Amantadine Combines Astroglial System Xc− Activation with Glutamate/NMDA Receptor Inhibition

Abstract

A glutamate/NMDA receptor (NMDA-R) antagonist, amantadine (AMA) exhibits a broad spectrum of clinically important properties, including antiviral, antiparkinsonian, neuroprotective, neuro-reparative and cognitive-enhancing effects. However, both clinical and pre-clinical studies have demonstrated that noncompetitive NMDA-R antagonists induce severe schizophrenia-like cognitive deficits. Therefore, this study aims to clarify the clinical discrepancy between AMA and noncompetitive NMDA-R antagonists by comparing the effects of AMA with those of a noncompetitive NMDA-R antagonist, MK801, on rat tripartite glutamatergic synaptic transmission using microdialysis and primary cultured astrocytes. Microdialysis study demonstrated that the stimulatory effects of AMA on L-glutamate release differed from those of MK801 in the globus pallidus, entorhinal cortex and entopeduncular nucleus. The stimulatory effect of AMA on L-glutamate release was modulated by activation of cystine/glutamate antiporter (Sxc). Primary cultured astrocytes study demonstrated that AMA also enhanced glutathione synthesis via Sxc activation. Furthermore, carbon-monoxide induced damage of the astroglial glutathione synthesis system was repaired by AMA but not MK801. Additionally, glutamate/AMPA receptor (AMPA-R) antagonist, perampanel enhanced the protective effects of AMA. The findings of microdialysis and cultured astrocyte studies suggest that a combination of Sxc activation with inhibitions of ionotropic glutamate receptors contributes to neuroprotective, neuro-reparative and cognitive-enhancing activities that can mitigate several neuropsychiatric disorders.

Lurasidone inhibits NMDA receptor antagonist‐induced functional abnormality of thalamocortical glutamatergic transmission via 5‐HT7 receptor blockade

“…Drug doses and sample size were selected according to previous studies (Bonaventure et al, ; Fukuyama et al, ; Kusek et al, ; Nakano, Hasegawa, Suzuki, Motomura, & Okada, ; Okada, Fukuyama, Kawano, Shiroyama, Suzuki, & Ueda, ; Okada, Fukuyama, Kawano, Shiroyama, & Ueda, ). According to previous studies, all experiments in this study were designed with equally sized animal groups ( N = 6) without carrying out a formal power analysis (Fukuyama et al, ; Nakano et al, ; Okada, Fukuyama, Kawano, Shiroyama, Suzuki, & Ueda, ; Okada, Fukuyama, Kawano, Shiroyama, & Ueda, ), and all values were expressed as mean ± SD . A P < .05 (two‐tailed) was considered statistically significant for all tests.…”

Activation of Astroglial Connexin Is Involved in Concentration-Dependent Double-Edged Sword Clinical Action of Clozapine

“…2019-3-R1) and are reported in accordance with the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines [40]. Astrocytes were prepared using a protocol adapted from previously described methods [5,6,12,24,[41][42][43][44].…”

Vortioxetine Subchronically Activates Serotonergic Transmission via Desensitization of Serotonin 5-HT1A Receptor with 5-HT3 Receptor Inhibition in Rats

“…In our recent studies, hyperactivation of thalamocortical glutamatergic transmission has been considered as contributing to the cognitive impairment of several neuropsychiatric disorders [25,26,[49][50][51]. Under physiological conditions, the MDTN regulates a wide range of cognitive processes, and the enhancement of the sensitivity and reliability of MDTN signaling contributes to the augmentation of flexibility and stability against environmental changes [25][26][27].…”

“…The analytical column (YMC Triart C18, particle 1.8 µm, 50 × 2.1 mm; YMC, Kyoto, Japan) was maintained at 45 • C. The flow rate was set at 500 µL/min, and elution was performed using a linear gradient of mobile phases A (0.05 M acetate buffer, pH 5.0) and B (0.05 M acetate buffer containing 30% acetonitrile and 30% methanol, pH 3.5) over 10 min. The excitation/emission wavelengths of the fluorescence detector were set at 280/455 nm [26,34,37,49,51].…”

“…Where possible, we sought to randomize and blind sample data. In particular, for the determination of extracellular transmitter levels, a sample order was set on the autosampler according to a random number table [25][26][27]34,[49][50][51].…”