Amino acid neurotransmitters and their pathways in the mammalian central nervous system

Schizophrenia is a serious mental disease with unknown etiology that affects approximately 1 % of the population around the world. Altered levels of amino acid neurotransmitters may underlie the physiopathology of schizophrenia (SZ). This study aimed to develop a rapid and robust liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of glutamate acid (Glu), aspartic acid (Asp), γ-aminobutyric acid (GABA), glycine acid (Gly), and Taurine acid (Tau) in patients with schizophrenia plasma and establish reference intervals for Chinese adult populations, and applied to patients with schizophrenia for a preliminary exploration of changes in their plasma levels of five amino acid neurotransmitters. Sample treatment involved protein precipitation followed by dansyl chloride (DNS-Cl) derivatization and total run time is 5.8 min. The method was validated according to the latest national and international guidelines, which achieved acceptable precision (0.54–14.54 %) and accuracy (97.06–103.82 %). The reference interval for Glu, Asp, Gly, Tau, and GABA were 55.51–189.06, 27.51–92.38, 204.01–574.55, 107.50–227.65, and <1 μmol/L, respectively. Increased Tau levels and decreased Asp and Glu levels were shown in patients with schizophrenia. This method was suitable for clinical routine detection of plasma 5 amino acid neurotransmitters in Chinese adult populations.

Derivatization reagents based on azobenzene containing different N-hydroxysuccinimidyl moieties– AzoB (carbamate) and AzoC (ester) – are proposed for the LC-ESI-MS analysis of free amino acids in fermented beverages and juices. A dual comparison between LC-MS/MS in positive and negative ESI modes in dynamic Multiple Reaction Monitoring (dMRM) and Neutral Loss Scan was investigated. The results indicate that the studied carbamate derivatization reagent, AzoB, can be employed for targeted analysis (MS/MS) but also for non-targeted analysis of derivatized amino acids thanks to its constant neutral loss (223 Da) that is the same in both ionisation modes. For amines, precursor ion scan can be used as identification tool. The derivatization properties of AzoB and AzoC were compared against other derivatization reagents, and they showed advantages such as fast derivatization reaction and good reactivity with secondary amines. AzoC also displayed a disadvantage –side products were formed that affect the quantitation. Free amino acids profile of Kvass (a fermented beverage from eastern Europe) was determined for first time, proline was found to be the most abundant amino acid.

The primary focus of environmental toxicological studies is to address the direct effects of chemicals on exposed organisms (parental generation – F0), mostly overlooking effects on subsequent non-exposed generations (F1 and F2 – intergenerational and F3 transgenerational, respectively). Here, we addressed the effects of simvastatin (SIM), one of the most widely prescribed human pharmaceuticals for the primary treatment of hypercholesterolemia, using the keystone crustacean Gammarus locusta. We demonstrate that SIM, at environmentally relevant concentrations, has significant inter and transgenerational (F1 and F3) effects in key signaling pathways involved in crustaceans’ neuroendocrine regulation (Ecdysteroids, Catecholamines, NO/cGMP/PKG, GABAergic and Cholinergic signaling pathways), concomitantly with changes in apical endpoints, such as depressed reproduction and growth. These findings are an essential step to improve hazard and risk assessment of biological active compounds, such as SIM, and highlight the importance of studying the transgenerational effects of environmental chemicals in animals’ neuroendocrine regulation.

Glutamate is a crucial neurotransmitter of the mammalian central nervous system, a molecular component of our diet, and a popular food-additive. However, for decades, concerns have been raised about the issue of glutamate’s safety as a food additive; especially, with regards to its ability (or otherwise) to cross the blood-brain barrier, cause excitotoxicity, or lead to neuron death. Results of animal studies following glutamate administration via different routes suggest that an array of effects can be observed. While some of the changes appear deleterious, some are not fully-understood, and the impact of others might even be beneficial. These observations suggest that with regards to the mammalian brain, exogenous glutamate might exert a double-sided effect, and in essence be a two-faced molecule whose effects may be dependent on several factors. This review draws from the research experiences of the authors and other researchers regarding the effects of exogenous glutamate on the brain of rodents. We also highlight the possible implications of such effects on the brain, in health and disease. Finally, we deduce that beyond the culinary effects of exogenous glutamate, there is the possibility of a beneficial role in the understanding and management of brain disorders.

γ-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the nervous system. It plays a crucial role in many physiological processes. Upon release from the presynaptic element, it is removed from the synaptic cleft by reuptake due to the action of GABA transporters (GATs). GATs belong to a large SLC6 protein family whose characteristic feature is sodium-dependent relocation of neurotransmitters through the cell membrane. GABA transporters are characterized in many contexts, but their spatial structure is not fully known. They are divided into four types, which differ in occurrence and role. Herein, the special attention was paid to these transporting proteins. This comprehensive review presents the current knowledge about GABA transporters. Their distribution in the body, physiological functions and possible utilization in the therapy of different diseases were fully discussed. The important structural features were described based on published data, including sequence analysis, mutagenesis studies, and comparison with known SLC6 transporters for leucine (LeuT), dopamine (DAT) and serotonin (SERT). Moreover, the most important inhibitors of GABA transporters of various basic scaffolds, diverse selectivity and potency were presented.

Remembering and forgetting are fundamental features of an organism. Extinction is a type of forgetting where there is a decrease in the significance and/or the meaning of an associative memory when elements of that memory no longer predict one another. The neural mechanisms underlying extinction of fear memories have been extensively studied in the laboratory because extinction processes are clinically relevant to exposure therapies that treat anxiety disorders. However, only in the last decade have we begun to unveil the similarities and differences in plasticity underlying extinction across development. So far it is clear that extinction is a developmentally dissociated process in behavior and in pharmacology, however there are many large gaps in the literature in understanding how the developmental trajectory of different neurotransmitters contribute to changes in the nature of extinction across development. We attempt to address these gaps in the present review. Major neurotransmitter systems including the glutamatergic and GABAergic systems, the monoamines, the endogenous opioid and cannabinoid systems, acetylcholines, and neuropeptides such as oxytocin have all been identified to play some role in extinction of fear memories and have been covered in this review. We hope to facilitate more research into mechanisms of extinction at different stages of life, especially noting that mental disorders are increasingly classified as neurodevelopmental disorders.