7-Aminobutyric acid—the major inhibitory neurotransmitter system in the CNS—is one of the most abundant neurotransmitters, and GABA-containing neurons are located in virtually every area of the brain. Unlike the monoamines, GABA occurs in the brain in high concentrations in the order of micromoles per milligrams (about 1,000-fold higher than concentrations of monoamines) (Cooper et al. 2001; Nestler et al. 2001; Squire et al. 2003). GABA is produced when glucose is converted to tx-ketoglutarate, which is then transaminated to glutamate by GABA iv.-oxoglutarate transaminase (GABA-T). Glutamic acid is decarboxylated by glutamic acid decarboxylase, which leads to the formation of GABA (Figure 1-8). Indeed, the neurotransmitter and the rate-limiting enzyme are localized together in the brain and at approximately the same concentration. Catabolism of GABA occurs via GABA-T, which is also important in the synthesis of this transmitter.
FIGURE 1-8. The GABAergic system.
This figure depicts the various regulatory processes involved in GABAergic neurotransmission. The amino acid (and neurotransmitter) glutamate serves as the precursor for the biosynthesis of 7-aminobutyric acid (GABA). The rate-limiting enzyme for the process is glutamic acid decarboxylase (GAD), which utilizes pyridoxal phosphate as an important cofactor. Furthermore, agents such as L-glutamine-7-hydrazide and ally I glycine inhibit this enzyme and, thus, the production of GABA. Once released from the presynaptic terminal, GABA can interact with a variety of presynaptic and postsynaptic receptors. Presynaptic regulation of GABA neuron firing activity and release occurs through somatodendritic (not shown) and nerve-terminal GABAb receptors, respectively. Baclofen is a GABAb receptor agonist. The binding of GABA to ionotropic GABAa receptors and metabotropic GABAb receptors mediates the effects of this receptor. The GABAb receptors are thought to mediate their actions by being coupled to Ca2+ or K+ channels via second-messenger systems. Many agents are able to modulate GABAa receptor function. Benzodiazepines, such as diazepam, increase Cl- permeability, and there are numerous available antagonists directed against this site. There is also a distinctive barbiturate binding site on GABAA receptors, and many psychotropic agents are capable of influencing the function of this receptor (see blown-up diagram). GABA is taken back into presynaptic nerve endings by a high-affinity GABA uptake transporter (GABAT) similar to that of the monoamines. Once inside the neuron, GABA can be broken down by GABA transaminase (GABA-T), which is localized in the mitochondria; GABA that is not degraded is sequestered and stored into secretory vesicles by vesicle GABA transporters (VGTs), which differ from VMATs in their bioenergetic dependence. The metabolic pathway that produces GABA, mostly from glucose, is referred to as the GABA shunt The conversion of cc-ketoglutarate into glutamate by the action of GABA-T and GAD catalyzes the decarboxylation of glutamic acid to produce GABA. GABA can undergo numerous transformations, of which the simplest is the reduction of succinic sem¡aldehyde (SS) to 7-hydroxybutyrate (GHB). On the other hand, when SS is oxidized by succinic sem¡aldehyde dehydrogenase (SSADH), the production of succinic acid (SA) occurs. GHB has received attention because it regulates narcoleptic episodes and may produce amnestic effects. The mood stabilizer and antiepileptic drug valproic acid is reported to inhibit SSADH and GABA-T. TBPS = i-butylbicyclophosphorothionate.
Source. Adapted from Cooper JR, Bloom FE, Roth RH: The Biochemical Basis of Neuropharmacology, 7th Edition. New York, Oxford University Press, 2001. Copyright 1970, 1974, 1978, 1982, 1986, 1991, 1996, 2001 by Oxford University Press, Inc. Used by permission of Oxford University Press, Inc.
The function of this dual-role enzyme becomes apparent when placed in the context of its role in the metabolic process. GABA-T converts GABA to succinic acid, and subsequent removal of the amino group yields Ct-ketoglutarate. Thus, OL-ketoglutarate is able to be used by GABA-T in GABA biosynthesis as mentioned above (Cooper et al. 2001). This process, called the GABA shunt, maintains a steady GABA supply in the brain. As with the monoamines, the major mechanism by which the effects of GABA are terminated in the synaptic cleft is by reuptake through GABA transporters. The GABA transporters have a high affinity for GABA and mediate their reuptake via a Na+ and Cl- gradient (Squire et al. 2003).
Detailed studies from the Rajkowska laboratory (Grazyna Rajkowska, The University of Mississippi Medical Center, Jackson, MS) have measured the density and size of calbindin-immunoreactive neurons (presumed to be GABAergic) in layers II and III of the dorsolateral prefrontal cortex, revealing a 43% reduction in the density of these neurons in patients with major depressive disorder compared with controls (discussed in Goodwin and Jamison 2007). Of particular note, in the rostral orbitofrontal cortex, there was a trend toward a negative correlation between the duration of depression and the size of neuronal cell bodies, suggesting changes associated with disease progression. Valproate has also been shown to have neurogenic effects in at least one study. In cultured embryonic rat cortical cells and striatal primordial stem cells, valproate markedly increased the number and percentage of primarily GABAergic neurons and promoted neurite outgrowth (Laeng et al. 2004).
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