Cerebrospinal Fluid GABA Research Articles

Levels of gamma-aminobutyric acid in cerebrospinal fluid and plasma during alcohol withdrawal

γ-Aminobutyric acid (GABA) is implicated in the biochemical pathophysiology of alcohol intoxication, dependence and withdrawal. We therefore measured GABA in both cerebrospinal fluid (CSF) and plasma from 14 male alcohol-dependent patients during acute alcohol withdrawal (day 1) and again after 21 days of inpatient treatment (day 21). Plasma GABA levels on admission correlated with indices of liver function. When corrected for differences in liver function, plasma levels of GABA levels on day 1 were significantly higher than on day 21. CSF GABA concentrations were also significantly higher during withdrawal compared with concentrations after 3 weeks of abstinence. The change in plasma GABA levels correlated significantly with the change in CSF GABA levels, although there was no correlation between plasma and CSF levels at either time. These findings demonstrate that changes in CSF GABA may be reflected in plasma GABA, and they highlight the potential importance of the GABA system in alcohol dependence and withdrawal.

GABA levels in cerebrospinal fluid and plasma during alcohol withdrawal

The GABA system is closely linked to the biochemical pathophysiology of alcohol intoxication, dependence, and withdrawal. Previous research has shown plasma GABA, which reflects brain GABA activity, to be low in a subset of patients with alcohol dependence 2-4 weeks after cessation of drinking. We now report on a study of GABA, with simultaneous measures in cerebrospinal fluid (CSF) and plasma, in 14 male alcoholdependent patients during acute alcohol withdrawal (day 1) and again after 21 days of inpatient treatment (Day 21). On admission, plasma GABA levels correlated with indices of liver function. When corrected for differences in liver function, plasma levels of GABA on day 1 were significantly higher than on day 21 (p < 0.001). CSF levels of GABA were also higher during withdrawal than after 3 weeks of abstinence, although this difference was only a trend (p < 0.1). The change in plasma GABA levels correlated significantly with the change in CSF GABA levels (r = 0.69, p = 0.006); however, plasma GABA and CSF GABA levels did not show a significant correlation at either time point studied. Although the present study did not incorporate controls, levels of plasma GABA were significantly lower than the established normal range for healthy controls of 100-150 pmol/ml. These findings replicate our previous work showing plasma GABA levels to correlate with liver function in recently detoxifled alcoholics, and to decrease after abstinence. Also, this work suggests that changes in CSF GABA may be reflected in plasma GABA, adding to the validity of the peripheral marker. Whether low GABA in alcoholics reflects an induced deficit or a vulnerability awaits further research.

Determination of γ-Aminobutyric Acid Levels in Human Cerebrospinal Fluid Using Pseudomonas

The principle objective was to demonstrate the efficacy of a bacterial, radioligand, competitive binding method in determining γ-aminobutyric acid (GABA) levels in human cerebrospinal fluid (CSF). In a double blind study, CSF GABA concentrations were measured by the bacterial method using a mutant of Pseudomonas fluorescens and by a standard radioligand competitive binding assay using rat brain membranes. Linear regression analysis demonstrated a highly significant correlation (r = 0.84; P < 0.001) between the two methods. In an ancillary study, a similar correlation (r = 0.90; P < 0.001) was found between the bacterial method and HPLC, another standard procedure in determining CSF GABA levels. Furthermore, the mean CSF GABA measurements found with the bacterial method were in agreement with those reported in the literature using the brain membrane method or HPLC. The bacterial method was highly reproducible and reliable with a detection to 5 nM GABA. It was specific for GABA and was not affected by other naturally occurring compounds which are found in higher concentrations in CSF than GABA or which were suspected to interfere with the neurotransmitter in a binding assay. The bacterial radioligand method was shown to be an accurate, sensitive, and rapid assay for CSF GABA.

Topical Review: Putative Neurotransmitter Abnormalities in Infantile Spasms: Cerebrospinal Fluid Neurochemistry and Drug Effects

The neuropharmacologic basis of infantile spasms and the mechanism by which adrenocorticotropic hormone (ACTH) exerts its therapeutic effects are unknown. This is a critical review of cerebrospinal fluid neurotransmitters or their metabolites in infantile spasms before and during treatment with ACTH, and of clinical drug trials with drugs acting on neurotransmission. Cerebrospinal fluid studies have shown lower gamma-aminobutyric acid (GABA), ACTH, and 5-hydroxyindoleacetic acid concentrations in patients with infantile spasms compared to controls, elevated lysine and glutamate, variable or no differences in homovanillic acid, 3-methoxy-4-hydroxyphenylglycol, norepinephrine, corticotropin-releasing hormone, and beta-endorphin. Chronic treatment with ACTH in infantile spasms reduces cerebrospinal fluid GABA, beta-endorphin, and somatostatin, increases norepinephrine and tyrosine, and has variable or no effect on homovanillic acid, 3-methoxy-4-hydroxyphenylglycol, 5-hydroxyindoleacetic acid, histamine, and tryptophan. Small therapeutic trials with drugs that act through different neurotransmitters such as methysergide, alpha-methylparatyrosine, various benzodiazepine agonists, and vigabatrin lend some support to a role for GABA and monoamines in infantile spasms. These data, though promising, provide only a hint of potential neurotransmitter disturbances, and more basic and clinical data are needed.

Sequential neuropathology of dogs treated with vigabatrin, a GABA-transaminase inhibitor.

Vigabatrin (Sabril) is a gamma-aminobutyric acid-transaminase (GABA-T) inhibitor that is effective in the treatment of certain types of drug-resistant or uncontrolled epilepsy but is known to cause microscopic vacuolation (intramyelinic edema) in the brains of treated rats, mice, and dogs. The effects of high oral doses (300 mg/kg/day) of vigabatrin administered orally to Beagle dogs were studied during treatment weeks 1-12 and recovery weeks 13, 14, 16, 20, 24, and 28. Emesis, loose stools, and anorexia and 3 drug-related deaths were observed during the first 4 wk of treatment but were virtually nonexistent thereafter because of adaptation to the drug aided by food supplementation. In more sensitive areas of the brain (columns of the fornix, thalamus, and hypothalamus), microscopic quantitative differences between background vacuolation in controls and drug-related vacuolation in treated dogs could be delineated after 4 wk, generally reached highest levels of severity between 8 and 12 wk, and were reversible upon cessation of dosing. Inhibition of brain GABA-T and elevation of brain GABA were noted after 1 wk of treatment. During the course of treatment vigabatrin ranged between 4-17 nmol/ml (plasma) and 42-1,570 nmol/ml [cerebrospinal fluid (CSF)] while CSF GABA concentrations were 4-32 nmol/ml (treated dogs) and 0.1-0.6 nmol/ml (control dogs). Although the cause of vigabatrin-induced microvacuolation is unknown, the results of the study demonstrated that GABA-T inhibition with subsequent GABA elevation occurred within the first week of treatment and was followed by the onset of detectable microvacuolation several weeks later.

Vigabatrin.

To introduce the reader to the use of a new agent, vigabatrin, in the treatment of refractory complex partial seizures. Clinical trials and pharmacokinetic data are reviewed, as well as neuropathology, adverse effects, drug interactions, and dosage guidelines. A MEDLINE search through March 1992 was used to identify pertinent English-language literature, including clinical trials, reviews, abstracts, and conference proceedings. Indexing terms included vigabatrin and anticonvulsants. All clinical trials (total of 21) were reviewed, as were all pharmacokinetic studies (total of 8). Selected studies highlighting chemistry, pharmacology, neuropathology, and adverse effects were also reviewed. Performed subjectively by the author. Trials were assessed by design, sample size, types of seizures of the subjects, and clinical response. Vigabatrin represents the first of a new class of antiepileptic drugs (AEDs)--the gamma-aminobutyric acid transaminase (GABA-T) inhibitors. Vigabatrin works by selective, irreversible inhibition of GABA-T, thus preventing the breakdown of GABA. It has been shown to produce dose-dependent increases in cerebrospinal fluid GABA concentrations, and decreases in GABA-T activity. Vigabatrin may also cause a decrease in excitation-related amino acids. It is well absorbed, is not protein bound, and is eliminated by glomerular filtration. However, even with a short half-life (5-7 h), vigabatrin may be given once or twice daily because of its mechanism of action. Few drug interactions have been reported with this agent, although decreases in phenytoin concentration may reach clinical significance. Concern over neuropathologic findings (microvacuolization of white matter) in animals caused trials of vigabatrin to be halted in 1983, but trials have now resumed as there is no evidence of toxicity in humans. Clinical efficacy of vigabatrin has been evaluated in controlled trials and appears to be most effective in complex partial seizures, producing a 50 percent or greater reduction in seizure frequency in approximately 50 percent of the adult patients studied. Efficacy in children with partial seizures also appears promising, and one uncontrolled study suggests that further study of vigabatrin in infantile spasms may be warranted. Vigabatrin appears to be effective in treating refractory complex partial seizures in adults and refractory partial seizures in children. Its relatively benign adverse-effect profile and few known drug interactions may given this agent an advantage over existing anticonvulsants. However, definitive conclusions about the role of vigabatrin in epilepsy treatment should await the completion of ongoing Phase II and Phase III trials.

Monitoring of Neurotransmitter Amino Acids by Means of An Indwelling Cisterna Magna Catheter: A Comparison of Two Rodent Models of Fulminant Liver Failure

Alterations of brain and cerebrospinal fluid amino acids have consistently been described in human and experimental fulminant liver failure. To evaluate the significance of such changes in the pathogenesis of hepatic encephalopathy in fulminant liver failure, brain and cerebrospinal fluid amino acids (glutamate, aspartate, GABA, glycine, taurine) were measured at various stages during the development of neurological dysfunction in rats after hepatic devascularization or thioacetamide treatment to induce acute liver failure. To facilitate repetitive removal of cerebrospinal fluid, a technique employing long-term implantation of cisterna magna catheters in conscious, freely moving rats was developed. Brain but not cerebrospinal fluid concentrations of the excitatory amino acids glutamate and aspartate were reduced in both animal models of fulminant liver failure in parallel with deterioration of neurological status. Brain and cerebrospinal fluid GABA levels were not significantly altered. Cerebrospinal fluid glycine levels were increased two to three times in parallel with increasing brain glycine content in the devascularized rat but were unchanged in thioacetamide-induced liver failure, suggesting distinct pathophysiological mechanisms in these two experimental situations. On the other hand, onset of coma in both animal models of fulminant liver failure was accompanied by significantly increased cerebrospinal fluid taurine levels. We suggest that such changes result from taurine release from astrocytes in brain into the extracellular fluid; this is consistent with taurine's role in the regulation of intracellular osmolarity in brain. Sequential measurements of amino acids in the cerebrospinal fluid of small rodents with indwelling cisterna magna catheters adds a useful new approach for exploring the neurobiology of hepatic encephalopathy in fulminant liver failure.

Stability of plasma γ-aminobutyric acid with time in healthy controls

Several lines of evidence suggest that ~-aminobutyric acid (GABA) plays an importaat role in mood disorders. Drugs whose primary effect is on the GABA system, such as progabide and valproic acid, have demonstrated efficacy in the treatment of depression (Lloyd et al 1983) and mania (Pope et a11990). GABAA receptors were elevated in frontal cortex from post.morten suicide brain (Cheetham 1988), and an inverse correlation between conical GABA levels in biopsy specimens and degree of depression was reported (Honig et al 1989). Cerebrospinal fluid (CSF) levels of GABA were lower in patients with depression (Gerner et a11984). Plasma levels of GABA were lower in 40%-50% of patients with unipolar depression, and also in bipolar patients whether depressed, manic, or euthymic (Petty et al 1990; Berrettini et al 1982). Plasma for GABA determination is readily obtained, compared with CSF or brain tissue. Additionally, plasma GABA correlates well with CSF GABA (Uhlhaas et al 1986) in healthy controls. In laboratory animals, plasma GABA reflects brain GABA activity (Loscher 1979). Plasma GABA is low in both depressed and manic patients, does not correlate with symptom severity, and does not normalize with clinical improvement on follow-up (Petty et ai 1990).

Interictal Behavioral Alterations and Cerebrospinal Fluid Amino Acid Changes in a Chronic Seizure Model of Temporal Lobe Epilepsy

This study extends our previous work in which we described the presence of an interictal behavioral disturbance in a chronic animal model of temporal lobe epilepsy (TLE). In this study, we investigated the cerebrospinal fluid (CSF) neurotransmitter changes underlying the development of chronic recurrent seizures of temporal lobe origin and interictal behavioral disturbance in cats made epileptic after intrahippocampal injection of kainic acid (KA). Using high-performance liquid chromatography, we measured 22 putative neurotransmitter amino acids. After intrahippocampal KA injection, cats developed an initial acute period of intense seizure activity. Cisternal CSF amino acids, which were repeatedly sampled during the acute period through a permanent indwelling cannula, were unchanged apart from a mild elevation in CSF alanine. The high-level seizure activity gradually decreased, and cats entered a chronic epileptic period characterized by recurrent yet intermittent temporal lobe seizures. CSF GABA levels during the chronic epileptic period were significantly decreased. In contrast, CSF levels of other amino acids--alanine, tyrosine, taurine, aspartic acid, and glutamic acid--did not change significantly. Behavioral testing also showed a heightened interictal defensive reactivity during the chronic epileptic period. To the extent that CSF GABA concentration reflects brain GABA concentration, this study suggests that a decrease in brain GABA may contribute both to the epilepsy and interictal emotional lability of animals with a chronic seizure disorder of temporal lobe origin.

CSF GABA and neuropeptides in pathological gamblers and normal controls

We previously reported that pathological gamblers may have increased central noradrenergic activity. Neurons releasing γ-aminobutyric acid (GABA) are known to be a part of an inhibitory system regulating the activity of central noradrenergic neurons. Therefore, we examined cerebrospinal fluid (CSF) levels of GABA in pathological gamblers and normal controls. There was no significant difference between the groups. Also, depressed and nondepressed gamblers did not differ significantly in their CSF levels of GABA. Among controls, however, there was a significant negative correlation between CSF levels of GABA and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and a significant positive correlation between CSF levels of GABA and corticotropin releasing hormone (CRH). Also, CSF levels of CRH showed a significant positive correlation with CSF levels of adrenocorticotropic hormone in both pathological gamblers and controls.

Levels of total γ-aminobutyric acid (GABA), free GABA and homocarnosine in cerebrospinal fluid of epileptic patients before and during γ-vinyl-GABA (vigabatrin) treatment

Levels of total γ-aminobutyric acid (TGABA), free GABA (FGABA), and homocarnosine (HC) were studied in CSF taken from 12 controls and 28 patients with drug-refractory epilepsy before and during 7 months of γ-vinyl-GABA (GVG) administration. At baseline TGABA and FGABA in CSF of epileptic patients did not differ from that of the controls. In epileptic patients HC was 127% of that in controls. During GVG treatment TGABA was 283%, FGABA 197%, and HC 310% of the levels at baseline in the same patients. The patients who had over 50% reduction in seizure frequency during GVG (responders, 46% of the study population) at baseline had higher TGABA and HC in CSF than patients with less than 50% reduction in seizures (non-responders). During GVG the responders and nonresponders had similar levels of different GABAergic markers. The present study shows that in man GVG treatment effectively suppresses seizures in nearly half of the epileptic patients who had previously been drug-refractory. The elevated levels of GABAergic markers in CSF are not, however, necessarily related to good seizure control during GVG.

Effects of single doses of vigabatrin on CSF concentrations of GABA, homocarnosine, homovanillic acid and 5-hydroxyindoleacetic acid in patients with complex partial epilepsy

Vigabatrin, as a single oral dose of 50 mg/kg, was administered to 11 patients with drug-refractory complex partial epilepsy. Serial lumbar punctures were performed prior to and 5 times within the first week following treatment. Cerebrospinal fluid (CSF) concentrations of total GABA, free GABA, homocarnosine, homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and vigabatrin were determined as well as blood vigabatrin levels. CSF GABA, homocarnosine, HVA and 5-HIAA concentrations increased by 6 h after the single dose and remained elevated for up to 5–7 days. In contrast, CSF and blood vigabatrin levels were maximal within the first 24 h and were no longer detectable thereafter. Hence, these results are consistent with vigabatrin acting as an irreversible inhibitor of GABA-transaminase and suggest that it may also increase biogenic amine turnover.

Diazepam increases gamma-aminobutyric acid in human cerebrospinal fluid.

In 11 neurological patients, levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) were determined in cerebrospinal fluid (CSF) before and 1, 3, 5, and 8 min after intravenous injection of diazepam (2 or 5 mg). GABA levels increased progressively after intravenous injection of 5 but not 2 mg of the benzodiazepine, the differences from preinjection values being significant at 3, 5, and 8 min. Furthermore, when relative CSF GABA alterations determined after injection of diazepam were compared to those determined in sequential CSF aliquots of 10 patients without diazepam injection, mean GABA increases after diazepam were significantly different from controls in all CSF fractions. The data suggest that, in addition to its well-known effects on postsynaptic GABA function, diazepam may exert effects on endogenous GABA concentrations and/or on GABA release in the human CNS as reflected by elevation of GABA levels in human CSF.

Cerebrospinal fluid gamma-aminobutyric acid levels in dogs with chronic portosystemic encephalopathy.

Cerebrospinal fluid (CSF) gamma-aminobutyric acid (GABA) levels were measured in a dog model of spontaneous chronic portosystemic encephalopathy. Dogs with congenital portacaval shunts (intra- or extra-hepatic) develop neurological features of abnormal psychomotor behaviour and depressed consciousness that are consistent with the symptoms of chronic portosystemic encephalopathy in humans. In the five dogs studied, plasma ammonia was elevated, as was CSF tryptophan, both usual biochemical abnormalities in portosystemic encephalopathy. CSF levels of GABA in five dogs with portosystemic encephalopathy (100 +/- 13 pmol/ml) were not significantly different from those in five control dogs (96 +/- 14 pmol/ml). CSF levels of GABA were not altered after ammonia infusion. If enhanced GABA-ergic neurotransmission, due to influx of gut-derived GABA into the brain, is responsible for the pathophysiology of chronic portosystemic encephalopathy in this model, it is not reflected by increased levels of GABA in CSF.

GABA levels in cerebrospinal fluid of patients with epilepsy.

The lumbar cerebrospinal fluid (CSF) gamma-aminobutyric acid (GABA) levels were measured in 27 patients with epilepsy, another three epileptic patients with status epilepticus and three epileptic patients with chronic cerebellar ataxia. The mean lumbar CSF GABA levels of the 27 patients with epilepsy were not significantly different from those of normal controls. Six of these 27 patients who had daily partial complex and partial motor seizures showed significantly low CSF GABA levels as did the six other patients, three each with status epilepticus and chronic cerebellar ataxia. These findings suggest that some epileptic patients have impaired brain GABAergic neurons.

Clinical and biochemical effects of calcium-hopantenate on neuroleptics-induced tardive dyskinesia.

Calcium-hopantenate (HOPA), a derivative of GABA, was administered to 9 psychiatric patients with neuroleptics-induced tardive dyskinesia. In a clinical study, involuntary movements have improved significantly after a 4-8-week medication. Although there was no correlation between the cerebrospinal fluid (CSF) levels of HOPA, GABA, HVA or clinical response, the CSF HOPA levels significantly correlated with changes in the CSF GABA levels. These results suggest that HOPA alleviates the symptoms of tardive dyskinesia being mediated by the central GABAergic mechanisms.

Elevation of γ-aminobutyric acid in human brain may increase dopaminergic neuronal function

Studies in experimental animals have yielded conflicting findings as to the influence of γ-aminobutyric acid (GABA) on the activity of nigrostriatal and mesolimbic dopaminergic neurons. We measured cerebrospinal fluid (CSF) concentrations of GABA and homovanillic acid (HVA) in 19 patients before and during treatment with isoniazid. CSF GABA concentrations increased markedly during isoniazid administration, presumably reflecting increases in brain GABA content. At the same time, HVA concentrations in CSF rose significantly. The net effect of elevating brain GABA content in humans appears to be to increase dopamine release from dopaminergic neurons.

Free and conjugated GABA in human cerebrospinal fluid: Effect of degenerative neurologic diseases and isoniazid

γ-Aminobutyric acid (GABA) was measured in CSF as such and following acid hydrolysis by the ion-exchange/fluorometric method. The conjugated GABA level was obtained by subtracting the free GABA level from the total GABA level. Results showed that at room temperature, while the free GABA level increased, the level of conjugated GABA decreased in a linear fashion during the first 24 h ( r = −0.974; P < 0.001). Aging and CSF conjugated GABA levels were inversely correlated ( r = −0.613; P < 0.05). Unlike free GABA levels, the levels of conjugated GABA were not altered in Huntington's disease, Parkinson's disease, cerebellar ataxias, dementias, epilepsy and multiple sclerosis compared to controls. In patients with Huntington's disease, on administration of isoniazid at 900 mg/day, along with pyridoxine at 100 mg/day, a 4-fold increase of both free ( P < 0.005) and conjugated GABA ( P < 0.0025) was seen. The results indicate that while total GABAergic peptides are not altered in several of the neurologic disease studied, drugs such as isoniazid and/or pyridoxine can significantly elevate both free and conjugated GABA levels in human CSF.

Cerebrospinal fluid GABA levels in children with infantile spasms.

The mean CSF GABA level in 22 children with infantile spasms was significantly lower than in 35 controls. There was no significant difference between the CSF GABA levels in untreated children and those treated with anticonvulsants, or between uncontrolled and temporarily controlled patients. After treatment with ACTH, CSF GABA levels were lower than before treatment, and seizures disappeared. Brain GABAergic neuronal function may be disturbed in children with infantile spasms, but the decreased CSF GABA level does not directly correlate with the seizures of infantile spasms.

Cerebrospinal fluid GABA as an index of brain GABA activity.

Cerebrospinal fluid GABA as an index of brain GABA activity.