Abstract
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.
Highlights
Schizophrenia is a heterogenous disease with diverse psychotic symptoms including positive and negative symptoms, neurocognitive impairments, and mood disturbances [1,2,3,4]
It is well-known that hyperactivity of the meso-limbic dopaminergic system is involved in the pathogenesis of schizophrenia, and numerous first-generation antipsychotics, which commonly antagonize dopamine D2 receptors, have been developed [4,5,6]
First generation antipsychotics were only effective for positive symptoms, not negative symptoms or cognitive impairments, suggesting that multiple mechanisms other than the dopaminergic system are involved in the generation of schizophrenia symptoms [1,7,8,9]
Summary
Schizophrenia is a heterogenous disease with diverse psychotic symptoms including positive and negative symptoms, neurocognitive impairments, and mood disturbances [1,2,3,4] It is well-known that hyperactivity of the meso-limbic dopaminergic system is involved in the pathogenesis of schizophrenia (dopamine hypothesis), and numerous first-generation antipsychotics, which commonly antagonize dopamine D2 receptors, have been developed [4,5,6]. These agents effectively improve positive symptoms (e.g., hallucinations, delusion, and excitement) in patients with schizophrenia through D2 receptor blockade in the limbic regions (e.g., the nucleus accumbens) [5]. Mmoul. lStciip. l2e017m, 18e,c1h4a16nisms (e.g., serotonergic and glutamatergic systems) other than 2 othf 1e2 dopaminergic system are involved in the generation of schizophrenia symptoms [1,7,8,9]
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