The role of NMDA receptors in the signal attenuation rat model of obsessive–compulsive disorder

Albelda, Noa; Bar-On, Nitza; Joel, Daphna

doi:10.1007/s00213-010-1808-9

Cited by 39 publications

(25 citation statements)

References 61 publications

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“…Compulsive lever pressing was also selectively decreased by 5-HT 2C or D 1 receptor antagonists [62,63]. Contrary to what was observed in the deer mouse model [35,] an NMDA antagonist had no effect on compulsive lever pressing, while an NMDA agonist decreased this behavior [64].…”

Section: Overviewmentioning

confidence: 74%

Animal models of obsessive compulsive disorder: recent findings and future directions

Hoffman¹

2011

Expert Opinion on Drug Discovery

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The use of animal models takes us beyond simple serotonin- or dopamine-based models of OCD that are founded on the often limited, and still unexplained, response of OCD symptoms to serotonin reuptake inhibitors or antipsychotic therapy. Pharmacological challenges that selectively target neurochemical systems that modulate either corticostriatal glutamate or striatal dopamine neurotransmission, or indeed both, should be investigated in animal models of compulsive-like behavior. Such systems include metabotropic glutamate, adenosine and endocannabinoid receptors, among others.

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Section: Overviewmentioning

confidence: 74%

Animal models of obsessive compulsive disorder: recent findings and future directions

Hoffman¹

2011

Expert Opinion on Drug Discovery

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“…This sequence of events is modeled in rats through a series of purely behavioral manipulations in an operant chamber; the result is a ‘compulsive’ repetition of unproductive activity despite a lack of reward (Joel, 2006). In this model, D-cycloserine (DCS), a partial agonist at the glycine co-agonist site on the NMDA receptor (see Figure 4), decreased compulsive lever-pressing (Albelda, Bar-On, & Joel, 2010). …”

Section: Animal Modelsmentioning

confidence: 99%

Glutamate abnormalities in obsessive compulsive disorder: Neurobiology, pathophysiology, and treatment

Pittenger

Bloch

Williams

2011

Pharmacology & Therapeutics

356

259

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Obsessive compulsive disorder is prevalent, disabling, incompletely understood, and often resistant to current therapies. Established treatments consist of specialized cognitive-behavioral psychotherapy and pharmacotherapy with medications targeting serotonergic and dopaminergic neurotransmission. However, remission is rare, and more than a quarter of OCD sufferers receive little or no benefit from these approaches, even when they are optimally delivered. New insights into the disorder, and new treatment strategies, are urgently needed. Recent evidence suggests that the ubiquitous excitatory neurotransmitter glutamate is dysregulated in OCD, and that this dysregulation may contribute to the pathophysiology of the disorder. Here we review the current state of this evidence, including neuroimaging studies, genetics, neurochemical investigations, and insights from animal models. Finally, we review recent findings from small clinical trials of glutamate-modulating medications in treatment-refractory OCD. The precise role of glutamate dysregulation in OCD remains unclear, and we lack blinded, well-controlled studies demonstrating therapeutic benefit from glutamate-modulating agents. Nevertheless, the evidence supporting some important perturbation of glutamate in the disorder is increasingly strong. This new perspective on the pathophysiology of OCD, which complements the older focus on monoaminergic neurotransmission, constitutes an important focus of current research and a promising area for the ongoing development of new therapeutics.

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“…The compulsive lever pressing is reduced by SSRIs, but not by drugs known to be less effective for human OCD such as desipramine and diazepam (Joel et al, 2004). Interestingly, rats in this model that are treated with D-cycloserine (DCS), an NMDA receptor agonist, display decreased compulsive lever pressing; whereas the treatment of MK 801, an NMDA antagonist, has no effect on lever pressing (Albelda et al, 2010). Based on these findings, the authors hypothesized that under normal physiological conditions, NMDA receptor activity does not play a role in the production of compulsive behaviours.…”

Section: Animal Modelsmentioning

confidence: 99%

The role of glutamate signaling in the pathogenesis and treatment of obsessive–compulsive disorder

Hanna

Rosenberg

et al. 2012

Pharmacology Biochemistry and Behavior

235

144

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Obsessive-compulsive disorder (OCD) is a common and often debilitating neuropsychiatric condition characterized by persistent intrusive thoughts (obsessions), repetitive ritualistic behaviours (compulsions) and excessive anxiety. While the neurobiology and etiology of OCD has not been fully elucidated, there is growing evidence that disrupted neurotransmission of glutamate within corticalstriatal-thalamocortical (CSTC) circuitry plays a role in OCD pathogenesis. This review summarizes the findings from neuroimaging, animal model, candidate gene and treatment studies in the context of glutamate signalling dysfunction in OCD. First, studies using magnetic resonance spectroscopy are reviewed demonstrating altered glutamate concentrations in the caudate and anterior cingulate cortex of patients with OCD. Second, knockout mouse models, particularly the DLGAP3 and Slitrk5 knockout mouse models, display remarkably similar phenotypes of compulsive grooming behaviour associated with glutamate signalling dysfunction. Third, candidate gene studies have identified associations between variants in glutamate system genes and OCD, particularly for SLC1A1 which has been shown to be associated with OCD in five independent studies. This converging evidence for a role of glutamate in OCD has led to the development of novel treatment strategies involving glutamatergic compounds, particularly riluzole and memantine. We conclude the review by outlining a glutamate hypothesis for OCD, which we hope will inform further research into etiology and treatment for this severe neuropsychiatric condition.

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The role of NMDA receptors in the signal attenuation rat model of obsessive–compulsive disorder

Abstract: Activation of NMDA receptors may have an anti-compulsive effect in OCD patients.

Cited by 39 publications

References 61 publications

Animal models of obsessive compulsive disorder: recent findings and future directions

Animal models of obsessive compulsive disorder: recent findings and future directions

Glutamate abnormalities in obsessive compulsive disorder: Neurobiology, pathophysiology, and treatment

The role of glutamate signaling in the pathogenesis and treatment of obsessive–compulsive disorder

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