Glycine-Binding Site Stimulants of NMDA Receptors Alleviate Extrapyramidal Motor Disorders by Activating the Nigrostriatal Dopaminergic Pathway
نویسندگان
چکیده
Dysfunction of the N-methyl-d-aspartate (NMDA) receptor has been implicated in the pathogenesis of schizophrenia. Although agonists for the glycine-binding sites of NMDA receptors have potential as new medication for schizophrenia, their modulation of antipsychotic-induced extrapyramidal side effects (EPS) has not yet been clarified. We herein evaluated the effects of glycine-binding site stimulants of NMDA receptors on antipsychotic-induced EPS in mice and rats. d-cycloserine (DCS) and d-serine significantly improved haloperidol (HAL)-induced bradykinesia in mice, whereas glycine showed no effects. Sodium benzoate, a d-amino acid oxidase inhibitor, also attenuated HAL-induced bradykinesia. Improvements in HAL-induced bradykinesia by DCS were antagonized by the NMDA antagonist dizocilpine or nitric oxide synthase inhibitor L-NG-Nitro-l-arginine methyl ester. In addition, DCS significantly reduced HAL-induced Fos expression in the dorsolateral striatum without affecting that in the nucleus accumbens. Furthermore, a microinjection of DCS into the substantia nigra pars compacta significantly inhibited HAL-induced EPS concomitant with elevations in dopamine release in the striatum. The present results demonstrated for the first time that stimulating the glycine-binding sites of NMDA receptors alleviates antipsychotic-induced EPS by activating the nigrostriatal dopaminergic pathway, suggesting that glycine-binding site stimulants are beneficial not only for efficacy, but also for side-effect management.
منابع مشابه
Possible Involvement of Glutamatergic, Adrenergic and Dopaminergic System in Methylphenidate - induced Motor Activity and Mood-related Alterations in Rats
Background and Objective: Methylphenidate (MPH), as a central nervous system stimulant, is often used to manage hyperactive disorders. The literature is scarce regarding the behavioral consequences of chronic MPH treatment and the role of involved receptors. Thus, in the current study involved receptors in MPH induced-anxiety, depression and motor activity disorders were evaluated. Materials a...
متن کاملEstrogen agonist genistein differentially influences the cognitive and motor disorders in an ovariectomized animal model of Parkinsonism
Objective(s): Parkinson's disease (PD) is a progressive neurological disorder associated with motor disabilities and cognitive dysfunction as well. Evidence indicates that PD occurs less frequently in women than men, confirming a role for steroid hormones in protection of dopaminergic nigrostriatal neurons. It is reported that soy genistein, an estrogen agonist phytoestrogen, display neuroprote...
متن کاملEffects of nigrostriatal dopamine denervation on ionotropic glutamate receptors in rat caudate-putamen.
Changes in ionotropic glutamate NMDA, AMPA and KA receptor binding in rat caudate-putamen were examined by quantitative in vitro receptor autoradiography 5 weeks after lesioning nigrostriatal dopaminergic projections. In this animal model of Parkinson's disease, density of binding in caudate-putamen increased at KA, but not NMDA or AMPA receptors. The findings indicate that nigrostriatal dopami...
متن کاملGlycine uptake governs glycine site occupancy at NMDA receptors of excitatory synapses.
Glycine uptake governs glycine site occupancy at NMDA receptors of excitatory synapses. J. Neurophysiol. 80: 3336-3340, 1998. At central synapses occupation of glycine binding sites of N-methyl--aspartate receptors (NMDA-Rs) is a necessary prerequisite for the excitatory neurotransmitter glutamate to activate these receptors. There is conflicting evidence as to whether glycine binding sites nor...
متن کاملMalva sylvestris aqueous extract could ameliorate 6-hydroxydopamine-induced motor asymmetry with no protective effect on dopaminergic nigrostriatal neurons in the rat
Background and Objective: Parkinson’s disease (PD) is a common neurological disorder due to degeneration of dopaminergic neurons within pars compacta of substantia nigra (SNC). With regard to protective effect of Malva sylvestris (MS), this study was conducted to evaluate the effect of aquaeous extract of this plant in an experimental model of PD induced by 6-hydroxydopamine (6-OHDA). Material...
متن کامل