Brain Gamma-aminobutyric Acid Contents Research Articles

The effect of monoamine depletors on metrazol induced convulsions and brain gamma-aminobutyric acid (GABA) contents in rats.

The thresholds for metrazol (pentylenetetrazol) clonic convulsions and brain gamma-aminobutyric acid contents were significantly reduced after treatment with the monoamine depletors reserpine, tetrabenazine and p-chlorophenylalanine. Moreover, alpha-methyltyrosine, and alpha-methyl-m-tyrosine also lowered metrazol threshold seizures, but had no effect on brain alpha-aminobutyric acid contents. Furthermore, neither 5-hydroxytryptophan nor tranylcypromine had a significant effect on metrazol threshold seizures or brain alpha-aminobutyric acid contents, but blocked the changes previously induced by p-chlorophenyl alanine and reserpine.

Chapter 26 Antiepileptic drug treatment: Clinical considerations and concerns

Publisher Summary Epileptology is a multifaceted discipline spanning from basic neurobiology to the psychosocial problems of the individual patient. The ongoing close cooperation between neuroscientists and clinicians has accelerated the creation of new antiepileptic drugs (AEDs) and is generating a time of considerable activity and promise in the field of clinical epileptology. Among the diseases for which the glutamate synapse is a potential therapeutic target, the epilepsies are rather unique because many drugs with other mechanisms of action are already available. The chapter presents a general overview of AEDs to provide some insight in how current and future drugs affecting glutamatergic transmission will find their place among the existing therapies. It also outlines some of the general concerns that must be kept in mind when introducing new drugs for the treatment of neurological disease. The chemical structure of many new drugs is designed to affect specific mechanisms involved in the balance between neuronal excitation and inhibition. Vigabatrin (VGB) is an inhibitor of gamma-aminobutyric acid (GABA)-transaminase and enhances GABAergic neuronal inhibition. Its clinical effects are primarily limited to partial seizures and infantile spasms. The increased brain GABA content may contribute to adverse effects on mood and cognitive function in some patients and may occasionally lead to psychosis.

Cleft palate and decreased brain gamma-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase.

In addition to its role as an inhibitory neurotransmitter, gamma-aminobutyric acid (GABA) is presumed to be involved in the development and plasticity of the nervous system. GABA is synthesized by glutamic acid decarboxylase (GAD), but the respective roles of its two isoforms (GAD65 and 67) have not been determined. The selective elimination of each GAD isoform by gene targeting is expected to clarify these issues. Recently we have produced GAD65 -/- mice and demonstrated that lack of GAD65 does not change brain GABA contents or animal behavior, except for a slight increase in susceptibility to seizures. Here we report the production of GAD67 -/- mice. These mice were born at the expected frequency but died of severe cleft palate during the first morning after birth. GAD activities and GABA contents were reduced to 20% and 7%, respectively, in the cerebral cortex of the newborn GAD67 -/- mice. Their brain, however, did not show any discernible defects. Previous pharmacological and genetic investigations have suggested the involvement of GABA in palate formation, but this is the first demonstration of a role for GAD67-derived GABA in the development of nonneural tissue.

The effect of phenytoin on glutamate and GABA transport.

Phenytoin was observed to inhibit competitively the sodium dependent high affinity synaptosomal transport of both glutamate (Glu) and gamma-aminobutyric acid (GABA) with Ki values of 66 +/- 10 and 185 +/- 65 microM, respectively. This contrasted with a previous report that the uptakes of Glu and GABA were enhanced by phenytoin. The degree of inhibition is dependent on the concentrations of the competing drug and substrate present. Taking the therapeutic levels of phenytoin and the overall brain Glu and GABA contents, the degrees of inhibition obtainable appear to be negligible. However, as most of the high levels of Glu and GABA in the brain are intracellular, Glu, and GABA concentrations in the microenvironment of the uptake sites may be sufficiently small so that the ability of phenytoin to inhibit Glu and GABA transport may contribute significantly to the anticonvulsant property of this drug.

Effects of anesthetic agents on synaptosomal GABA disposal.

In brain slices, halothane was shown to inhibit the metabolic breakdown of GABA (gamma-aminobutyric acid), an inhibitory neurotransmitter. This inhibition leads to increased brain GABA content, presumably in the synaptic areas, and to the postulation that halothane anesthesia may arise from an enhanced synaptic inhibition due to this elevated GABA. The ability of many neurotropic agents to inhibit GABA breakdown was studied by assessing synaptosomal "GABA disposal". GABA disposal by intact synaptosomes, which simulate miniature synapses, measures the conversion of [1-14C]GABA to 14CO2 and includes the processes of uptake, release, and catabolism of GABA. The most potent inhibitor is chloroform, followed by halothane, enflurane, ether, and thiopental. Pentobarbital, ethanol, paraldehyde, and ketamine are weak inhibitors. Phenobarbital, morphine, and phenytoin are not inhibitory at pharmacologic concentrations. As a whole, anesthetic agents show particular inhibitory action on this metabolic process in this model system where the ID10 values (i.e., concentration of a drug necessary to produce 10 per cent inhibition of GABA disposal) correlate well with known pharmacologic potencies, ED50 values, or MACs. These observations support the possibility that anesthesia may be related to an inhibition of GABA disposal.

Low cerebrospinal fluid gamma-aminobutyric acid content in seizure patients.

Gamma-Aminobutyric acid (GABA) has been implicated in the neurochemistry of epilepsy. Lumbar cerebrospinal fluid (CSF) GABA concentrations determined using an ion-exchange fluorometric assay reflect brain GABA content. The mean lumbar CSF GABA concentration among 21 medicated patients with intractable seizures was significantly lower (p less than 0.001) than that of 20 unmedicated normal volunteers. Patients with generalized tonic-clonic (grand mal) and complex partial (psychomotor) seizures had significantly lower (p less than 0.05) CSF GABA concentrations than those with simple partial (focal sensory/motor) seizures. Although lumbar CSF GABA levels in our seizure patients did not significantly correlate with serum concentrations of phenytoin, phenobarbital, or primidone, additional study of medication-free epileptic patients may be required to evaluate the possibility of anticonvulsant-drug-induced CSF GABA alterations.

Toxic, neurochemical and behavioral effects of dieldrin exposure in mallard ducks.

Toxic, neurochemical and behavioral alterations were evaluated in ducks fed various dietary levels of dieldrin. Increasing amounts of dieldrin in the diet caused an appreciable decrease in the levels of three biogenic amines in whole brain, i.e. serotonin, norepinephrine and dopamine. No effect was noted in whole brain gamma aminobutyric acid contents. Hepatic microsomal enzymes were assayed in these birds using p-nitroanisol and O-ethyl-O-p-nitrophenyl benzenethionophosphate as substrates. Sublethal amounts of dieldrin caused an increase in hepatic drug metabolizing enzymes. Similar alterations were noted in liver protein, deoxyribonucleic acid and ribonucleic acid contents. Studies involving encounters between mallard drakes indicated a decline in the tendency for dieldrin exposed drakes to take the initiative and establish rights of access in approach confrontations. Although many of these changes are compatible with life processes, their significance is not well understood, especially in terms of lifelong exposure to persistent pesticides. The possible relationship between neurochemical alterations and the mechanisms of insecticide neurotoxicity is discussed.