from NIH PubChem

Gamma-Aminobutyric Acid is a naturally occurring neurotransmitter with central nervous system (CNS) inhibitory activity. Gamma-aminobutyric acid (GABA), converted from the principal excitatory neurotransmitter glutamate in the brain, plays a role in regulating neuronal excitability by binding to its receptors, GABA-A and GABA-B, and thereby causing ion channel opening, hyperpolarization and eventually inhibition of neurotransmission.

GABA Agents

Substances used for their pharmacological actions on GABAergic systems. GABAergic agents include agonists, antagonists, degradation or uptake inhibitors, depleters, precursors, and modulators of receptor function.

from NIH PubMed

GABA Receptor Physiology and Pharmacology

Because GABA is widely distributed and utilized throughout the CNS, early GABAergic drugs had very generalized effects on CNS function. The development of more selective agents has led to the identification of at least two distinct classes of GABA receptor, GABAA and GABAB. They differ in their pharmacological, electrophysiological and biochemical properties. Electrophysiological studies of the GABAA-receptor complex indicate that it mediates an increase in membrane conductance with an equilibrium potential near the resting level of −70 mV. This conductance increase often is accompanied by a membrane hyperpolarization, resulting in an increase in the firing threshold and, consequently, a reduction in the probability of action potential initiation, causing neuronal inhibition. This reduction in membrane resistance is accomplished by the GABA-dependent facilitation of Cl ion influx through a receptor-associated channel. On the other hand, increased Cl permeability can depolarize the target cell under some conditions of high intracellular Cl. This in turn potentially can excite the cell to fire or to activate Ca2+ entry via voltage-gated channels and has been proposed as a physiologically relevant event, especially in embryonic neurons.

Electrophysiological data [8] suggest that there are two GABA-recognition sites per GABAA-receptor complex. An increase in the concentration of GABA results in an increase in the mean channel open time due to opening of doubly liganded receptor forms, which exhibit open states of long duration. It has been demonstrated, using a membrane preparation from rat brain, that the increase in the ionic permeability of the GABAA receptor complex is transient in the continuing presence of agonist [9]. This phenomenon is known as desensitization and is rapidly reversible. The molecular mechanism of desensitization is not understood, and various hypotheses remain under investigation. The existence of GABA-binding sites specific for the initiation of desensitization and distinct from sites mediating opening of the Cl channel has been proposed.

There have been numerous studies on the role of GABAA receptors in anesthesia. A considerable amount of evidence has been compiled to suggest that general anesthetics, including barbiturates, volatile gases, steroids and alcohols, enhance GABA-mediated Cl conductance. A proper assessment of this phenomenon requires not only a behavioral assay of anesthesia but also in vitro models for the study of receptor function. In this regard, not only electrophysiological methods but also neurochemical measurements of Cl flux and ligand binding have been useful. For example, a strong positive correlation exists between anesthetic potencies and the stimulation of GABA-mediated Cl uptake. This is seen with barbiturates and anesthetics in other chemical classes

Neurosteroids, which may be physiological modulators of brain activity, enhance GABAreceptor function

This enhancement by steroids involves direct action on the membrane receptor protein rather than through the classical genomic mechanism mediated by soluble high-affinity cytoplasmic steroid hormone receptors (see Chap. 49). Chemically reduced analogs of the hormones progesterone and corticosterone derivatives administered to animals and humans exert sedative—hypnotic and anti-anxiety effects. This led to the development of a synthetic steroid anesthetic, alphaxalone. These neuroactive steroids are potent modulators of GABAA– receptor function in vitro. The neuroactive steroids can be produced in the brain endogenously and may influence CNS function under certain physiological or pathological conditions. Some observations suggesting that neurosteroids physiologically affect the CNS include the rapid behavioral effects of administered steroids; diurnal and estrous cycle effects on behavior; gender-specific pharmacology, especially of GABAergic drugs; and the development of withdrawal symptoms following cessation of chronically administered steroids. Neuroactive steroids have effects similar to those of barbiturates in that they enhance agonist binding to the GABA site and allosterically modulate benzodiazepine and TBPS binding.

Relaxation and immunity enhancement effects of gamma-aminobutyric acid (GABA) administration in humans.

The effect of orally administrated gamma-aminobutyric acid (GABA) on relaxation and immunity during stress has been investigated in humans. Two studies were conducted. The first evaluated the effect of GABA intake by 13 subjects on their brain waves. Electroencephalograms (EEG) were obtained after 3 tests on each volunteer as follows: intake only water, GABA, or L-theanine. After 60 minutes of administration, GABA significantly increases alpha waves and decreases beta waves compared to water or L-theanine. These findings denote that GABA not only induces relaxation but also reduces anxiety. The second study was conducted to see the role of relaxant and anxiolytic effects of GABA intake on immunity in stressed volunteers. Eight acrophobic subjects were divided into 2 groups (placebo and GABA). All subjects were crossing a suspended bridge as a stressful stimulus. Immunoglobulin A (IgA) levels in their saliva were monitored during bridge crossing. Placebo group showed marked decrease of their IgA levels, while GABA group showed significantly higher levels. In conclusion, GABA could work effectively as a natural relaxant and its effects could be seen within 1 hour of its administration to induce relaxation and diminish anxiety. Moreover, GABA administration could enhance immunity under stress conditions.

Growth hormone isoform responses to GABA ingestion at rest and after exercise.

Oral administration of the amino acid/inhibitory neurotransmitter gamma aminobutyric acid (GABA) reportedly elevates resting serum growth hormone (GH) concentrations.

At rest, GABA ingestion elevated both irGH and ifGH compared with placebo. Specifically, peak concentrations of both hormones were elevated by about 400%, and the area under the curve (AUC) was elevated by about 375% (P < 0.05). Resistance exercise (EX-P) elevated time-point (15-60 min) irGH and ifGH concentrations compared with rest (P < 0.05). The combination of GABA and resistance exercise (EX-GABA) also elevated the peak, AUC, and the 15- to 60-min time-point irGH and ifGH responses compared with resting conditions (P < 0.05). Additionally, 200% greater irGH (P < 0.01) and 175% greater ifGH (P < 0.05) concentrations were observed in the EX-GABA than in the EX-P condition, 30 min after ingestion. GABA ingestion did not alter the irGH to ifGH ratio, and, under all conditions, ifGH represented approximately 50% of irGH.

Conclusion data indicates that ingested GABA elevates resting and postexercise irGH and ifGH concentrations. The extent to which irGH/ifGH secretion contributes to skeletal muscle hypertrophy is unknown, although augmenting the postexercise irGH/ifGH response may improve resistance training-induced muscular adaptations.

The GABA system in anxiety and depression and its therapeutic potential.

In the regulation of behavior, the role of GABA neurons has been extensively studied in the circuit of fear, where GABA interneurons play key parts in the acquisition, storage and extinction of fear. Therapeutically, modulators of α(2)/α(3) GABA(A) receptors, such as TPA023, have shown clinical proof of concept as novel anxiolytics, which are superior to classical benzodiazepines by their lack of sedation and much reduced or absent dependence liability. In view of the finding that anxiety disorders and major depression share a GABAergic deficit as a common pathophysiology, the GABA hypothesis of depression has found increasing support. It holds that α(2)/α(3) GABA(A) receptor modulators may serve as novel antidepressants. Initial clinical evidence for this view comes from the significantly enhanced antidepressant therapeutic response when eszopicole, an anxiolytic/hypnotic acting preferentially on α(2)/α(3) and α(1) GABA(A) receptors, was coadministered with an antidepressant. This effect persisted even when sleep items were not considered. These initial results warrant efforts to profile selective α(2)/α(3) GABA(A) receptor modulators, such as TPA023, as novel antidepressants. In addition, GABA(B) receptor antagonists may serve as potential antidepressants. This article is part of a Special Issue entitled ‘Anxiety and Depression’.

GABA supplementation and growth hormone response.

The secretion of growth hormone (GH) is regulated through a complex neuroendocrine control system, especially by the functional interplay of two hypothalamic hormones, GH-releasing hormone and somatostatin. These hormones are subject to modulation by a host of neurotransmitters and are the final mediators of endocrine and neural influences for GH secretion. Interest in the possible role of γ-aminobutyric acid (GABA) in the control of GH secretion began decades ago. However, interest in its role as an ergogenic aid is only recent. It is well accepted that GABAergic neurons are found in the hypothalamus and recent evidence suggests its secretion within the pituitary itself. Inhibition of GABA degradation and blockade of GABA transmission as well as administration of GABA and GABA mimetic drugs have all been shown to affect GH secretion. However, there are many controversial findings. The effects may depend on the site of action within the hypothalamic-pituitary unit and the hormonal milieu. Experimental and clinical evidence support the presence of a dual action of GABA – one mediated centrally, the other exerted directly at the pituitary level. The two sites of action may be responsible for excitatory and inhibitory effects of GABA on GH secretion.