Publisher Summary This chapter discusses epilepsy and γ-aminobutyric acid (GABA) mediated inhibition. The inhibitory action of short-chain ω-amino acids (such as β-alanine, GABA, and taurine) on central neurons has been established by the microiontophoretic studies. Additional data that have led to the widespread acceptance of the hypothesis that GABA is the inhibitory transmitter at numerous central sites include (1) the demonstration of high GABA content and glutamic acid decarboxylase (GAD) activity in synaptosome preparations, (2) the evidence for the selective local release of GABA when known inhibitory systems are activated in the cerebral cortex or cerebellum, and (3) evidence from intracellular recordings that the changes in membrane potential and in specific ionic conductances produced by physiological inhibitory inputs are similar to those produced by the iontophoretic application of GABA. The principal sites where GABA produces hyperpolarization of the neuronal membrane, which resembles the physiologically induced inhibitory postsynaptic potential (IPSP) in its dependence on an enhanced chloride conductance, and where naturally induced inhibition and the action of applied GABA are blocked by picrotoxin or bicuculline, are the neocortex, the cerebellum, the hippocampus, and the thalamus.

Epilepsy and gamma-aminobutyric acid-mediated inhibition.

Publisher Summary This chapter discusses the important roles of glutamate and gamma-aminobutyric acid (GABA) in brain metabolism. The chapter shows the amino acids as excitatory and inhibitory transmitters in the CNS. The inactivation of these transmitters is generally brought about by sodium-dependent high-affinity uptake systems rather than enrymatic degradation. The importance of the different cell types in these processes and the characteristics of the different transport systems are discussed. The quantitative importance of the high-affinity uptake of glutamate and GABA into glial cells is investigated in primary cultures of astrocytes that seem to constitute a valid model for such cells in vivo. From these studies, it can be concluded that astrocytes are quantitatively important for uptake of putative transmitter amino acids. Whether this uptake has to do primarily with the transmitter pools of these amino acids, and hence their inactivation, or the uptake is involved in the metabolic processes remains to be finally elucidated. The fact that the processes of astrocytes control a large surface area around synapses seems to favor a function of such cells in the inactivation of these amino acids.On the other hand, it is undoubtedly correct that these amino acids can be taken up into presynaptic nerve endings through high-affinity transport processes. In the case of GABA, it is even possible to distinguish between these transport mechanisms employing inhibitors that have been shown to be selective for the transport carriers.

Transport and metabolism of glutamate and GABA in neurons are glial cells.

Localization of transmitter candidates in the brain: the hippocampal formation as a model

Two issues concerning sensorimotor EEG operant conditioning, or biofeedback, as a therapeutic modality for the treatment of seizure disorders are the focus of this review. The first relates to the question of whether relevant physiological changes are associated with this procedure. This question is addressed through review of an extensive neurophysiological literature that is likely unfamiliar to many clinicians but that documents both immediate and sustained functional changes that are consistent with elevation of seizure thresholds. The second focuses on the clinical efficacy of this method and whether it should carry the designation of "experimental". This designation is challenged through an assessment of over 25 years of peer-reviewed research demonstrating impressive EEG and clinical results achieved with the most difficult subset of seizure patients.

Basic Concepts and Clinical Findings in the Treatment of Seizure Disorders with EEG Operant Conditioning

Recent neurophysiological findings in relation to thalamocortical mechanisms for sensory processing, together with established anatomical and expanding functional evidence, have provided a rational theoretical framework for the interpretation of normal and abnormal EEG rhythmic activities. This perspective is integrated here with earlier animal studies which were the foundation for many current applications of EEG self-regulation as a clinical tool. Basic evidence concerning the origins, frequency modulation, and functional significance of normal EEG rhythmic activities is reviewed here in an effort to provide guiding principles for the interpretation of clinical abnormalities and their remediation with EEG feedback training.

Physiological origins and functional correlates of EEG rhythmic activities: Implications for self-regulation

— At high dosage levels AOAA acted as a convulsant agent in mice and rats but in lower amounts it was an effective anticonvulsant agent against INH-induced seizures, by tripling the time to the onset of the convulsions. AOAA elevated brain GABA levels as a result of a preferential inhibition of the GABA-T enzyme system but, contrary to previous reports, the activity of the GAD enzyme system was also inhibited, even by relatively low dosage levels of AOAA. The state of excitability of the brain following the administration of AOAA was related, within the limits of the present study, to changes in GAD activity and GABA levels, but additional data are required before the relationship can be properly evaluated.

The role of gaba metabolism in the convulsant and anticonvulsant actions of aminooxyacetic acid

—The effect of intramuscularly administered INH on brain levels of GABA in chicks was dependent on the amount injected. A subconvulsant dose of INH (1·1 mmol/kg) produced a slow steady decline in the level of GABA, whereas a convulsant dose (2·19 mmol/kg) brought about a sequential fall and rise in GABA level. This sequence of events reflected changes in the relative activities of GAD and GABA-T brought about by the hydrazide. The administration of pyridoxine together with the INH (2·19 mmol/kg) prevented the onset of seizures and lessened the effect of the INH on GABA levels and GAD activity but not on GABA-T activity. The possibility that a deranged GABA metabolism is responsible for hydrazide-induced seizures is discussed.

The effect on gaba metabolism in brain of isonicotinic acid hydrazide and pyridoxine as a function of time after administration

— The GABA-elevating agents, aminooxyacetic acid, hydrazine, and hydroxylamine, all possessed anticonvulsant properties, although to a widely varying degree. Aminooxyacetic acid was the most efficacious in delaying drug-induced seizures in mice whereas hydroxylamine brought about only a slight delay in the onset of seizures. The anticonvulsant action was observed against various convulsant agents regardless of whether the convulsant mechanism might involve a deranged GABA metabolism (allylglycine, isonicotinic acid hydrazide, hydrazine), an interference with GABA function (picrotoxin) or some other mechanism (pentylenetetrazol). The anticonvulsant action was not related in a simple manner to either GABA levels or glutamic acid decarboxylase (GAD) activities but the anomalous situation whereby seizures occurred when the GABA content of brain was above normal could be resolved on the basis of an expression which included changes in both GABA levels and GAD activity. The possibility was proposed that the anticonvulsant action of aminooxyacetic acid involved two separate mechanisms.

The anticonvulsant action of GABA-elevating agents: a re-evaluation.

—The effect of hydrazine, unsymmetrical dimethylhydrazine (UDMH) and symmetrical dimethyl hydrazine (SDMH) on GABA metabolism in mouse brain was studied. All three compounds inhibited the activity of glutamic acid decarboxylase, although to different extents. In contrast, very different effects were observed on GABA levels; UDMH causing a decrease, SDMH no effect, and hydrazine a marked increase in the content of the amino acid. These results together with previous data obtained by the authors were used to develop an equation which related the excitable state of the brain to changes in overall GABA metabolism. The major factor affecting brain excitability was a change in the activity of glutamic acid decarboxylase, with a change in the concentration of GABA playing a more minor role. It was suggested that the values obtained from the equation might reflect the content of GABA in a critical subcellular location such as the synaptic cleft.

Development of an expression which relates the excitable state of the brain to the level of GAD activity and GABA content, with particular reference to the action of hydrazine and its derivatives.

S. J. Peesker

Papers

The role of gaba metabolism in the convulsant and anticonvulsant actions of aminooxyacetic acid

The effect on gaba metabolism in brain of isonicotinic acid hydrazide and pyridoxine as a function of time after administration

The anticonvulsant action of GABA-elevating agents: a re-evaluation.

Development of an expression which relates the excitable state of the brain to the level of GAD activity and GABA content, with particular reference to the action of hydrazine and its derivatives.