Low Gamma-aminobutyric Acid Levels Research Articles

Frontal lobe GABA levels in cocaine dependence: a two-dimensional, J-resolved magnetic resonance spectroscopy study

Non-invasive measures of brain gamma-aminobutyric acid (GABA) concentrations may be especially useful in the identification of cocaine-related changes in brain chemistry that can be used to guide the development of future treatments for cocaine-dependent persons. This study assessed whether brain GABA levels in cocaine-dependent subjects with and without an alcohol disorder differ from GABA levels in healthy comparison subjects. Two-dimensional, proton magnetic resonance spectroscopy was used to determine GABA levels in the left prefrontal lobe of cocaine-dependent subjects ( N=35) recruited from a National Institute on Drug Abuse (NIDA)-sponsored treatment trial of cocaine dependence and a comparison group ( N=20). At treatment baseline, mean GABA concentrations were 0.93±0.27 mM/kg in cocaine-dependent subjects and 1.32±0.44 mM/kg in the comparison sample ( t [d.f.=53]=3.65, P<0.001). Cocaine-dependent subjects with a history of a co-morbid alcohol disorder ( N=23) had significantly lower baseline GABA levels (0.87 mM/kg) ( t [d.f.=41]=4.31, P<0.001) than the comparison group. However, cocaine-dependent subjects without an alcohol disorder ( N=12) also had lower GABA levels (1.04 mM/kg) than the comparison subjects ( t [d.f.=30]=2.09, P=0.045), suggesting that cocaine dependence alone can decrease GABA levels.

Low posttrauma GABA plasma levels as a predictive factor in the development of acute posttraumatic stress disorder

Background Gamma amino-butyric acid (GABA) regulates the intensity and the duration of the central hyperadrenergic response in times of high stress and has been negatively associated with anxiety, depression, and sleep problems. We hypothesized that individuals with low plasma GABA levels may be more prone to develop posttraumatic stress disorder (PTSD) in the aftermath of trauma exposure. Methods To test this hypothesis, we measured plasma GABA levels in a population of 108 road traffic accident victims on arrival at a traumatology department and assessed them for PTSD 6 weeks later. Results The mean GABA level (nmol/mL) in the PTSD group ( n = 55; M = .20; SD = .08) was significantly lower compared with members of the trauma-exposed group who did not develop PTSD [n = 17; M = .30; SD = .09), t(70) = 3.94, p = .0002]. Conclusions Provided that GABA levels in the brain are genetically predetermined, our results would suggest that individuals with low plasma GABA levels are premorbidly more vulnerable to stress-related disorders such as acute PTSD. If replicated, plasma GABA levels measured in the aftermath of trauma exposure might help to identify individuals at high risk for developing PTSD.

GABAergic dysfunction in mood disorders.

The authors review the available literature on the preclinical and clinical studies involving GABAergic neurotransmission in mood disorders. Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter present almost exclusively in the central nervous system (CNS), distributed across almost all brain regions, and expressed in interneurons modulating local circuits. The role of GABAergic dysfunction in mood disorders was first proposed 20 years ago. Preclinical studies have suggested that GABA levels may be decreased in animal models of depression, and clinical studies reported low plasma and CSF GABA levels in mood disorder patients. Also, antidepressants, mood stabilizers, electroconvulsive therapy, and GABA agonists have been shown to reverse the depression-like behavior in animal models and to be effective in unipolar and bipolar patients by increasing brain GABAergic activity. The hypothesis of reduced GABAergic activity in mood disorders may complement the monoaminergic and serotonergic theories, proposing that the balance between multiple neurotransmitter systems may be altered in these disorders. However, low GABAergic cortical function may probably be a feature of a subset of mood disorder patients, representing a genetic susceptibility. In this paper, we discuss the status of GABAergic hypothesis of mood disorders and suggest possible directions for future preclinical and clinical research in this area.

Plasma GABA levels correlate with aggressiveness in relatives of patients with unipolar depressive disorder

Plasma gamma-aminobutyric acid (GABA) levels are decreased in some patients with depression, mania and alcoholism. Medications which increase plasma GABA improve symptoms of mood disorders and can decrease aggression. We examined the relationship between plasma GABA and aggressiveness on the Buss-Durkee Hostility Inventory in 77 psychiatrically healthy adults. In subjects selected for having a first-degree relative with primary unipolar depressive disorder (FH+, n=33), plasma GABA was negatively correlated with aggressiveness (beta=−0.338, P=0.036), as was age (beta=−0.483, P=0.005). A relationship between plasma GABA levels and aggressiveness was not observed in subjects with no such family history (FH−, n=44). Moreover, FH+ subjects had significantly lower plasma GABA concentrations than FH− subjects. These data suggest that low GABA levels may correlate with some aspects of aggressiveness and may be genetically regulated.

Low taurine, gamma-aminobutyric acid and carnosine levels in plasma of diabetic pregnant rats: consequences for the offspring.

Gestational diabetes compromises fetal development and induces a diabetogenic effect in the offspring, including the development of gestational diabetes and the transmission of the effect to the next generation. Changes are not limited to glucose and insulin metabolism, and appear to be modulated by alterations at the hypothalamo-hypophyseal axis. In the present work, serum concentrations are given for the non-protein amino-acids taurine and gamma-aminobutyric acid (GABA), both neurotransmitters essential for normal brain development, and for the endogenous neuroprotector carnosine, a known anti-oxydans. Taurine levels are significantly below normal values in mildly diabetic mothers, in their fetal and adult offspring, virgin and pregnant, and in the fetuses of these pregnant offspring. GABA and carnosine levels are at the limit of detection in the diabetic mothers and their offspring at every stage. It is concluded that the low taurine, GABA and carnosine levels in diabetic mothers and their fetuses might compromise the normal structural and functional development of the fetal brain. When adult, these offspring present a deficiency of the circulating levels of these neurotransmitters involved in the hypothalamo-hypophyseal regulation of insulin secretion. This might contribute to the development of impaired glucose tolerance and gestational diabetes, thereby transmitting the effect to the next generation.

Synaptic localization of GABAA receptor subunits in the striatum of the rat

The inhibitory amino acid gamma-aminobutyric acid (GABA) is widely distributed in the basal ganglia. It plays a critical role in the functioning of the striatum as it is the transmitter of projection neurons and sub-populations of interneurons, as well as afferents from the globus pallidus. Some of the factors controlling GABA transmission are the type(s) of GABA receptor expressed at the site of transmission, their subunit composition, and their location in relation to GABA release sites. To address these issues, we examined the sub-cellular localization of subunits of the GABA(A) receptor in the striatum of the rat. Sections of freeze-substituted, Lowicryl-embedded striatum were immunolabelled by the post-embedding immunogold technique with antibodies specific for subunits of the GABA(A) receptor. Immunolabelling for alpha1, beta2/3, and gamma2 GABA(A) receptor subunits was primarily located at symmetrical synapses on perikarya, dendrites, and spines. Quantitative analysis of the distribution of immunolabelling for the beta2/3 subunits revealed that the majority of membrane associated immunogold particles were at synapses and that, on average for the whole population, they were evenly distributed across the synapse. Double labelling for the beta2/3 subunits and for GABA itself revealed that receptor-positive synapses were formed by at least two populations of terminals. One population (59.3%) of terminals forming receptor-positive synapses was positive for GABA, whereas the other (40.7%) had low or undetectable levels of GABA. Furthermore, the post-synaptic neurons were characterised on neurochemical and morphological grounds as both medium spiny neurons and GABA interneurons. Triple immunolabelling revealed the co-localization of alpha1, beta2/3, and gamma2 subunits at some symmetrical axodendritic synapse. It is concluded that fast GABA(A)-mediated transmission occurs primarily at symmetrical synapses within the striatum, that the populations of boutons giving rise to receptor-positive synapses are heterogeneous, and that previously reported co-existence of different subunits of the GABA(A) receptor at the cellular level also occurs at the level of individual synapses.

Low brain GABA level is associated with poor seizure control.

Low gamma-aminobutyric acid (GABA) concentrations in the cerebrospinal fluid are seen in a variety of epileptic syndromes. Low GABA levels outside of the epileptic focus may facilitate spread of discharges beyond the focus. In vivo measurements of GABA were made by 1H spectroscopy using a 2.1-T magnetic resonance imager-spectrometer and an 8-cm surface coil to measure a 14-cm3 volume in the occipital lobe. Patients with complex partial seizures had lower GABA levels (1.03 mmol/kg of brain; 95% confidence interval [CI], 0.95-1.12; n = 28; p < 0.02) than did subjects without epilepsy (1.18; 95% CI, 1.13-1.24; n = 19). There was a significant association between low GABA levels and recent seizures (correlation coefficient of 0.548, p < 0.01, df of 32). Conversely, patients with well-controlled seizures had higher brain GABA levels than did patients with recent seizures. Patients with seizures within a day of the measurement had lower GABA levels (0.92 mmol/kg; 95% CI, 0.78-1.06; n = 7) than did patients who were seizure free for 5 years or longer (1.28; 95% CI, 1.09-1.47; n = 4). Poor seizure control is associated with low brain GABA levels.

Stability of plasma GABA at four-year follow-up in patients with primary unipolar depression

The biology of mood disorders involves gamma-aminobutyric acid (GABA), a neurotransmitter whose levels in plasma likely reflect brain GABA activity. Previous research has shown that a subset of patients with primary unipolar major depression have low plasma GABA levels, which parallels findings from studies of cerebrospinal fluid. We have completed a 4-year follow-up on 46 male patients with primary unipolar depression. Plasma levels of GABA were stable over this time. For the group, mean plasma GABA levels on follow-up did not change significantly from entry levels. Plasma GABA levels measured on follow-up were significantly (p < .001) correlated with entry levels. Patients with low plasma GABA levels (< 100 pmol/ml) on entry into the study were likely to remain low on follow-up, and patients with plasma GABA levels in the control range (> or = 100 pmol/ml) at entry similarly remained in this category (chi 2 = 7.23, p = .007). This was true whether or not the patient had recovered from depression on follow-up. Levels of plasma GABA did not significantly correlate with severity of depression at either entry (p = .40) or follow-up (p = .52), nor was there a significant correlation between change in plasma GABA and change in the 17-item Hamilton Depression Rating Scale score from entry to follow-up (p = .89). These data are consistent with the notion that plasma GABA is independent of clinical state in patients with primary unipolar depression. Low plasma GABA may be a trait marker of illness in a subset of patients with mood disorder.

Dominantly inherited apathy, central hypoventilation, and Parkinson's syndrome

We describe 2 new patients from a family in which 10 persons in 3 successive generations had a dominant neuropsychiatric disorder characterized by apathy, central hypoventilation, and parkinsonism. Neuropathologically, both patients showed severe neuronal loss and reactive gliosis in the substantia nigra. Neurochemical studies showed a marked depletion of dopamine in substantia nigra, putamen, and caudate nucleus, as well as reduction in serotonin content in the substantia nigra. Glutamate contents were low in frontal cortex and thalamus, and gamma-aminobutyric acid (GABA) contents were low in thalamus and substantia nigra of both patients. In addition, phosphoethanolamine contents were reduced in all brain regions of both patients, especially in the substantia nigra. One patient with severe symptoms had low levels of homovanillic acid, 5-hydroxyindoleacetic acid, and GABA in his CSF repeatedly for 3 years before death (aged 58), while the 2nd patient died (aged 51) of an unrelated cause before developing any symptoms of the familial disorder. Because brain deficiencies of multiple neurotransmitters appear to be involved, this disorder is unlikely to respond to treatment; however, neurochemical studies of CSF may make presymptomatic diagnosis feasible.

GABA-Agonist Therapy for Alzheimerʼs Disease

Evidence suggesting a reduction of cerebral gamma-aminobutyric acid (GABA) neurons in Alzheimer's disease has been reported. To evaluate the possible contribution of GABA system dysfunction to the intellectual decline associated with this disorder, a controlled therapeutic trial of a potent and specific GABA agonist, THIP [4,5,6,7-tetrahydroisoxazolo(5,4,-c)pyridin-3-ol], was undertaken. Six Alzheimer patients with mild to moderately severe dementia and low spinal-fluid GABA levels received THIP at maximum individually tolerated dosage. No significant change in cognitive function could be discerned, despite attainment of dose levels that produced centrally mediated adverse effects similar to those of other GABA agonists. The results support the views that pharmacologic attempts to stimulate central GABA-mediated synaptic function may not confer therapeutic benefit to patients with Alzheimer's disease and that a GABA system deficit may not serve as a critical determinant of the dementia that characterizes this disorder.

CSF levels of gamma-aminobutyric acid in schizophrenia. Low values in recently ill patients.

gamma-Aminobutyric acid (GABA) levels in CSF were not significantly different in 30 drug-free schizophrenic patients and in 39 normal control subjects, because the control subjects were significantly older. Schizophrenic women had significantly lower levels than age-matched normal control women (less than 30 years). The GABA levels increased with duration of illness, number of hospitalizations, and months of hospitalizations, as well as with age. They correlated nonsignificantly with psychosis levels. After short-term pimozide treatment, GABA levels in all patients were raised, albeit nonsignificantly. The date suggest that low GABA levels may be observed only in the early years of the illness, particularly in female schizophrenic patients, and that these levels increase with time and with long-term neuroleptic treatment.

Study on hyperbaric oxygen-induced convulsion with particular reference to gamma-aminobutyric acid in synaptosomes.

When mice were exposed to 100% oxygen at a pressure of 6 atm. absolute, the animals suffered from severe convulsions. The content of gamma-aminobutyric acid (GABA) in synaptosomes was lower in the exposed animals than in unexposed ones. The exposure to high pressure oxygen produced a considerable reduction in GABA formation rate in synaptosomes, due to the inhibition of glutamic acid decarboxylase activity. Exposure to air at the same high pressure produced no reduction in the GABA levels in synaptosomes. The results support the view that low GABA levels in synaptosomes were involved in the etiology of the seizures.

Postnatal development of GABA-ergic neurons in the rabbit retina.

Uptake, synthesis, storage, and release of gamma-aminobutyric acid (GABA) are some of the characteristic properties of GABA-ergic neurons. In the present study, we have used these properties as physiological probes to follow the emergence and maturation of GABA-ergic neurons during postnatal development of the rabbit retina. There is autoradiographic, immunocytochemical, and pharmacological evidence that some amacrine cells and certain neurons in the ganglion cell layer probably use GABA as the neurotransmitter. These neurons take up GABA, contain the GABA-synthesizing enzyme L-glutamic acid decarboxylase (GAD, EC 4.1.1.15), and release the accumulated GABA by a CA++-dependent mechanism when depolorized with high extracellular K+ concentration. In this study, we show that certain neurons in the newborn retina already possess a specific mechanism for GABA uptake. The positions and numbers of these cells in the developing retina suggest that they will become GABA-ergic neurons in the adult retina. These putative GABA-ergic neurons are, however, probably immature at birth because newborn retinas contain only low levels of GABA and GAD. Additionally, there is relatively little K+-stimulated, Ca++-dependent release of (3H)-GABA from the newborn retinas. GABA concentrations and GAD activities in developing retinas increase steadily postnatally, reaching about 80% of the adult levels by day 9. The activities of the GABA-degrading enzyme, GABA-glutamate transaminase (GABA-T, EC 2.6.1.19), follow a similar pattern of maturation during retinal development. K+ stimulated GABA release, however, remains low until about day 6, and then increases dramatically from 20% to 85% of the adult level over the next 3 days. Taken together, our results indicate that in the rabbit retina, the commitment by certain neurons to use GABA as the transmitter is made prenatally. These neurons are immature at birth but are biochemically, physiologically, and probably functionally mature by about 9 days after birth.

Huntington's disease. Cerebrospinal fluid GABA levels in at-risk individuals.

Gamma-aminobutyric acid (GABA) was measured by the ion-exchange fluorometric method in CSF from 22 individuals at risk for Huntington's disease (HD), six individuals with HD, and five neurologically normal controls. The mean (+/- SD) GABA level in the specimens from patients with HD was 142 +/- 27 pmoles/ml, whereas that of the normal control specimens was 297 +/- 87 pmoles/ml. The mean GABA level of the specimens from the individuals at risk for HD was 209 +/- 79 pmoles/ml; however, nine of these were in the normal range with a mean value of 281 +/- 72 pmoles/ml, while the other 13 were below the normal range with a mean value of 159 +/- 27 pmoles/ml. The data indicate that low GABA levels in CSF are evident prior to the onset of symptoms of HD but a predictive value can only be determined by continued observation of the clinical course of these at-risk individuals.

Effect of 6-hydroxydopamine on brain and blood catecholamine, ammonia, and amino acid metabolism in rats subjected to high pressure oxygen induced convulsions.

Effects of 6-hydroxydopamine (6-OHDA) on rat brain and blood adrenaline (A), noradrenaline (NA), ammonia (NH3), gamma-aminobutyric acid (GABA), and amino acid metabolism prior to and after high pressure oxygen (OHP) induced convulsions have been studied. 6-OHDA reduces GABA and glutamate (Glu) rior to OHP exposure in rat brain so that the concentration is even equal to that seen in nondrugged animals after convulsion. Concomitantly, 6-OHDA reduces the latency of OHP-induced convulsion significantly, and increases brain NH3, glutamine, and asparagine significantly. Although 6-OHDA, in increasing dosage, elevates blood A concentration, convulsion produces a significant further increase in A. Blood NA was not significantly changed in drugged, convulsed animals and was much less than blood NA concentrations in nondrugged convulsed animals. Increasing doses of 6-OHDA also increase NH3 in the blood significantly and convulsion increases its concentration further. Latency of convulsion seems to be related to certain monoamine levels since in some drugged animals where A and total catecholamines are still reduced 96 h after the first of two doses of 6-OHDA, NA concentrations are recovered to relatively normal and the convulsion latency time is also increased although it remains significantly abbreviated from undrugged animals' convulsion time. Low brain GABA levels seem to be a prime effector of convulsive activity.

The genetics of sound induced seizure in inbred mice.

USCEPTIBILITY to audiogenic seizure in mice (HALL 1947; MILLER, GINSBURG and POTAS 1952) and rats (MAIER and GLASER 1940; MAIER 1943) has been shown to depend on the genotype of the animal. Different investigators have suggested different modes of inheritance for sound induced seizure including single-gene ( WITT and HALL 1949), two-gene ( GINSBURG and MILLER 1963) and polygenic modes of inheritance (FULLER and THOMPSON 1960). SCHLESINGER, BOGGAN and FREEDMAN (1965) have suggested that some of these discrepancies may depend on the particular phenotype used as an index of seizure, i.e., whether wild running, clonic, o r tonic seizures are used as indices. Another variable that could determine the outcome of such analyses is the exact age of the animal at the time of the seizure test, since age is known to be a major factor in determining susceptibility within a genotype (FULLER 1962; SCHLESINGER et al. 1965). The purpose of the experiments reported here is to investigate further the mode of inheritance of susceptibility to audiogenic seizure, using statistical methods developed by ELSTON (1966) and paying close attention to these two variables, i.e., to the phenotype used as an index and to the age of the animals. HUFF and HUFF (1962) and HUFF and FULLER (1964) have suggested that the dilute gene ( d ) might be involved in determining susceptibility to audiogenic seizure in the mouse. COLEMAN (1960) has postulated a mechanism that might account for the effects of the d locus on audiogenic seizures: dilute strains of mice are deficient in phenylalanine hydroxylase activity and excrete abnormal phenylalanine metabolites such as phenylacetic acid. Since phenylacetic acid inhibits decarboxylating reactions ( SANDLER and CLOSE 1959; HANSON 1958) d/d strains of mice might be expected to have low levels of gamma-aminobutyric acid, norepinephrine, and serotonin in the brain; and this might, in turn, account for the high incidence of seizures typically observed in these mice. SCHLESINGER et al. (1965), in an attempt to test this hypothesis, were able to show that DBA/2J mice, a d/d strain with high seizure-incidence at a certain age, had lower levels of norepinephrine and serotonin in brain than nonsusceptible mice, but only at an age which corresponded to the period of maximal seizure risk for the DBA/BJ mice. A secondary purpose of these experiments, therefore, was to test whether the d locus is indeed important in audiogenic seizure; for this purpose single-gene mutants on DBA/2J background were also used. (Breeding pairs of this mutant stock were kindly supplied by DR. E. RUSSELL, The Jackson Laboratory, Bar