Plasma GABA Research Articles

Plasma GABA: Stable trait marker for mood disorders? : Frederick Petty, Ph.D., M.D., Gerald L. Kramer, B.S., David Dunnam, B.S., A. John Rush, M.D. Department of Veterans Affairs, University of Texas Southwestern Medical School, Dallas, TX 75216

Plasma GABA: Stable trait marker for mood disorders? : Frederick Petty, Ph.D., M.D., Gerald L. Kramer, B.S., David Dunnam, B.S., A. John Rush, M.D. Department of Veterans Affairs, University of Texas Southwestern Medical School, Dallas, TX 75216

Plasma Gaba–Like Activity in Rats With Hepatic Encephalopathy Is Due to Gaba and Taurine

Significant discrepancy exists between radioreceptor and high-performance liquid chromatographic estimates of plasma GABA concentrations in animal models of hepatic encephalopathy. A possible explanation for this discrepancy is the presence in plasma of a substance that can inhibit [3H]-GABA binding but is not GABA itself. The aim of this study was to determine whether any of the amino acids that are increased in the plasma of animal models of acute and chronic hepatic encephalopathy (glutamine, glutamate, phenylalanine, tyrosine, citrulline and taurine) can significantly inhibit [3H]-GABA binding and contribute to the GABA-like activity of plasma aliquots. At final assay concentrations equivalent to plasma concentrations found in hepatic encephalopathy, only taurine was found to significantly inhibit [3H]-GABA binding to whole rat brain synaptosomal membranes (36% inhibition at 30 mumol/L final assay concentration). The concentration of taurine that resulted in 50% inhibition (final assay concentration) was 158 mumol/L, corresponding to a plasma concentration of 1.58 mmol/L. Taurine inhibition of [3H]-GABA binding was competitive because the receptor density was unaltered, but the receptor affinity decreased with increasing concentration of taurine. Plasma GABA-like activity (determined by radioreceptor assay) and plasma GABA and taurine concentrations (determined by high-performance liquid chromatography) were measured in 18 rats with acute or chronic hepatic encephalopathy and 9 control rats. Plasma GABA-like activity and plasma GABA and taurine concentrations were significantly increased in rats with hepatic encephalopathy compared with control rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for gamma-aminobutyric acid as the inhibitor of gamma-aminobutyric acid binding in the plasma of humans with liver disease and hepatic encephalopathy.

1. Gas-liquid chromatography and a radioreceptor assay were used to measure plasma gamma-aminobutyric acid (GABA) in patients with liver disease and hepatic encephalopathy. 2. There was a significant correlation between the results obtained by the two methods, and compared with controls plasma GABA was elevated. 3. These findings suggest that the increased GABA binding inhibitory activity of plasma of these patients is probably due to GABA itself.

Is plasma GABA of peripheral origin?

Plasma levels of γ-aminobutyric acid (GABA) appear to be altered in affective disorders and alcoholism. Plasma levels of GABA were not affected by menstrual cycle, exercise, gender, gut flora, nor by cholinergic stimulation by bethanechol. An obvious peripheral source for plasma GABA could not be demonstrated.

ALCOHOLISM and PLASMA GABA LEVELS

ALCOHOLISM and PLASMA GABA LEVELS

γ-aminobutyric acid plasma levels and brain binding in Eck fistula dogs

It has been hypothesized that γ-aminobutyric acid (GABA), the principle inhibitory neurotransmitter of the mammalian brain, contributes to the neural inhibition of hepatic encephalopathy. Eck fistulae were created in seven dogs and celiotomy alone performed in five dogs to determine plasma GABA levels, brain GABA binding, and synaptic membrane changes in dogs after creation of Eck fistulae. Eck fistula dogs lost 19 ± 9% body weight, lost hair, ate poorly, and developed atrophic livers with classic hepatic histological changes. Control dogs maintained body weight, normal behavior, and normal liver histology. Plasma GABA levels were elevated significantly in the Eck fistula dogs (312 ± 105.9 n M) both as compared to controls (154.4 ± 69.8) and to preoperative levels (161.6 ± 56.7, P < 0.05). Brain GABA binding for animals sacrificed at 6–9 weeks was not statistically different from sham-operated dogs sacrificed at 6 weeks (1.87 ± .54 pmole/mg protein vs 1.186 ± 24, P < 0.2). Synaptic membrane fluidity and cholesterol were likewise unchanged. Plasma GABA levels are increased significantly following complete portal diversion but do not correlate with the degree of encephalopathy. GABA binding to neural membranes are not significantly increased in Eck fistula dogs. These findings do not support a direct relationship between plasma GABA levels and neurologic impairment in Eck fistula dogs.

Plasma GABA: A possible indicator of altered GABA function in psychiatric illness

A variety of lines of experimental evidence has suggested altered activity of GABAergic neurons in a number of neuropsychiatric illnesses. We report here a review and extension of our findings regarding the measurement of GABA levels in the plasma of psychiatric patients and controls. It appears that plasma GABA levels may be useful in distinguishing individuals suffering from primary affective illness and alcoholics from controls.

Plasma GABA levels in psychiatric illness

In two separate studies, we have obtained plasma levels of GABA in 134 psychiatric patients and 22 normal controls. Patients with a unipolar affective disorder had levels significantly lower than control (n = 58) as did patients with alcoholism (n = 10). Patients with a bipolar affective disorder had levels significantly higher than control when manic (n = 28) and also when euthymic on lithium prophylaxis (n = 17), but levels in the control range when depressed (n = 4). Patients with schizophrenia demonstrated a high degree of variability in their levels of plasma GABA but were not statistically different from control (n = 36). Patients with unipolar depression who received a dexamethasone suppression test had no correlation between nonsuppression of cortisol secretion and plasma levels of GABA. Diagnostic and research implication of plasma GABA in psychiatric illness are discussed.

Effect of dietary protein and GABA on food intake, growth and tissue amino acids in cats

GABA at 5%, but not 3%, of a low protein diet depressed food intake and growth of kittens. Adaptation to high protein prevented these effects. When cats adapted to low or high protein were fed a meal containing GABA, plasma GABA concentration after 2 hr was 8-fold higher in the low than in the high protein group; clearance was almost complete within 6 hr. Concentrations of proline, branched-chain, other large neutral and basic (especially ornithine) amino acids increased more when cats were fed a high rather than a low protein meal; glycine decreased. At 6 hr, concentrations had consistently returned to initial levels only in the low protein group. Feeding the high protein diet ad lib increased tissue concentrations of threonine, proline and the branched-chain amino acids. Hepatic or renal GABA-aminotransferase activity was not altered in kittens fed the high protein diet. Kidney activity was 10-fold that of liver, which may contribute to the better tolerance of GABA by cats than by rats.

Correlates of lithium response in psychotic-affective syndromes

We examined clinical and biochemical predictors of lithium response in 17 schizoaffective patients as well as the effect of lithium treatment upon several aminergic systems in this group. Ten patients were rated improved by the addition of lithium to the treatment regimen. No clinical predictors reached significance although DSM-III diagnosis and family history showed trends. Pretreatment plasma GABA was higher in the responders to lithium as compared to the nonresponders. Lithium tended to increase CSF HVA, CSF GABA, and plasma cAMP and to decrease plasma GABA. Lithium had little effect upon CSF 5HIAA, CSF cAMP, or plasma HVA.

Alterations in CSF GABA levels and seizure susceptibility developing during repeated administration of pentetrazole in dogs. Effects of γ-acetylenic GABA, valproic acid and phenobarbital

Daily administration of convulsive doses of pentetrazole in dogs resulted in a decrease in the seizure threshold and development of increasingly severe clonic-tonic convulsions. Concomitantly, the concentration of γ-aminobutyric acid (GABA) in cisternal cerebrospinal fluid (CSF) was markedly reduced, whereas plasma GABA levels were not altered. When re-tested after a 3-week resting period, animals were found to have retained their increased seizure sensitivity and reduction in CSF GABA levels. γ-Acetylenic GABA and phenobarbital in doses antagonizing the establishment of increased convulsive sensitivity in response to repeated pentetrazole injections also counteracted the fall in CSF GABA. Valproic acid proved less effective to influence the convulsive response of continued pentetrazole administration. The data suggest that a functional deficit in the GABA system may underlie the persistent changes in seizure susceptibility observed.

Relationship between GABA concentrations in cerebrospinal fluid and seizure excitability.

Various studies suggest that alterations in GABAergic function may be connected to epileptic seizures. Low CSF GABA levels have been reported in epilepsy and also febrile convulsions of children. In this study the pentetrazole seizure threshold of dogs was compared with the concentration of GABA in the CSF and blood plasma. A highly significant positive correlation was found between seizure excitability and CSF GABA level, but not between CSF and plasma GABA concentrations.

Plasma GABA in affective illness: A preliminary investigation

Plasma levels of γ-aminobutyric acid (GABA) were determined in 34 clinically symptomatic patients with diagnosis of affective disorder and in 20 normal controls. Lowest levels were found in patients with familial pure depressive disease and in depression spectrum disease, while levels of patients with sporadic depressive disease, though significantly lower than control, were not as low. Plasma GABA levels in secondary depression and in bipolar depression were similar to control. Bipolar manic patients had plasma GABA levels that were significantly higher than control values.

Plasma GABA levels in neurological patients under treatment with valproic acid

The effect of chronic treatment with valproic acid (VPA), administered as its sodium salt, on the plasma concentrations of GABA was studied in 5 in-patients. Within 2–10 days of treatment with daily doses of 1500–3000 mg sodium VPA GABA levels increased to 30–80 % compared to control days. This increase was transient in 3 out of 5 patients. In 19 epileptic patients under VPA medication plasma GABA levels were 40 % higher than those determined in non-epileptic patients serving as controls. The possibility that the increase in plasma GABA induced by VPA reflects similar increases in brain GABA content is discussed.

Effect of isoniazid on cerebrospinal fluid and plasma GABA levels in Huntington's disease

During a double-blind placebo controlled trial, γ-aminobutyric acid (GABA) was measured in cerebrospinal fluid (CSF) and plasma obtained from patients with Huntington's Disease prior to the start of the trial, at the end of the placebo period and following treatment with isoniazid. The results showed that the GABA concentrations in CSF tripled following treatment with isoniazid although no significant change occurred in plasma GABA levels. This finding in humans indirectly confirms reports of a similar increase of brain GABA content in experimental animals following isoniazid treatment and provides additional evidence that CSF GABA measurements reflect brain GABA activity.

GABA in peripheral tissues: Presence and actions in endocrine pancreatic function

Of 9 male Sprague-Dawley rat organs examined, GABA was present at highest levels in the pancreas, thymus, and adrenal (34–40 pmol/mg wet weight) and lowest in heart and testis (6–10). Intermediate levels were present in stomach, liver, spleen and lung. Streptozotocin, a B cytotoxic agent, lowered pancreas GABA levels to 1/3 control values without significantly affecting that of the other organs or plasma levels. Collagenase isolated rat islets contained 190 ± 25 (SE) whereas hand isolated catfish Brockmann bodies contained 121 ± 16 (SD) pmol GABA/mg wet weight. Rabbit pancreas contained 14 ± 4 and 3 ± 1 pmol/mg in the tail and body, respectively. In cannulated rats, injection of GABA increased plasma glucose with and without AOAA. In 15 normal SD rats, plasma glucose correlated with plasma GABA in a positive manner ( r + 0.644), though in 6 human diabetics (treated) this correlation was of a negative nature and of low order ( r = − 0.339). Incubation of rabbit pancreas pieces in vitro (method of Coore and Randle) indicated GABA may facilitate insulin release and inhibit glucagon release. Additionally, GABA was released in response to high glucose concentration, and pieces of pancreas incubated in 10 −3 M GABA for 30 min evidenced significant uptake of GABA whereas those in 10 −5 or 10 −7 did not. Though the variation in these later data is large, further experiments using more refined techniques are warranted. (Supported in part by H. D. Foundation and USPHS Grant MH-28243.)