Animal Model Of Obsessive-compulsive Disorder Research Articles

Opening new vistas on obsessive-compulsive disorder with the observing response task

Obsessive-compulsive disorder (OCD), a highly prevalent and debilitating disorder, is incompletely understood in terms of underpinning behavioural, psychological, and neural mechanisms. This is attributable to high symptomatic heterogeneity; cardinal features comprise obsessions and compulsions, including clinical subcategories. While obsessive and intrusive thoughts are arguably unique to humans, dysfunctional behaviours analogous to those seen in clinical OCD have been examined in nonhuman animals. Genetic, ethological, pharmacological, and neurobehavioural approaches all contribute to understanding the emergence and persistence of compulsive behaviour. One behaviour of particular interest is maladaptive checking, whereby human patients excessively perform checking rituals despite these serving no purpose. Dysfunctional and excessive checking is the most common symptom associated with OCD and can be readily operationalised in rodents. This review considers animal models of OCD, the neural circuitries associated with impairments in habit-based and goal-directed behaviour, and how these may link to the compulsions observed in OCD. We further review the Observing Response Task (ORT), an appetitive instrumental learning procedure that distinguishes between functional and dysfunctional checking, with translational application in humans and rodents. By shedding light on the psychological and neural bases of compulsive-like checking, the ORT has potential to offer translational insights into the underlying mechanisms of OCD, in addition to being a platform for testing psychological and neurochemical treatment approaches.

Baclofen and 4-Phenylpyrrolidone Derivative GIZH-290 Attenuates Compulsive-Like Behavior in Mice

Obsessive-compulsive disorder (OCD) is a mental disease characterized by the obsessions which cause marked distress or anxiety and/or compulsions intended to alleviate this distress. The results of experimental and clinical studies suggest a possible role of GABAB receptors in the pathogenesis of OCD, making it relevant to study the effect of ligands of these receptors on the behavior of rodents. Objectives: Studying the effects of GIZH-290 and baclofen in animal models of OCD. Methods. The effects of GIZH-290 (0.01, 0.1, 1 mg/kg, i.p.) and baclofen (0.1, 1, and 5 mg/kg, i.p.) were studied in the marble burying test and the rotarod test, as well as in the 8-OH-DPAT-induced decrease in spontaneous alternation in mice. Results. Baclofen and GIZH-290 attenuated compulsive-like behavior in mice by reducing the number of buried marbles in the marble burying test at all tested doses. However, the effect of baclofen at a dose of 5 mg/kg was accompanied by a disruption of the animals’ motor coordination in the rotarod test. At the same time, neither baclofen nor GIZH-290 attenuated 8-OH-DPAT-induced (2 mg/kg, i.p.) decrease in spontaneous alternation behavior in mice. On the contrary, baclofen at a dose of 1 mg/kg exacerbated this disruption. Conclusion. Baclofen and GIZH-290 have anticompulsive activity in the marble burying test, but not in the 8-OH-DPAT-induced decrease in spontaneous alternation behavior in mice.

Animal models of Obsessive-Compulsive Disorder (OCD)

Treatment developments, brain imaging studies, and results of pharmacological research elicit revision of related pathological theories to Obsessive-compulsive disorder (OCD) and new research patterns. One of the important and alluring new research patterns under the neurobiological approach corresponding to the pathology and treatment of obsessive-compulsive disorder (OCD) is animal models which are used in this disorder. Insomuch, many endeavors have been applied in order to expand animal models of OCD during recent 30 years. In the hope of, increasing our understanding and knowledge about pathology as well as the treatment of this disorder. By considering the methodology of developing obsessive behaviors in animals, OCD animal models are divided into three classifications behavioral, pharmacological, and genetic. Research and studies using different animal models indicate the role of the serotonin neurotransmitter particularly the 5-HT2c receptor, the Dopamine neurotransmitter particularly the D1 and D2 receptors, and at the less level the role of the NMDA receptor of the Glutamate neurotransmitter in the pathology of OCD disorder.

A virtual library for behavioral performance in standard conditions-rodent spontaneous activity in an open field during repeated testing and after treatment with drugs or brain lesions.

BackgroundBeyond their specific experiment, video records of behavior have future value—for example, as inputs for new experiments or for yet unknown types of analysis of behavior—similar to tissue or blood sample banks in life sciences where clinically derived or otherwise well-described experimental samples are stored to be available for some unknown potential future purpose.FindingsResearch using an animal model of obsessive-compulsive disorder employed a standardized paradigm where the behavior of rats in a large open field was video recorded for 55 minutes on each test. From 43 experiments, there are 19,976 such trials that amount to over 2 years of continuous recording. In addition to videos, there are 2 video-derived raw data objects: XY locomotion coordinates and plots of animal trajectory. To motivate future use, the 3 raw data objects are annotated with a general schema—one that abstracts the data records from their particular experiment while providing, at the same time, a detailed list of independent variables bearing on behavioral performance. The raw data objects are deposited as 43 datasets but constitute, functionally, a library containing 1 large dataset.ConclusionsSize and annotation schema give the library high reuse potential: in applications using machine learning techniques, statistical evaluation of subtle factors, simulation of new experiments, or as educational resource. Ultimately, the library can serve both as the seed and as the test bed to create a machine-searchable virtual library of linked open datasets for behavioral performance in defined conditions.

Effects of low doses of different nitric oxide (NO) donors in rat models of obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD)

Several lines of evidence suggest that the intra- and inter-cellular messenger nitric oxide (NO) is critically involved in anxiety. Contrasting findings are reported, however, regarding the effects of NO donors in preclinical models of anxiety. Previous research has shown that challenge with a low dose range of the NO donors sodium nitroprusside (SNP) and molsidomine induce anti-anxiety-like effects in rodents. There is poor information concerning the effects of these NO donors on preclinical models mimicking the obsessive-compulsive disorder (OCD) and the post-traumatic stress disorder (PTSD). The present research was designed to investigate this issue in the rat. To this end, the mCPP-induced excessive self-grooming and the contextual fear conditioning (CFC) test which are behavioural paradigms resembling OCD and PTSD respectively in rodents were used. Acute administration of SNP (1 mg/kg) and molsidomine (4 mg/kg) attenuated excessive self-grooming induced by the 5-HT2C receptor agonist mCPP (0.6 mg/kg). Further, at the same dosage, both these NO donors reduced freezing behaviour evidenced in the CFC test. The present results suggest that NO donors are efficacious in attenuating abnormal behaviours revealed in animal models of OCD and PTSD which are among the most severe pathologies of anxiety.

Memantine and Riluzole Exacerbate, Rather Than Ameliorate Behavioral Deficits Induced by 8-OH-DPAT Sensitization in a Spatial Task.

Chronic sensitization to serotonin 1A and 7 receptors agonist 8-OH-DPAT induces compulsive checking and perseverative behavior. As such, it has been used to model obsessive-compulsive disorder (OCD)-like behavior in mice and rats. In this study, we tested spatial learning in the 8-OH-DPAT model of OCD and the effect of co-administration of memantine and riluzole—glutamate-modulating agents that have been shown to be effective in several clinical trials. Rats were tested in the active place avoidance task in the Carousel maze, where they learned to avoid the visually imperceptible shock sector. All rats were subcutaneously injected with 8-OH-DPAT (0.25 mg/kg) or saline (control group) during habituation. During acquisition, they were pretreated with riluzole (1 mg/kg), memantine (1 mg/kg), or saline solution 30 min before each session and injected with 8-OH-DPAT (“OH” groups) or saline (“saline” groups) right before the experiment. We found that repeated application of 8-OH-DPAT during both habituation and acquisition significantly increased locomotion, but it impaired the ability to avoid the shock sector. However, the application of 8-OH-DPAT in habituation had no impact on the learning process if discontinued in acquisition. Similarly, memantine and riluzole did not affect the measured parameters in the “saline” groups, but in the “OH” groups, they significantly increased locomotion. In addition, riluzole increased the number of entrances and decreased the maximum time avoided of the shock sector. We conclude that monotherapy with glutamate-modulating agents does not reduce but exacerbates cognitive symptoms in the animal model of OCD.

The Effect of Lactobacillus casei Consumption in Improvement of Obsessive-Compulsive Disorder: an Animal Study.

Obsessive-compulsive disorder (OCD) is an important neuropsychiatric disorder worldwide. Common treatments of OCD include serotonergic antidepressants, which can cause potentially serious side effects. We assessed the effects of Lactobacillus casei (L. casei) Shirota consumption in an animal model of OCD. OCD-like symptoms were induced in rats by the chronic injection of the D2/D3 dopamine agonist quinpirole hydrochloride. Rats were classified into five groups of 6 rats. Four groups were injected chronically with quinpirole (0.5mg/kg, twice weekly for 5weeks). They were fed with L. casei Shirota (109CF/g, daily for 4weeks) (group 1), fluoxetine (10mg/kg, daily for 4weeks) (group 2), combination of L. casei Shirota and fluoxetine (group 3), and normal saline (positive control group). The last group did not receive dopamine agonist and was only injected with saline (negative control group). Expression levels of brain-derived neurotrophic factor (Bdnf), solute carrier family 6 member 4 (Slc6a4), and 5-hydroxytryptamine receptor type 2A (Htr2a) were assessed in orbitofrontal cortex tissues of all rats. Behavioral tests showed improvement of OCD signs in rats treated with L. casei Shirota, fluoxetine, and a combination of drugs. Quantitative PCR analysis showed a remarkable decrease in the expression of Bdnf and an increase in the expression of Htr2a in quinpirole-treated rats. After treatment with L. casei Shirota and fluoxetine, the expression level of Bdnf was increased remarkably, whereas Htr2a expression was decreased. The current study showed the effectiveness of L. casei Shirota in the treatment of OCD in a rat model. The beneficial effects of this probiotic are possibly exerted through the modulation of serotonin-related genes expression.

No effect of riluzole and memantine on learning deficit following quinpirole sensitization - An animal model of obsessive-compulsive disorder

RationaleChronic quinpirole (QNP) sensitization is an established animal model relevant to obsessive-compulsive disorder (OCD) that has been previously shown to induce several OCD-like behavioral patterns, such as compulsive-like checking and increased locomotion. ObjectivesIn current study we explored the effect of antiglutamatergic drugs, memantine and riluzole, on cognitive and behavioral performance of QNP sensitized rats. MethodsDuring habituation phase, the rats (N = 56) were injected with QNP (0.25 mg/kg) or saline solution (every other day up to 10 injections) and placed into rotating arena without foot shocks for 50-min exploration. Active place avoidance task in rotating arena with unmarked to-be-avoided shock sector was used during acquisition phase. Rats were injected with memantine (1 mg/kg or 5 mg/kg), riluzole (1 mg/kg or 5 mg/kg) or saline solution 30 min before the trial and with QNP (0.25 mg/kg) or saline right before they were placed inside the rotating arena with 60° unmarked shock sector. Locomotion and number of entrances into the shock sector were recorded. ResultsQNP sensitization led to a robust deficit in place learning. However, neither memantine nor riluzole did reverse or alleviate the deficit induced by QNP. Contrarily, memantine significantly aggravated QNP induced deficit. ConclusionsThe exacerbation of cognitive deficit following antiglutamatergic agents could be mediated by decreased glutamate concentration in nucleus accumbens and decreased hippocampal activation in the QNP sensitization model.

Back to basics: A methodological perspective on marble-burying behavior as a screening test for psychiatric illness

Animal models of human psychiatric illness are valuable frameworks to investigate the etiology and neurobiology underlying the human conditions. Accurate behavioral measures that can be used to characterize animal behavior, thereby contributing to a model’s validity, are crucial. One such measure, i.e. the rodent marble-burying test (MBT), is often applied as a measure of anxiety- and compulsive-like behaviors. However, the test is characterized by noteworthy between-laboratory methodological differences and demonstrates positive treatment responses to an array of pharmacotherapies that are often of little translational value. Therefore, using a naturalistic animal model of obsessive-compulsive disorder, i.e. the deer mouse (Peromyscus maniculatus bairdii), the current investigation attempted to illuminate the discrepancies reported in literature by means of a methodological approach to the MBT. Five key aspects of the test that vary between laboratories, viz. observer/scoring, burying substrate, optional avoidance, the use of repeated testing, and determinations of locomotor activity, have been investigated. Following repeated MB tests in four different burying substrates and in two zone configurations, we have demonstrated that 1) observer bias may contribute to the significant differences in findings reported, 2) MB seems to be a natural exploratory response to a novel environment, rather than being triggered by aberrant cognition, 3) burying substrates with a small particle size and higher density deliver the most accurate results with respect to the burying phenotype, and 4) to exclude the influence of normal exploratory behavior on the number of marbles being covered, assessments of marble-burying should be based on pre-occupation with the objects itself.

Field Potential Oscillations in the Bed Nucleus of the Stria Terminalis Correlate with Compulsion in a Rat Model of Obsessive-Compulsive Disorder.

The bed nucleus of the stria terminalis (BNST) is implicated in anxiety and reward processing, both of which are associated with obsessive-compulsive disorder (OCD). Specific neuronal groups in the BNST related to anxiety and reward have been identified, but quantitative data about the information carried by local field potential (LFP) signals in this area during obsession/compulsion are lacking. Here we investigate the BNST LFP in the schedule-induced polydipsia, an animal model of OCD. We implanted electrodes bilaterally in the BNST and random control brain regions in 32 male Wistar rats, and recorded corresponding LFP during compulsive and noncompulsive behavior. We first applied high-frequency (100 Hz) electrical stimulation through the implanted electrodes and analyzed its effects on compulsive behavior. We then performed time-frequency analysis of LFPs and statistically compared the normalized power of δ (1-4 Hz), θ (4-8 Hz), α (8-12 Hz), β (12-30 Hz), and lower γ (30-45 Hz) bands between different groups. Our data showed that the normalized δ, β, and γ powers in the right BNST were specifically correlated with compulsive behaviors. δ and γ oscillations increased and decreased during the initiation phase of compulsion, respectively, whereas β increased after compulsion stopped. Moreover, the effect of BNST electrical stimulation, in terms of suppression of compulsion, was significantly correlated with the percentage change of these bands during compulsion. Our research reveals potential biomarkers and underlying neurophysiological mechanisms of compulsion and warrants further assessment of the use of LFP for closed-loop neuromodulation in OCD. Although specific neuronal groups in the bed nucleus of the stria terminalis (BNST) related to anxiety and reward circuitries have been identified, psychopathological information carried by local field potentials in the BNST has not yet been described. We discovered that normalized powers of the right BNST δ, β, and γ oscillations were highly correlated with compulsion. Specifically, δ and γ oscillations increased and decreased during the initiation phase of compulsion, respectively, whereas β increased after compulsion stopped. Such correlations were not found in other parts of the brain during compulsion, or in the BNST during noncompulsive behavior. Current findings reveal real-time neurophysiological biomarkers of compulsion and warrant further assessment of the use of local field potentials for closed-loop neuromodulation for OCD.

Detrimental effect of clomipramine on hippocampus-dependent learning in an animal model of obsessive-compulsive disorder induced by sensitization with d2/d3 agonist quinpirole

Quinpirole (QNP) sensitization is one of the commonly used animal models of obsessive-compulsive disorder (OCD). We have previously shown that QNP-sensitized animals display a robust cognitive flexibility deficit in an active place avoidance task with reversal in Carousel maze. This is in line with numerous human studies showing deficits in cognitive flexibility in OCD patients. Here we explored the effect of clomipramine, an effective OCD drug that attenuates compulsive checking in QNP, on sensitized rats in acquisition and reversal performances in an active place avoidance task. We found that the addition of clomipramine to QNP-sensitization impairs acquisition learning to a degree that reversal learning could not be tested. In a hippocampal-independent two-way active avoidance task clomipramine did not have an effect on acquisition learning in QNP-treated rats; suggesting that the detrimental effect of clomipramine is hippocampus based. We also tested the effect of risperidone in QNP-sensitized animals, which is not effective in OCD treatment. Risperidone also marginally impaired acquisition learning of QNP-sensitized animals, but not reversal. Moreover, we explored the effect of the augmentation of clomipramine treatment with risperidone in QNP-sensitized rats- a common step in treating SRI-unresponsive OCD patients. Only under this treatment regime animals were unimpaired in both acquisition and reversal learning. Augmentation of SRI with neuroleptics therefore could be beneficial for improving cognitive flexibility, and possibly be considered a first line of treatment in patients with reduced cognitive flexibility.

EP 21. Neuromodulation of the hyperdirect pathway to study flexibility as an endophenotype of obsessive compulsive disorders

Obsessive-Compulsive Disorder (OCD) is a mental disorder featuring obsessions (intrusive ideas) and compulsions which are repetitive behaviors performed through rigid rituals. This phenomenological observation has led to explore the idea that OCD patients have diminished behavioral flexibility. The pathophysiology of OCD support this hypothesis with dysfunctional cortico-basal ganglia loops including two specific structures connected together through the hyperdirect pathway: the subthalamic nucleus and the orbitofrontal cortex, both also involved in behavioral flexibility. Thus, our objective is twofold: to verify the involvement of behavioral flexibility in the compulsive behavior and to explore the neurobiological bases underlying flexibility in patients and an animal model of OCD (SAPAP3-KO). We aim at developing similar behavioral tasks in both species where we could chronically modulate neural activity using deep brain stimulation and optogenetic. Behavioral flexibility may be challenged in reversal learning paradigms. In these tasks, the subject has to respond to either of two different visual stimuli but only one stimulus is positively rewarded while the other is not. When the association has been learned, reward contingencies are inverted. This task has been implemented easily for neuropsychological studies in human. However, the adaptation of non-spatial reversal learning task in rodents is much more laborious due to the high number of trials required for the acquisition. To overcome this issue, we developed automated behavioral cages where animals could live and be exposed continuously to the reversal learning task. Our protocol is based on 5 main successive stages of training and allow to perform multiple reversal within one session. This experimental setup has also be designed to integrate chronic neuronal stimulation device to automatically modulate neural activity in the hyperdirect pathway during relevant events of the task. We succeeded in designing a similar reversal learning task to explore the behavioral flexibility both in humans and rodents. With our automatic ecological behavioral setup for mice, we reduced very significantly the time necessary to perform visual reversal learning task compared to more classical paradigm. Moreover we obtained preliminary results which are in line with the hypothesis of an impaired behavioral flexibility in compulsive subjects. Indeed, we observed that both OCD patients and SAPAP3-KO mice showed perseverative maladaptive behaviors in our task. These preliminary results suggest that OCD conditions could be associated with a diminished behavioral flexibility. The development of a translational behavioral task is the first step of our aim to explore the neural basis of the behavioral flexibility and its link with compulsive behavior. For this purpose, our innovative designs will allow us to modulate the cortico-basal ganglia pathways both in patients (with DBS) and OCD mouse model (with optogenetic) during behavioral tasks to study their implications in compulsive behaviors.

Excessive nest building is a unique behavioural phenotype in the deer mouse model of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a phenotypically heterogeneous condition characterised by time-consuming intrusive thoughts and/or compulsions. Irrespective of the symptom type diagnosed, the severity of OCD is characterised by heterogeneity in symptom presentation that complicates diagnosis and treatment. Heterogeneity of symptoms would be invaluable in an animal model. Nest building behaviour forms part of the normal behavioural repertoire of rodents and demonstrates profound between-species differences. However, it has been proposed that within-species differences in nest building behaviour (i.e. aberrant vs. normal nest building) may resemble obsessive-compulsive-like symptoms. In an attempt to investigate whether other obsessive-compulsive-like behaviours are present in an animal model of OCD, or if aberrant nest building behaviour may represent a unique obsessive-compulsive phenotype in such a model, the current study assessed nest building behaviour in high (H, viz obsessive-compulsive) and non (N, viz normal) stereotypical deer mice. Subsequently, 12 N and H animals, respectively, were provided with an excess of cotton wool daily for one week prior to and following four weeks of high-dose oral escitalopram treatment (50 mg/kg/day). Data from the current investigation demonstrate daily nesting activity to be highly variable in deer mice, with stereotypy and nest building being independent behaviours. However, we identified unique aberrant large nest building behaviour in 30% of animals from both cohorts that was attenuated by escitalopram to pre-treatment nesting scores of the larger group. In summary, behavioural and drug-treatment evidence confirms that deer mouse behaviour does indeed resemble symptom heterogeneity related to OCD, and as such expands its face and predictive validity for the disorder.

Of mice and marbles: Novel perspectives on burying behavior as a screening test for psychiatric illness.

Burying forms part of the normal behavioral routine of rodents, although its expression is species-specific. However, it has been suggested that aberrant burying behavior, of which marble-burying (MB) is an example, may represent neophobic and/or compulsive-like behavior. In the present investigation, we assessed MB in an established animal model of obsessive-compulsive disorder (OCD)-namely, spontaneous stereotypy in the deer mouse-to establish whether high (H) stereotypy is associated with neophobia and/or another compulsive endophenotype, i.e. MB, as compared to nonstereotypical (N) controls. A three-trial, one-zone MB test was performed over three consecutive evenings both before and after chronic treatment with high-dose (50mg/kg/day) oral escitalopram. Neophobia was measured via the number of marbles buried during the first pre- and posttreatment MB trials, and compulsive-like behavior via the number of marbles buried over all pre- and posttreatment MB trials. The data from the present study support earlier findings that burying is a normal behavioral routine (inherent burying behavior, IBB) that is expressed by all deer mice, irrespective of stereotypical cohort, and is not associated with either neophobia or compulsiveness. Indeed, chronic escitalopram treatment, which is similarly effective in treating clinical anxiety and OCD, as well as in attenuating H behavior, failed to influence IBB. Although 11% of the animals presented with a unique burying endophenotype (high burying behavior), escitalopram also failed to attenuate said behavior, necessitating further investigation as to its relevance. In conclusion, MB cannot be regarded as a measure of anxiety-like or compulsive behavior in the deer mouse model of OCD.

There Is Much to Be Learned From Animal Models of Obsessive-Compulsive Disorder

There Is Much to Be Learned From Animal Models of Obsessive-Compulsive Disorder

Involvement of nitric oxide in anticompulsive-like effect of agmatine on marble-burying behaviour in mice

In view of the reports that nitric oxide modulates the neurotransmitters implicated in obsessive–compulsive disorder (OCD), patients with OCD exhibit higher plasma nitrate levels, and drugs useful in OCD influence nitric oxide. Agmatine is a polyamine and widely distributed in mammalian brain which interacts with nitrergic systems. Hence, the present study was carried out to understand the involvement of nitrergic systems in the anticompulsive-like effect of agmatine. We used marble-burying behaviour (MBB) of mice as the animal model of OCD, and nitric oxide levels in hippocampus (HC) and cortex homogenate were measured. Results revealed that, agmatine (20 and 40mg/kg, i.p) significantly inhibited the MBB. Intraperitoneal administration of nitric oxide enhancers viz. nitric oxide precursor – l-arginine (l-ARG) (400mg/kg and 800mg/kg) increased MBB as well as brain nitrites levels, whereas treatment with NG-nitro-l-arginine methyl ester (l-NAME) neuronal nitric oxide synthase inhibitor (30mg/kg and 50mg/kg, i.p.) and 7-nitroindazole (7-NI) (20mg/kg and 40mg/kg) attenuated MBB and nitrites levels in brain. Further, in combination studies, the anticompulsive-like effect of agmatine (20mg/kg, ip) was exacerbated by prior administration of l-ARG (400mg/kg) and conversely l-NAME (15mg/kg) or 7-NI (10.0mg/kg) attenuated OCD-like behaviour with HC and cortex changes in the levels of NO. None of the above treatment had any significant influence on locomotor activity. In conclusion, Agmatine is effective in ameliorating the compulsive-like behaviour in mice which appears to be related to nitric oxide in brain.

Are 5-HT3 antagonists effective in obsessive-compulsive disorder? A systematic review of literature.

The purpose of this literature database search-based review was to critically consider and evaluate the findings of literature focusing on efficacy and safety of 5-HT3 antagonists in the treatment of obsessive-compulsive disorder (OCD), so as to test whether preclinical data match clinical therapeutic trials. The PubMed database has been searched for papers on 5-HT3 antagonists and OCD in humans and for animal models of OCD and 5-HT3 receptors. Of the clinically tested 5-HT3 receptor antagonists, ondansetron has been used to treat OCD in five therapeutic studies, whereas granisetron only in one recent trial. Both showed some efficacy in open studies and superiority to placebo in double-blind studies, along with fair safety. No animal OCD model directly implicated 5-HT3 receptors. Overall, results indicate some utility, but the available literature is too scanty to allow for valid conclusions to be drawn. The mismatch between animal models of obsessive-compulsive disorder and clinical data with 5-HT3 antagonists needs more clinical data to ensure that it is not an artefact.

Separate mechanisms for development and performance of compulsive checking in the quinpirole sensitization rat model of obsessive-compulsive disorder (OCD)

Acute administration of serotonergic agonist, meta-chlorophenylpiperazine (mCPP), attenuates performance of compulsive checking in an animal model of obsessive-compulsive disorder (OCD). It is not known whether mCPP has a similar effect on development of compulsive checking. The objective of the study was to examine whether similar mechanisms mediate the development versus the performance of compulsive checking in the rat model. Four groups of male rats (N = 14/group) were tested: two experimental groups co-injected with D2/D3 dopamine agonist quinpirole (0.25 mg/kg) and mCPP (0.625 mg/kg or 1.25 mg/kg), and two control groups, one co-injected with quinpirole and saline, the other receiving injections of saline. The time course of development of compulsive checking across injections 1 to 10 in quinpirole-treated rats was compared to rats co-injected with quinpirole and mCPP. Results showed that during the course of chronic treatment, mCPP (1.25 mg/kg) significantly attenuated performance of checking behavior. However, when these rats were retested for expression of compulsive checking (that is, with an injection of quinpirole only), their profile of compulsive checking was no different from the control rats treated throughout with quinpirole only. Findings show that mCPP inhibits performance of compulsive checking but does not block quinpirole from inducing the neural substrate underlying this compulsive behavior. Hence, a separate mechanism underlies the induction of compulsive checking and the performance of it. It is suggested that development of the OCD endophenotype reflects neuroplastic changes produced by repeated dopamine D2/D3 receptor stimulation, while stimulation of serotonergic receptors mediates a negative feedback signal that shuts down the motor performance of checking.

Animal Models of Obsessive-Compulsive Disorder: Strain Differences

Obsessive-compulsive disorder (OCD) is characterized by obsessions (intrusive thoughts, images etc.) and compulsions (repetitive, stereotyped and perseverant acts). Animal models of OCD are specifically devoted to simulating compulsive features of the disorder. In OCD, compulsive behaviors are recognized as repetitive and maladaptive and symptoms relief can be experienced due to treatment with selective serotonin reuptake inhibitors. Many animal models of OCD are provided with some degree of validity. Genetically based differences in behavior in animal models of OCD are of great value, given that human OCD is reported to involve genetic factors. Some animal models of OCD were already used in studies for the evaluation of strain differences. These works were explored in the present review.

Reappraisal of spontaneous stereotypy in the deer mouse as an animal model of obsessive-compulsive disorder (OCD): Response to escitalopram treatment and basal serotonin transporter (SERT) density

Obsessive-compulsive disorder (OCD) is characterized by recurrent thoughts and repetitive motor actions. Hyposerotonergic signalling in the cortico-striatal circuitry is believed to be central to the pathology of OCD, while many patients only respond to chronic treatment with high dose selective serotonin (5HT) reuptake inhibitors (SSRIs). Confined deer mice spontaneously develop two forms of stereotypy, namely vertical jumping and pattern running. The purpose of this investigation was to reappraise these behaviours and strengthen the validity of deer mouse stereotypy as an animal model of OCD within a framework of three study questions: (1) can the time spent executing stereotypical behaviours be employed as a measure of extent of stereotypy, (2) does deer mouse stereotypy only respond to chronic, but not sub-chronic treatment with a high-dose SSRI, and (3) is deer mouse stereotypy associated with altered cortico-striatal 5HT transporter (SERT) binding? The current study demonstrates that treatment naïve high stereotypical (HS) deer mice spend significantly more time executing stereotypical behaviours while significantly less time is spent indulging in stereotypy following chronic, but not sub-chronic, treatment with escitalopram. Furthermore, HS deer mice present with a significant decrease in striatal SERT density compared to non-stereotypical (NS) controls. Building on previous validation studies, we conclude that deer mouse stereotypy is a valid naturalistic animal model of OCD with robust face, construct and predictive validity.