• 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • br Acknowledgement This work was supported in part


    Acknowledgement This work was supported in part by grants from the Ministerio de Economía y Competitividad from Spain (BFU2011-23034).
    Introduction The glutamate hypothesis of schizophrenia emerged from observations in the 1960s that phencyclidine and similar psychotomimetic agents produce schizophrenia-like symptoms in humans [1]. The mechanism of action of these compounds, blockade of the N-methyl--aspartate receptor (NMDAR), was first described in the late 1980s [2], [3], [4], turning attention to abnormalities of the glutamate system in the pathophysiology of schizophrenia. Unique to PCP and ketamine induced psychosis, as opposed to amphetamine induced psychosis, is the presence of thought disorder, negative and cognitive symptoms similar to schizophrenia [4]. This makes the glutamate system even further appealing for the development of novel treatments for persisting and burdensome features of the illness [5]. Following the original description, several glutamatergic models of schizophrenia have been hypothesized [6]. Initial models focused on NMDA receptor hypofunction, which was centered on preclinical observations of neurodegeneration in certain brain areas following high-dose administration of NMDAR antagonist [7]. This model was eventually replaced by a more complex hypothesis of glutamatergic hyperactivity. Hyperglutamatergic models converged from pre-synaptic glutamate efflux in the prefrontal cortex induced by NMDA receptor antagonist injection in animal models, resulting in detrimental behavioral effects such as impaired working memory [8]. Hyperglutamatergic models suggest psychotomimetic effects of NMDA receptor blockers are due to enhanced glutamate release onto other receptors, rather than glutamate hypofunction at the NMDA site. GABAergic models propose that NMDA receptor antagonists contribute to downregulation of parvalbumin-containing γ-aminobutyric Phosphoramidon Disodium Salt (GABA)–ergic interneurons, leading to excess glutamate release [9]. The Dopamine-Glutamate interaction model hypothesizes glutamate may impact dopamine activity in the substantia nigra (SN) and the ventral tegmental area (VTA). This model suggests that dysfunction of dopaminergic neurotransmitters in schizophrenia may be resultant of NMDA receptor hypofunction [10]. Nonetheless, over the past two decades several lines of evidence from preclinical and clinical studies have further supported the role of glutamate system dysfunction in the etiology and pathophysiology of schizophrenia [11]. Genome wide association studies (GWAS) of schizophrenia including The Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC), have also demonstrated several significant associations between the illness and genes involved in glutamatergic neurotransmission. Among the identified associations, the metabotropic glutamate receptor 3 (GRM3) contained the second most significant single-nucleotide polymorphism (SNP) after the dopamine receptor D2 (DRD2) [12]. A recent meta-analysis further supported the linkage between GRM3 and risk of schizophrenia [13]. Findings of proton magnetic resonance spectroscopy (H-MRS) studies implicated increased levels of glutamatergic indices in the medial prefrontal cortex (MPFC) and basal ganglia in medication-naïve patients. Furthermore, H-MRS studies have implicated a possible relationship between decreased hippocampal volume and elevated levels of glutamine and glutamate in the hippocampus of unmedicated patients [14].
    Results Table 1 provides a brief summary of the included studies for each gulatmate modulating agent and their reported outcome.
    Introduction Central chemoreceptors in the brain detect CO2/pH changes, promoting respiratory adjustments that are necessary to correct these alterations, contributing to the maintenance of acid-base balance and, consequently, homeostasis. Evidence indicates that central chemoreceptors are widely distributed throughout the central nervous system, and include the orexinergic neurons of the lateral hypothalamus and perifornical area (LH/PFA) (Ben-Shiang Deng et al., 2007; Dias et al., 2010; Kuwaki et al., 2010; Sunanaga et al., 2009; Williams et al., 2007).