Effects of glutamate-related drugs on marble-burying behavior in mice: Implications for obsessive-compulsive disorder

Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan.
European Journal of Pharmacology (Impact Factor: 2.53). 06/2008; 586(1-3):164-70. DOI: 10.1016/j.ejphar.2008.01.035
Source: PubMed


Clinical evidence demonstrates altered glutamatergic neurotransmission in patients suffering from obsessive-compulsive disorder (OCD). We examined the effects of glutamate-related drugs on marble-burying behavior, which is an animal model of OCD. The uncompetitive N-methyl-d-aspartate (NMDA) antagonists memantine (10 mg/kg, i.p.) and amantadine (30 mg/kg, i.p.) significantly inhibited marble-burying behavior without affecting locomotor activity in mice. Similarly, the uncompetitive NMDA receptor antagonist 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine hydrogen maleate (MK-801, 0.3 mg/kg, i.p.) inhibited marble-burying behavior. However, MK-801 at the same dose markedly increased locomotor activity. By contrast, the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX) and the glutamate release inhibitor riluzole showed no effect on marble-burying behavior and significant suppression of locomotor activity. MK-801 (0.3 mg/kg, i.p.) and memantine (10 mg/kg, i.p.) significantly disrupted prepulse inhibition as an operational measure of sensorimotor gating. By contrast, amantadine (30 mg/kg, i.p.) did not affect prepulse inhibition. These findings suggest that amantadine could be a useful drug for the treatment of OCD.

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    • "Patients with OCD present increased glutamate levels in CSF compared to healthy subjects (Chakrabarty et al., 2005; Bhattacharyya et al., 2009). Moreover, both preclinical and clinical studies suggest that drugs that attenuate glutamate neurotransmission such as riluzole and memantine could be helpful in the treatment of OCD patients (Grant et al., 2007; Aboujaoude et al., 2009) and are effective in animal models of this disorder (Egashira et al., 2008; Iijima et al., 2010). Finally, several independent genetic studies have consistently implicated the SLC1A1 gene, which encodes the neuronal glutamate transporter excitatory amino acid carrier 1 (EAAC1), in OCD (Arnold et al., 2006; Dickel et al., 2006; Stewart et al., 2007; Liang et al., 2008). "
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    ABSTRACT: Obsessive-compulsive disorder (OCD) is a chronic and fluctuating neuropsychiatric condition characterized by intrusive thoughts (obsessions) and repetitive ritualistic behaviors (compulsions). Recent evidence suggests that endocannabinoids (eCBs) can play a role in this disorder. Cannabinoid receptors are significantly expressed in most parts of the main circuitry related to OCD, the cortico-striatal-thalamic circuitry, being able to modulate the release of key neurotransmitters such as glutamate, dopamine, GABA, and serotonin. Preclinical studies using the marble burying test show that enhancement of CB1 function by direct agonists or inhibitors of the enzymes responsible for the metabolism of eCBs (including the phytocannabinoid cannabidiol) presents anti-compulsive behavior activity. Although additional studies are needed to elucidate the role of eCBs in OCD, these neurotransmitters could be an important future target for new therapeutic approaches to this disorder.
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    • "Although Grin1 knockdown mice exhibit hyperactivity and increased stereotypy, including over-grooming to the point of self-injury, they have profound deficits in marbleburying (Riddick et al., 2011). Similarly, MK-801 treatment in ICR mice has been shown to attenuate marble-burying, but at a dose with significant stimulant effects on locomotor activity (Egashira et al., 2008). "
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    ABSTRACT: Autism is a severe neurodevelopmental disorder, diagnosed on the basis of core behavioral symptoms. Although the mechanistic basis for the disorder is not yet known, genetic analyses have suggested a role for abnormal excitatory/inhibitory signaling systems in brain, including dysregulation of glutamatergic neurotransmission. In mice, the constitutive knockdown of NMDA receptors leads to social deficits, repetitive behavior, and self-injurious responses that reflect aspects of the autism clinical profile. However, social phenotypes differ with age: mice with reduced NMDA-receptor function exhibit hypersociability in adolescence, but markedly deficient sociability in adulthood. The present studies determined whether acute disruption of NMDA neurotransmission leads to exaggerated social approach, similar to that observed with constitutive disruption, in adolescent C57BL/6J mice. The effects of MK-801, an NMDA receptor antagonist, were compared with amphetamine, a dopamine agonist, and fluoxetine, a selective serotonin reuptake inhibitor, on performance in a three-chamber choice task. Results showed that acute treatment with MK-801 led to social approach deficits at doses without effects on entry numbers. Amphetamine also decreased social preference, but increased number of entries at every dose. Fluoxetine (10mg/kg) had selective effects on social novelty preference. Withdrawal from a chronic ethanol regimen decreased activity, but did not attenuate sociability. Low doses of MK-801 and amphetamine were also evaluated in a marble-burying assay for repetitive behavior. MK-801, at a dose that did not disrupt sociability or alter entries, led to a profound reduction in marble-burying. Overall, these findings demonstrate that moderate alteration of NMDA, dopamine, or serotonin function can attenuate social preference in wild type mice.
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    • "Recently, a single blind, case-control study reported memantine was an effective augmenting agent to standard Intensive Residential Treatment (IRT) in severe OCD (Stewart et al., 2010). It is interesting to note that amantadine, another NMDA antagonist, has been shown to reduce marble-burying behaviour in mice with greater effectiveness compared to memantine and riluzole (Egashira et al., 2008). Although there has not been any reported trial of amantadine in OCD, amantadine has been reported to induce hallucinations, delusions, increased aggression and nausea/vomiting in a minority of patients (Green et al., 2005). "
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    ABSTRACT: Obsessive-compulsive disorder (OCD) is a common and often debilitating neuropsychiatric condition characterized by persistent intrusive thoughts (obsessions), repetitive ritualistic behaviors (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 signaling 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 Sltrk5 knockout mouse models, display remarkably similar phenotypes of compulsive grooming behavior associated with glutamate signaling 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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