Depression is among the most common psychiatric illnesses, which imposes a major socioeconomic burden on patients, caregivers, and the public health system. Treatment with classical antidepressants (e.g. tricyclic antidepressants and selective serotonine reuptake inhibitors), which primarily affect monoaminergic systems has several limitations, such as delayed onset of action and moderate efficacy in a relatively large proportion of depressed patients. Furthermore, depression is highly heterogeneus, and its different subtypes, including post-partum depression, involve distinct neurobiology, warranting a differential approach to pharmacotherapy. Given these shortcomings, the need for novel antidepressants that are superior in efficacy and faster in onset of action is fully justified. The development and market introduction of rapid-acting antidepressants has accelerated in recent years. Some of these new antidepressants act through the GABAergic system. In this review, we discuss the discovery, efficacy, and limitations of treatment with classic antidepressants. We provide a detailed discussion of GABAergic neurotransmission, with a special focus on GABAA receptors, and possible explanations for the mood-enhancing effects of GABAergic medications (in particular neurosteroids acting at GABAA receptors), and ultimately, we present the most promising molecules belonging to this family which are currently used in clinical practice or are in late phases of clinical development.

The need to increase food safety and improve human health has led to a worldwide increase in interest in gamma-aminobutyric acid (GABA), produced by lactic acid bacteria (LABs). GABA, produced from glutamic acid in a reaction catalyzed by glutamate decarboxylase (GAD), is a four-carbon, non-protein amino acid that is increasingly used in the food industry to improve the safety/quality of foods. In addition to the possible positive effects of GABA, called a postbiotic, on neuroprotection, improving sleep quality, alleviating depression and relieving pain, the various health benefits of GABA-enriched foods such as antidiabetic, antihypertension, and anti-inflammatory effects are also being investigated. For all these reasons, it is not surprising that efforts to identify LAB strains with a high GABA productivity and to increase GABA production from LABs through genetic engineering to increase GABA yield are accelerating. However, GABA\'s contributions to food safety/quality and human health have not yet been fully discussed in the literature. Therefore, this current review highlights the synthesis and food applications of GABA produced from LABs, discusses its health benefits such as, for example, alleviating drug withdrawal syndromes and regulating obesity and overeating. Still, other potential food and drug interactions (among others) remain unanswered questions to be elucidated in the future. Hence, this review paves the way toward further studies.

NVA1309 is a non-brain penetrant next-generation gabapentinoid shown to bind Cavα2δ at R243 within a triple Arginine motif forming the binding site for gabapentin and pregabalin. In this study we have compared the effects of NVA1309 with Mirogabalin, a gabapentinoid drug with higher affinity for the voltage-gated calcium channel subunit Cavα2δ-1 than pregabalin which is approved for post-herpetic neuralgia in Japan, Korea and Taiwan. Both NVA1309 and mirogabalin inhibit Cav2.2 currents in vitro and decrease Cav2.2 plasma membrane expression with higher efficacy than pregabalin. Mutagenesis of the classical binding residue arginine R243 and the newly identified binding residue lysine K615 reverse the effect of mirogabalin on Cav2.2 current, but not that of NVA1309.

The master control of mammalian circadian rhythms is the suprachiasmatic nucleus (SCN), which is formed by the ventral and dorsal regions. In SCN neurons, GABA has an important function and even excitatory actions in adulthood. However, the physiological role of this neurotransmitter in the developing SCN is unknown. Here, we recorded GABAergic postsynaptic currents (in the perforated-patch configuration using gramicidin) to determine the chloride reversal potential (ECl) and also assessed the immunological expression of the Na-K-Cl cotransporter 1 (NKCC1) at early ages of the rat (postnatal days (P) 3 to 25), during the day and night, in the two SCN regions. We detected that ECl greatly varied with age and depending on the SCN region and time of day. Broadly speaking, ECl was more hyperpolarized with age, except for the oldest age studied (P20-25) in both day and night in the ventral SCN, where it was less negative. Likewise, ECl was more hyperpolarized in the dorsal SCN both during the day and at night; while ECl was more negative at night both in the ventral and the dorsal SCN. Moreover, the total NKCC1 fluorescent expression was higher during the day than at night. These results imply that NKCC1 regulates the circadian and developmental fluctuations in the [Cl-]i to fine-tune ECl, which is crucial for either excitatory or inhibitory GABAergic actions to occur in the SCN.

Huanglian Jiedu decoction (HLJD) has been used to treat ischemic stroke in clinic. However, the detailed protective mechanisms of HLJD on ischemic stroke have yet to be elucidated. The aim of this study is to elucidate the underlying pharmacological mechanisms of HLJD based on the inhibition of neuroinflammation and the amelioration of nerve cell damage. A middle cerebral artery occlusion reperfusion (MCAO/R) model was established in rats and received HLJD treatment. Effects of HLJD on neurological function was assessed based on Bederson\'s score, postural reflex test and asymmetry score. 2, 3, 5-Triphenyltetrazolium chloride (TTC) staining, Hematein and eosin (HE) and Nissl staining were used to observe the pathological changes in brain. Then, transcriptomics was used to screen the differential genes in brain tissue in MCAO/R model rats following HLJD intervention. Subsequently, the effects of HLJD on neutrophil extracellular trap (NET) formation-related neuroinflammation, gamma-aminobutyric acid (GABA)ergic synapse activation, nerve cell damage and proliferation were validated using immunofluorescence, western blot and enzyme-linked immunosorbent assay (ELISA). Our results showed that HLJD intervention reduced the Bederson\'s score, postural reflex test score and asymmetry score in MCAO/R model rats. Pathological staining indicated that HLJD treatment decreased the cerebral infarction area, mitigated neuronal damage and increased the numbers of Nissl bodies. Transcriptomics suggested that HLJD affected 435 genes in MCAO/R rats. Among them, several genes involving in NET formation and GABAergic synapses pathways were dysregulated. Subsequent experimental validation showed that HLJD reduced the MPO+CitH3+ positive expression area, reduced the protein expression of PAD4, p-P38/P38, p-ERK/ERK and decreased the levels of IL-1β, IL-6 and TNF-α, reversed the increase of Iba1+TLR4+, Iba1+p65+ and Iba1+NLRP3+ positive expression area in brain. Moreover, HLJD increased GABA levels, elevated the protein expression of GABRG1 and GAT3, decreased the TUNEL positive expression area and increased the Ki67 positive expression area in brain. HLJD intervention exerts a multifaceted positive impact on ischemia-induced cerebral injury in MCAO/R rats. This intervention effectively inhibits neuroinflammation by mitigating NET formation, and concurrently improves nerve cell damage and fosters nerve cell proliferation through activating GABAergic synapses.

Drug addiction is a chronic and relapse brain disorder. Psychostimulants such as cocaine and amphetamine are highly addictive drugs. Abuse drugs target various brain areas in the nervous system. Recent studies have shown that the prefrontal cortex (PFC) plays a key role in regulating addictive behaviors. The PFC is made up of excitatory glutamatergic cells and gamma-aminobutyric acid (GABAergic) interneurons. Recently, studies showed that GABA level was related with psychostimulant addiction. In this review, we will introduce the role and mechanism of GABA and γ-aminobutyric acid receptors (GABARs) of the PFC in regulating drug addiction, especially in psychostimulant addiction.

Neurons coordinate inter-tissue protein homeostasis to systemically manage cytotoxic stress. In response to neuronal mitochondrial stress, specific neuronal signals coordinate the systemic mitochondrial unfolded protein response (UPRmt) to promote organismal survival. Yet, whether chemical neurotransmitters are sufficient to control the UPRmt in physiological conditions is not well understood. Here, we show that gamma-aminobutyric acid (GABA) inhibits, and acetylcholine (ACh) promotes the UPRmt in the Caenorhabditis elegans intestine. GABA controls the UPRmt by regulating extra-synaptic ACh release through metabotropic GABAB receptors GBB-1/2. We find that elevated ACh levels in animals that are GABA-deficient or lack ACh-degradative enzymes induce the UPRmt through ACR-11, an intestinal nicotinic α7 receptor. This neuro-intestinal circuit is critical for non-autonomously regulating organismal survival of oxidative stress. These findings establish chemical neurotransmission as a crucial regulatory layer for nervous system control of systemic protein homeostasis and stress responses.

The Sogatella furcifera (Horváth) (Homoptera: Delphacidae) is a white-backed planthopper (WBPH) that causes \"hopper burn\" in rice, resulting in severe yield loss. Gamma-aminobutyric acid (GABA) is a well-known neurotransmitter that inhibits neurotransmission in insects by binding to specific receptors. In this study, we investigated the potential role of GABA in modulating rice resistance to WBPH and evaluated possible defense mechanisms. The experiment was conducted in green house in pots consist of four groups: control, GABA-treated, WBPH-infested, and WBPH-infested treated with GABA. Among the various tested concentration of GABA, 15 mM GABA was applied as a single treatment in water. The treatment was administered one week before WBPH infestation. The results revealed that 15 mM GABA treatment strongly increased WBPH resistance. A plate-based assay indicated that direct application of 15 mM GABA increased the mortality rate of WBPH and increased the damage recovery rate in rice plants. We found that GABA treatment increased the activation of antioxidant enzymes and reduced the reactive oxygen species content and malondialdehyde contents, and reduced the damage rate caused by WBPH. Interestingly, GABA-supplemented plants infested with WBPH exhibited increased phenylalanine ammonia-lyase and pathogenesis-related (PR) genes expression levels. GABA induced the accumulation of abscisic acid (ABA) and salicylic acid (SA) and enhanced the stomata closure and reduced leaf vessels to reduce water conductance during WBPH stress. Furthermore, we found that GABA application to the plant induced the expression of Jasmonic acid (JA) biosynthesis genes (LOX, AOS, AOC, and OPR) and melatonin biosynthesis-related genes (TDC, T5H, ASMT, and SNAT). Our study suggested that GABA increases resistance against WBPH infestation by regulating antioxidant defense system, TCA cycle regulation, phytohormonal signaling, and PR gene regulation.

OBJECTIVE: Mirogabalin is a novel gabapentinoid medication for the treatment of neuropathic pain. The purpose of this review is to discuss current evidence for its use. Gabapentinoids are widely prescribed for neuropathic pain. Mirogabalin offers theoretical advantages over traditional gabapentinoids due to its specificity for the α2δ-1 subunit of voltage-gated calcium channels. It is theorised that this specificity may reduce adverse drug reactions by minimising binding to the α2δ-2 subunit which is responsible for many of the gabapentinoid side effects.
RESULTS: Mirogabalin\'s slower dissociation from the α2δ-1 compared with α2δ-2, and its higher potency may also impart an efficacy benefit over traditional gabapentinoids. These theoretical advantages of mirogabalin remain inconclusive in clinical practice, with mixed evidence regarding mirogabalin versus traditional gabapentinoids. Some studies suggest a reduced side effect profile yet, others fail to demonstrate significant differences. Regarding efficacy, mirogabalin may be superior to placebo for several neuropathic pain syndromes, but evidence of widespread benefit over traditional gabapentinoids is currently lacking.
CONCLUSIONS: Mirogabalin offers theoretical promise, but large, independent studies are required to further assess its performance versus traditional gabapentinoids.

Translating sensory inputs to perceptual decisions relies on building internal representations of features critical for solving complex tasks. Yet, we still lack a mechanistic account of how the brain forms these mental templates of task-relevant features to optimize decision-making. Here, we provide evidence for recurrent inhibition: an experience-dependent plasticity mechanism that refines mental templates by enhancing γ-aminobutyric acid (GABA)-mediated (GABAergic) inhibition and recurrent processing in superficial visual cortex layers. We combine ultrahigh-field (7 T) functional magnetic resonance imaging at submillimeter resolution with magnetic resonance spectroscopy to investigate the fine-scale functional and neurochemical plasticity mechanisms for optimized perceptual decisions. We demonstrate that GABAergic inhibition increases following training on a visual (i.e., fine orientation) discrimination task, enhancing the discriminability of orientation representations in superficial visual cortex layers that are known to support recurrent processing. Modeling functional and neurochemical plasticity interactions reveals that recurrent inhibitory processing optimizes brain computations for perpetual decisions and adaptive behavior.