ENTRIES A–Z
Philip Winn in Dictionary of Biological Psychology, 2003
(Gamma aminobutyric acid or y-aminobutyric acid) GABA is the most important of the inhibitory NEUROTRANSMITTERS in the brain (though there are others, including GLYCINE). The term GABAERGIC is used to describe a neuron that contains GABA. About one-third of the synapses in the brain appear to use GABA as their neurotransmitter. It is synthesized from GLUTAMATE, a reaction catalysed by GLUTAMIC ACID DECARBOXYLASE and broken down by GABA aminotransferase to succinic semialdehyde, which is further broken down to SUCCINATE, a reaction catalyzed by succinic semialdehyde dehydrogenase. It is stored in VESICLES prior to release and, following CALCIUM dependent release, there are high affinity REUPTAKE mechanisms to remove it from the synaptic cleft. GABAergic neurons are found virtually in all regions of the CENTRAL NERVOUS SYSTEM, including INTERNEURONS as well as PROJECTION NEURONS such as PURKINJE CELLS in the CEREBELLUM. GABA is found in very few places outside the central nervous system: the PANCREAS has the highest concentration outside the CNS.
Genetics of Anxiety
Siegfried Kasper, Johan A. den Boer, J. M. Ad Sitsen in Handbook of Depression and Anxiety, 2003
Target of anxiolytic drugs: GABA and its receptors. The GABAergic systems are implicated in the pathophysiology and treatment of anxiety disorders: GABA-A agonists like benzodiazepines are anxiolytic and there is evidence for a decreased benzodiazepine receptor function in anxious patients; in temporal correlation with the onset of anxiolytic action, mRNA of specific GABA-receptor subunits is expressed by benzodiazepines in critical areas in the brain. The genes of GABA-receptor subunits carry multiple polymorphisms. Unfortunately, candidate gene studies of GABA-receptor subunits did not form replicable associations with panic disorder [94]. However, recently an association study with behavior inhibition, an anxiety-related phenotype, found modest evidence that an isoform of the glutamic acid decarboxylase (GAD65) was less common in affected subjects. While this finding requires replication, it is noteworthy that the GAD65 knock-out mouse revealed increased anxiety-like behavior [68].
Synthesis, Enzyme Localization, and Regulation of Neurosteroids
Sheryl S. Smith in Neurosteroid Effects in the Central Nervous System, 2003
GABA-potentiating steroids may have relevance to several psychiatric and neurological disorders. Endogenous GABA-potentiating steroids have recently been proposed to be involved in the etiology of depressive illnesses, including major depression45 and postpartum depression.46 Like other GABAergic agents (e.g., barbiturates and benzodiazepines), GABA-potentiating steroids have anxiolytic, sedative-hypnotic, and anticonvulsant effects. In animal models of anxiety, levels of GABA-potentiating steroids increase,47 presumably reflecting an endogenous anxi-olytic mechanism. Alterations in endogenous GABA-potentiating steroids have not been clearly implicated in any seizure disorders, but there is interest in whether catamenial epilepsy, seizures associated with women’s menstrual cycles, might be related to decreases in progesterone-derived GABA-potentiating steroids.48
Investigational drugs in early-stage clinical trials for autism spectrum disorder
Published in Expert Opinion on Investigational Drugs, 2019
Michael P. Hong, Craig A. Erickson
A leading neurobiological theory describing potential excitatory/inhibitory imbalance in the ASD brain has emerged as a force driving drug development. In 2003, Rubenstein and Merzenich described an increase in the ratio between excitation and inhibition leading to hyper-excitability of cortical circuits in the autistic brain [14]. However, in subsequent years, studies have suggested the opposite, specifically a reduction in the inhibitory to excitatory balance [15]. Gamma-aminobutyric Acid (GABA) is the primary inhibitory neurotransmitter in the human brain, and GABAergic dysfunction has been demonstrated in murine ASD models as well as human genetic, post-mortem, and neuroimaging studies [16,17]. Abnormal peripheral levels of the primary excitatory neurotransmitter glutamate, aberrant glutamate expression in post-mortem brains, and genetic abnormalities in glutamate signaling genes have been identified in individuals with ASD [18].
High-yield synthesis and purification of recombinant human GABA transaminase for high-throughput screening assays
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Mingu Gordon Park, Ah-reum Han, Su Yeon Kim, Tai Young Kim, Ho Min Kim, C. Justin Lee
γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter synthesised and released from GABAergic neurons and astrocytes in the mammalian central nervous system (CNS)1–4. GABA is synthesised by glutamate decarboxylase (GAD; EC 4.1.1.15) in GABAergic neurons and by monoamine oxidase (MAO-B; EC 1.4.3.4) or diamine oxidase (DAO; EC 1.4.3.22) in astrocytes4–6. However, the only GABA-catabolizing enzyme in the mammalian CNS is GABA transaminase (GABA-T; EC 2.6.1.19) encoded by the ABAT gene7. GABA-T catalyses the conversion of GABA to succinic semialdehyde (SSA) concomitantly with the conversion of α-ketoglutarate (α-KG) to glutamate. Subsequently, SSA is oxidised to succinic acid (SA) by the enzyme SSA dehydrogenase (SSADH; EC 1.2.1.24). GABA-T and SSADH are mitochondrial enzymes and exist both in GABAergic neurons and astrocytes8–10. Because the transaminase reaction cannot be directly monitored, we can utilise dehydrogenation of SSA from GABA-T reaction to indirectly monitor GABA-T activity by detecting a conversion of NADP+ to NADPH11.
The potential effects of anticonvulsant drugs on neuropeptides and neurotrophins in pentylenetetrazol kindled seizures in the rat
Published in International Journal of Neuroscience, 2020
Hasan Tekgul, Erdem Simsek, Mumin Alper Erdoğan, Gürkan Yiğittürk, Oytun Erbaş, Dilek Taşkıran
The main molecular mechanisms that are responsible for the action of anticonvulsant drugs can be related to inhibition of neuronal excitatory (i) Na+ channels; (ii) low voltage-activated (T-type) Ca2+ channels or (iii) facilitation of inhibitory GABAergic neurotransmission. Among the investigated drugs in the present study, anticonvulsant action of midazolam is mainly via GABAergic neurotransmission. On the other hand, the antiepileptic effect of levetiracetam is mediated through binding to synaptic vesicle glycoprotein 2A (SV2A), a protein localized in the membrane of synaptic vesicles, and suppressing Ca2+ mobilization from the endoplasmic reticulum. Levetiracetam also affects GABA-receptor mediated currents, and reverses the inhibitory effects of GABA and glycine receptor modulators [53]. Besides, neuroprotective effects of levetiracetam have been reported in several experimental models such as hypoxic ischemic brain injury [37], traumatic brain injury [54] and Parkinson’s disease [55]. In the present study, in accordance with the previous reports, levetiracetam treatment considerably prevented the neuronal loss and reactive astrogliosis in the epileptic hippocampus.
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