dizocilpine-maleate and Obsessive-Compulsive-Disorder

In recent years, an increasing body of evidence points to the involvement of the glutamatergic system and specifically the glutamatergic ionotropic N-methyl-D-aspartate (NMDA) receptor in the pathophysiology of obsessive-compulsive disorder (OCD).. To test the role of NMDA receptors in compulsive behavior using the signal attenuation rat model of OCD. In this model, 'compulsive' behavior is induced by attenuating a signal indicating that a lever-press response was effective in producing food.. The NMDA antagonist, MK 801 (0.025-0.100 mg/kg) and the partial NMDA agonist, D-cycloserine (3-100 mg/kg) were administered to rats just before assessing their lever-press responding following signal attenuation (Experiments 1 and 2, respectively). Because the effects of signal attenuation are assessed under extinction conditions, drug doses that were effective in Experiments 1 and 2 were also tested in an extinction session of lever-press responding that was not preceded by signal attenuation (Experiment 3).. Systemic administration of D: -cycloserine (15 mg/kg) selectively decreased compulsive lever pressing, whereas systemic administration of MK 801 did not affect compulsive lever-pressing but dramatically increased resistance to extinction.. Activation of NMDA receptors may have an anti-compulsive effect in OCD patients.

Topics: Animals; Cycloserine; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Extinction, Psychological; Male; Obsessive-Compulsive Disorder; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Signal Transduction

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.

Topics: Acoustic Stimulation; Amantadine; Animals; Behavior, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamic Acid; Male; Memantine; Mice; Mice, Inbred ICR; Motor Activity; Obsessive-Compulsive Disorder; Quinoxalines; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Reflex, Startle; Riluzole

We previously created a transgenic mouse model of comorbid Tourette's syndrome and obsessive-compulsive disorder (TS+OCD), by expressing a neuropotentiating cholera toxin (CT) transgene in a subset of dopamine D1 receptor-expressing (D1+) neurons thought to induce cortical and amygdalar glutamate output. To test glutamate's role in the TS+OCD-like disorder of these transgenic mice (D1CT-7 line), the effects of glutamate receptor-binding drugs on their behavior were examined. MK-801, a non-competitive NMDA receptor antagonist that indirectly stimulates cortical-limbic glutamate output, aggravated a transgene-dependent abnormal behavior (repetitive climbing and leaping) in the D1CT-7 mice at doses insufficient to induce stereotypies, and more readily induced stereotypies and limbic seizure behaviors at high doses. NBQX, a seizure-inhibiting AMPA receptor antagonist, reduced only the MK-801-dependent stereotypic and limbic seizure behavior of D1CT-7 mice, but not their transgene-dependent behaviors. These data imply that TS+OCD-like behavior is mediated by cortical-limbic glutamate, but that AMPA glutamate receptors are not an essential part of this behavioral circuit. Our findings lead to the prediction that the symptoms of human Tourette's syndrome and obsessive-compulsive disorder are elicited by excessive forebrain glutamate output.

Topics: Animals; Cerebral Cortex; Comorbidity; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Humans; Limbic System; Male; Mice; Mice, Inbred BALB C; Mice, Transgenic; Motor Activity; Obsessive-Compulsive Disorder; Quinoxalines; Seizures; Tourette Syndrome