD models which actually fail in the clinic. While it is more difficult to model obsessive cognition than compulsive behaviour in experimental animals, it is feasible to infer cognitive inflexibility in certain animal paradigms. Finally, key future neurobiological and treatment research areas are highlighted. LINKED ARTICLESThis article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi. org/10.1111/bph.2011.164.issue-4 Abbreviations 5CSRTT, 5-choice serial reaction time test; 5-HT, serotonin; APA, American Psychiatric Association; BOLD, blood oxygen level-dependent; CS, conditioned stimulus; DBS, deep brain stimulation; DSM, Diagnostic and Statistical Manual; ELP, excessive lever presses; (f)MRI, (functional) magnetic resonance imaging; ID-ED, intra-dimensional -extra-dimensional; mCPP, meta-chlorophenylpiperazine; NMDA, N methyl-d aspartic acid; O-C, Obsessive-compulsive; OCD, ObsessiveCompulsive Disorder; OCSDs, Obsessive-Compulsive Spectrum Disorders; OFC, Orbitofrontal Cortex; SR, stimulusresponse; SSRIs, selective serotonin reuptake inhibitors; SSRT, stop-signal reaction time BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2011 1044 British Journal of Pharmacology (2011) IntroductionObsessive-compulsive disorder (OCD) is a common neuropsychiatric disorder, affecting roughly 2% of the adult population worldwide (Zohar, 1999), and...

Schedule-induced polydipsia as a model of compulsive behavior: neuropharmacological and neuroendocrine bases

“…Whereas fluoxetine reduced SIP after 5 to 6 days of treatment, these reductions began 1 day earlier when fluoxetine was co-administered with ineffective doses of either the 5-HT 1A antagonist WAY100635 or the 5-HT 1B/1D antagonist GR127935. Moreover, SIP model data are in accordance with evidence from animal and human studies suggesting that 5-HT 2 receptors may underpin compulsive behavior (for review, see Fineberg et al 2010Fineberg et al , 2011. Amperozide, an antipsychotic drug with a high affinity for 5-HT 2 receptors, reduced SIP without causing motor dysfunction (Tung et al 1994).…”

“…There is a considerable evidence of phenotypic heterogeneity and overlap between these disorders that share compulsive symptoms; many of them tend to occur together either within the same individual or family members, with also similarities in the treatment response, pointing towards shared pathophysiological mechanisms (Fineberg et al 2011;Hollander et al 2007). Compulsive symptoms across different disorders typically respond to pharmacological treatment with serotonin reuptake inhibitors (SRIs, clomipramine), selective SRIs (SSRIs, fluoxetine), atypical antipsychotics (olanzapine, risperidone), and the combination of SSRIs and antipsychotics; indeed, evidence from animal and human studies implicates 5-HT 2 receptors in compulsivity (for review, see Fineberg et al 2010Fineberg et al , 2011.…”

“…Compulsive symptoms across different disorders typically respond to pharmacological treatment with serotonin reuptake inhibitors (SRIs, clomipramine), selective SRIs (SSRIs, fluoxetine), atypical antipsychotics (olanzapine, risperidone), and the combination of SSRIs and antipsychotics; indeed, evidence from animal and human studies implicates 5-HT 2 receptors in compulsivity (for review, see Fineberg et al 2010Fineberg et al , 2011. Moreover, human neuroimaging studies have identified particular limbic regions, such as the nucleus accumbens, the orbitofrontal cortex and hippocampus, of the affective orbito-fronto-striatal circuit to underlie compulsive spectrum disorders (Baxter 1999;Chamberlain et al 2008;Menzies et al 2008).…”

“…Experimental measures used to assess compulsive behavior in animal models have included: stereotypy, signal attenuation, retarded extinction in reversal learning tasks (for review, see Boulougouris et al 2009;Fineberg et al 2011), compulsive drug seeking in self-administration (Belin et al 2008), perseverative responses on the sustained attention 5-choice serial reaction time (5-CSRT) task (Carli et al 2006(Carli et al , 2011a, and adjunctive or displacement behavioral models (Woods-Kettelberger et al 1997).…”

Dopaminergic control of cognitive flexibility in humans and animals

“…In line with this, OCD models that show a combination of the critical face, predictive and construct validities (Korff and Harvey, 2006; Wang et al, 2009; Fineberg et al, 2011; Albelda and Joel, 2012b) predominantly mirror the compulsive acts of OCD patients. This applies for models based on spontaneous behavior [ethological models, e.g., compulsive dogs, (Vermeire et al, 2012)], behavioral models [e.g., compulsive lever-pressing during signal attenuation in rats (Joel, 2006)], pharmacological models [e.g., quinpirole-induced checking in rats (Szechtman et al, 1998)], and transgenic models [e.g., compulsive grooming in Sapap3-mutant mice, (Welch et al, 2007)].…”