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PubMed2001

Effect of alkylpyrazine derivatives on the duration of pentobarbital-induced sleep, picrotoxicin-induced convulsion and gamma-aminobutyric acid (GABA) levels in the mouse brain.

The effect of alkylpyrazine derivatives on pentobarbital-induced sleeping time, picrotoxicin-induced convulsion and gamma-aminobutyric acid (GABA) levels in mouse brain were studied. The duration of pentobarbital-induced sleep in mice was dose-dependently increased by 2,5-dimethylpyrazine (DMP). The duration of pentobarbital-induced sleep was also increased by an administration route of intracerebroventricular injection. Sleep duration was also increased by the administration of isomers of DMP, 2-chloro-3,6-dimethylpyrazine (DMP-Cl) and 2-fluoro-3,6-dimethylpyrazine (DMP-F), but 3,6-dimethylpyrazine-2-thiol (DMP-SH) did not affect sleep duration. The interval until the appearance of picrotoxicin-induced convulsion was prolonged by DMP and DMP-Cl. Increased sleep duration was obtained by administering DMP in combination with aminooxyacetic acid (AOAA) and diazepam compared to a single injection. The interval until convulsion due to picrotoxin was also prolonged by the administration of DMP combined with diazepam and valproic acid (VPA). The interval until the appearance of bicuculline-induced convulsion was also prolonged by pretreatment with DMP. The GABA level in mouse brain was increased by the administration of AOAA, VPA, DMP and DMP-Cl. These results suggest that DMP and other derivatives may strengthen the GABAnergic system in the brain.

Aminooxyacetic Acid↗
PubMed1998

The effect of intrathecal gabapentin and 3-isobutyl gamma-aminobutyric acid on the hyperalgesia observed after thermal injury in the rat.

UNLABELLED: Gabapentin is an anticonvulsant that may represent a novel class of drugs, which has novel spinal antihyperalgesic activity. We sought to characterize this spinal action in a model of hyperalgesia that involves a mild thermal injury to the hind paw of the rat. Rats were prepared with chronic spinal catheters. Under brief halothane anesthesia, a thermal injury was induced by applying the left hind paw to a thermal surface (52.5 degrees C) for 45 s. This exposure results in mild erythema but no blistering. Thermal escape latency of the hind paw was determined using an underglass thermal stimulus with which response latencies of the injured and uninjured (normal) paw could be obtained. Thirty minutes after thermal injury, the response latency in all groups decreased from 10-12 s to 5-7 s. Uninjured paw withdrawal latency was unaltered. The intrathecal injection of gabapentin (30-300 microg) produced a dose-dependent reversal of the hyperalgesia but had no effect on the response latency of the normal hind paw, even at the largest doses. A similar reversal was observed after intrathecal delivery of the structural analog S(+)-3-isobutyl gamma-aminobutyric acid (GABA) (30-300 microg), but not after the largest dose of its stereoisomer R(-)-3-isobutyl GABA (300 microg). The effects of both intrathecal gabapentin and S(+)-3-isobutyl GABA were reversed by intrathecal D-serine, but not L-serine. All effects were observed at doses that had no significant effect on motor function. These observations, in conjunction with the accumulating data on binding and transmitter release, emphasize that these gabapentinoids can selectively modulate the facilitation of spinal nociceptive processing otherwise generated by persistent small afferent input generated by tissue injury. IMPLICATIONS: Gabapentin and its analog, 3-isobutyl gamma-aminobutyric acid, given spinally, produce a dose-dependent, D-serine-sensitive reversal of the thermal hyperalgesia evoked by mild thermal injury.

Acetates↗
PubMed2000

gamma-aminobutyric Acid(A) (GABA(A)) agonist 4,5,6, 7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol persistently increases sleep maintenance and intensity during chronic administration to rats.

Many hypnotics, such as benzodiazepines, are agonistic modulators of gamma-aminobutyric acid(A) (GABA(A)) receptors. Such compounds increase the ability to fall and stay asleep, but inhibit rapid-eye movement (REM) sleep and deep non-REM sleep. However, tolerance to their hypnotic action may develop rapidly. Previous findings in rats and humans demonstrate that the gamma-aminobutyric acid(A) agonist 4, 5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (THIP) promotes deep non-REM sleep and increases non-REM sleep continuity. To investigate the effects of repeated administration, we assessed sleep in rats before, during, and after chronic dosing of THIP (3 mg/kg, once daily for 5 days; n = 9) or of placebo (n = 8). The substances were administered i.p. at the onset of darkness. The electroencephalogram (EEG) and electromyogram were recorded during the first 6 h after injection. During baseline recording, the placebo and the THIP group exhibited similar sleep patterns. After the first THIP injection, rats displayed more non-REM sleep, longer non-REM episodes, and higher levels of slow wave activity in the EEG within non-REM sleep than the placebo group rats. The effects were sustained during all treatment days. REM sleep was not affected. After drug withdrawal, the sleep patterns of the THIP and the placebo group were practically identical again. These observations suggest that THIP does not rapidly produce tolerance toward its sleep effects and abrupt drug withdrawal may not be associated with sleep disturbances. These findings confirm and extend the existing information suggesting that THIP may be promising for treatment of insomnia.

Animals↗
PubMed1999

Activity-dependent enhancement of hyperpolarizing and depolarizing gamma-aminobutyric acid (GABA) synaptic responses following inhibition of GABA uptake by tiagabine.

The effects of the 7-aminobutyric acid (GABA) uptake blocker tiagabine on isolated inhibitory postsynaptic potentials (IPSPs) were examined in CA1 pyramidal cells of the rat hippocampal slice preparation. The IPSPs were elicited by either single stimuli or by high frequency (100 Hz, 200 ms) stimulation (HFS) of inhibitory interneurons. Bath applied tiagabine (20 microM) produced little or no increase in the amplitude of IPSPs evoked by low (30-50 microA) or high (200-400 microA) intensity single stimuli. Only the duration of IPSPs evoked by high intensity stimuli was substantially prolonged by tiagabine, the time integral of the hyperpolarizing response being increased 3.2-fold. HFS elicited much larger fast and slow IPSPs than a single stimulus. In addition, with increments in the intensity (80-550 microA) of HFS, a GABA(A) receptor-mediated depolarizing response of progressively larger amplitude appeared between, and overlapped with, the fast and slow hyperpolarizing components of the IPSP. Tiagabine application markedly increased the GABA-mediated responses evoked by both low and high intensity HFS. Increasing the intensity of HFS enhanced the drug effect. Thus, measurements of the time integral of evoked responses showed that with weak (60 microA) HFS, tiagabine caused a 3.6-fold increase in the area of hyperpolarization while, in contrast, with strong (530 microA) HFS, tiagabine produced a 13.5-fold increase in the depolarizing actions of GABA. Our results suggest that tiagabine, a therapeutically effective anticonvulsant, may paradoxically increase, through a GABA(A) receptor-mediated mechanism, neuronal depolarization during the high frequency discharge of neurons involved in epileptiform activity.

Animals↗
PubMed1994

Pharmacological discrimination between gamma-aminobutyric acid type B receptors regulating cholecystokinin and somatostatin release from rat neocortex synaptosomes.

The gamma-aminobutyric acid (GABA)B receptors modulating the depolarization-evoked release of somatostatin (SRIF) or cholecystokinin (CCK) from superfused rat cerebrocortical synaptosomes have been characterized pharmacologically. GABA inhibited the 15 mM KCl-evoked overflow of both SRIF and CCK; the EC50 values were 1.3 microM and 1.4 microM, respectively. The GABAB receptor agonist (-)-baclofen also diminished the release of SRIF (EC50 = 1.9 microM) and CCK (EC50 = 2.6 microM). The novel compound CGP 47656, a highly selective GABAB receptor ligand, inhibited the release of SRIF, with its affinity and efficacy being similar to those of GABA or (-)-baclofen; however, the compound was unable to affect CCK release even when tested at 300 microM. The GABAB receptor antagonist phaclofen prevented, with identical affinities, the effects of (-)-baclofen on SRIF (pKb = 4.9) and CCK (pKb = 4.8) release. The same was true for CGP 35348, another GABAB receptor antagonist, which blocked (-)-baclofen with a pKb value of 6.1 at both the GABAB receptors regulating SRIF and CCK release. The effects of (-)-baclofen were also counteracted by the novel GABAB receptor antagonist CGP 52432. However, the affinity of the drug at the GABAB receptors modulating SRIF release (pKb = 6.2) was about 30-fold lower than that at the receptors regulating CCK release (pKb = 7.6). The data suggest that the GABAB receptors situated on nerve terminals releasing SRIF and CCK display pharmacological heterogeneity and may represent different subtypes of GABAB receptors.

Animals↗
PubMed1981

Possible inhibitory influence of gamma-aminobutyric acid on growth hormone secretion in the rat.

Increasing the levels of endogenous gamma-aminobutyric acid (GABA) by treating rats with GABA-transaminase inhibitors (ethanolamine-O-sulphate and gamma acetylenic GABA) resulted in a decrease in plasma levels of GH. Diminishing GABAergic activity by inhibiting GABA synthesis with 3-mercaptopropionic acid or by blocking GABA receptors with bicuculline increased plasma concentration of GH. The presence of GABA was without effect on the basal, somatostatin-inhibited or high K+-stimulated secretion of GH by hemipituitary glands in vitro. The results suggest that GABA inhibits secretion of GH under the given experimental circumstances.

4-Aminobutyrate Transaminase↗
PubMed2003

Induced panic attacks shift gamma-aminobutyric acid type A receptor modulatory neuroactive steroid composition in patients with panic disorder: preliminary results.

BACKGROUND: Certain metabolites of progesterone such as 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP; allopregnanolone) and 3alpha,5beta-THP (pregnanolone) are potent, positive allosteric modulators of gamma-aminobutyric acid type A receptors. Although animal studies suggest anxiolytic properties of these endogenous modulators of central nervous excitability, no clinical data indicate whether they are also involved in the pathophysiology of anxiety disorders and panic attacks. METHODS: We quantified the concentrations of 3alpha,5alpha-THP, 3alpha,5beta-THP, the isomer 3beta,5alpha-THP, and their precursors in the plasma of 10 patients with panic disorder and matched control subjects during panic attacks induced by means of sodium lactate and cholecystokinin tetrapeptide administration, using a highly sensitive gas chromatography-mass spectrometry analysis. RESULTS: Panic attacks induced by sodium lactate and cholecystokinin tetrapeptide in patients with panic disorder were accompanied by pronounced decreases in the concentrations of 3alpha,5alpha-THP and 3alpha,5beta-THP and a concomitant increase in the concentrations of the functional antagonistic isomer 3beta,5alpha-THP, findings that are compatible with a decreased gamma-aminobutyric acid-ergic tone. No changes in neuroactive steroid concentrations were observed after placebo administration in patients with panic disorder or after placebo, sodium lactate, or cholecystokinin tetrapeptide administration in controls. CONCLUSIONS: The association between changes in plasma neuroactive steroid concentrations and experimentally induced panic attacks and the well-documented pharmacological properties of these compounds as gamma-aminobutyric acid type A receptor modulators suggest that neuroactive steroids may play a role in the pathophysiology of panic attacks in patients with panic disorder.

Adult↗
PubMed1994

Involvement of gamma-aminobutyric acid in the stimulatory effect of metoclopramide on gastrointestinal motility.

The involvement of gamma-aminobutyric acid (GABA) in the mechanism of action of metoclopramide (MCP) on gastrointestinal (GI) tract was investigated employing guinea-pig myenteric plexus longitudinal muscle preparations. MCP induced a concentration dependent enhancement of electrically induced twitch responses of the myenteric plexus and this effect was further intensified by arecaidine and L-2, 4-diaminobutyric acid (L-DABA; GABA uptake inhibitors) and ethylenediamine (EDA; GABA releasing agent). The facilitatory effect of MCP was reduced by 3-mercaptopropionic acid (3-MPA; GABA synthesis and release inhibitor) and after GABA desensitization but remained unchanged after bicuculline methiodide, a specific GABA receptor antagonist. The MCP induced contraction of the unstimulated preparation was also reduced after GABA desensitization and EDA without affecting responses to exogenous acetylcholine (ACh). The study indicates that GABA plays a role in the facilitatory effect of MCP on both stimulated and unstimulated preparations of guinea pig myenteric plexus.

Aminobutyrates↗
PubMed1983

Brain receptor binding of analogues of gamma-aminobutyric acid (GABA).

This paper reports the synthesis of some 4-(beta-hydroxyalkyl)-gamma-aminobutyric acid analogues (I a-h). The compounds were biologically tested as inhibitors of 3H-GABA binding to rat cortex synaptosomal membranes. The most potent compounds were (I c,d) which exhibited a linear alkyl chain at C4.

Animals↗
PubMed1982

Presence of gamma-aminobutyric acid and glutamic acid decarboxylase in Auerbach's plexus of cat colon.

Regional distributions of endogenous gamma-aminobutyric acid (GABA) and ganglion cells in Auerbach's plexus were studied in the gastrointestinal tract of cats. GABA was determined by enzymatic and fluorometric assay. There was a positive correlation between the GABA content and the number of cells in this plexus. We analyzed the precise localization of GABA and glutamic acid-decarboxylase (GAD) in individual layers, mucosa, circular and longitudinal muscles and Auerbach's plexus, from freeze-dried sections of cat colon by the enzymatic cycling method. Both GABA contents and GAD activity in Auerbach's plexus were highest in all 4 layers. Thus, the possibility that GABA is synthesized and localized within Auerbach's plexus has to be considered.

Animals↗
PubMed1983

Stress-induced alterations in metabolism of gamma-aminobutyric acid in rat brain.

The effect of a stressful manipulation on the metabolism of gamma-aminobutyric acid (GABA) in the rat brain was studied. Application of an immobilized stress to animals induced a significant increase in the striatal and hypothalamic GABA contents without affecting those in other central structures examined. It was also found that the increase in striatal GABA level preceded that in the hypothalamus. This increase in steady-state levels of GABA in the striatum and hypothalamus disappeared at 12 h after the termination of the application of stress for 3 h, which exhibited a maximal stimulatory action on the GABA contents in both central areas. The activity of L-glutamic acid decarboxylase was found to be significantly elevated in the striatum and hypothalamus following the stress application with a concomitant decrease in the content of L-glutamic acid, which is converted to GABA by the catalytic action of the latter enzyme. The in vivo turnover of GABA in the brain was estimated by taking advantages of the postmortem accumulation of GABA following decapitation and of the selective inhibitory action of a low dose of aminooxyacetic acid on the GABA degrading system, respectively. Analysis using these two different methods revealed that the cerebral turnover of GABA in vivo was not significantly altered under stressful situations despite of the increase in its steady-state level. These results suggest that central GABA system may respond to the input of painful stimuli resulting from the application of a severe physical and psychological stressor, in addition to the well-known functional alterations in catecholamine neurons. The functional significance of these alterations in the central GABA neurons is also discussed.

Animals↗
PubMed1973

Effect of inhibitors of -aminobutyrate aminotransferase on the accumulation of 3H- -aminobutyric acid by the retina.

1. Rat retinae pre-incubated and incubated at 37 degrees C in media containing amino-oxyacetic acid (AOAA) (0.1 muM to 1 mM) accumulated more (3)H-gamma-aminobutyric acid ((3)H-GABA) than control retinae incubated in the absence of AOAA. This increased accumulation of (3)H-GABA by tissue exposed to AOAA was not apparent at short incubation times (0-20 min), but became significant after incubations of 30 min, and maximal after incubation for 60 minutes.2. At a concentration of 10 muM, AOAA did not alter the apparent K(m) for (3)H-GABA uptake or V(max) for either the low or the high affinity GABA uptake systems present in retina.3. The potentiation of (3)H-GABA accumulation produced by AOAA appeared to parallel the inhibitory effect of this compound on 2-oxoglutarate-4-aminobutyrate aminotransferase (GABA-T). Similarly, hydrazinopropionic acid inhibited retinal GABA-T and potentiated the accumulation of (3)H-GABA, but hydroxylamine and thiosemicarbazide which did not affect GABA-T, were also without effect on the retinal accumulation of (3)H-GABA.4. In vitro incubation with AOAA did not increase the endogenous levels of GABA or other amino acids in the retina.5. AOAA did not significantly increase the retinal accumulation of radioactive L-glutamate, L-glutamine, taurine, glycine, alpha-aminoisobutyrate or dopamine: the accumulation of L-aspartate was increased by approximately 30%.6. The inhibition of retinal GABA-T by AOAA was time-dependent and was not reversed by pyridoxal-5'-phosphate or by repeated washing of the tissue with fresh medium.7. AOAA also inhibited glutamate decarboxylase (GAD) in retinae incubated in vitro. This inhibitory effect was partially reversed by pyridoxal-5'-phosphate.8. Efflux of radioactivity from the retina was strikingly reduced in the presence of AOAA at concentrations sufficient to inhibit GABA-T by 100%.9. These findings suggest that AOAA potentiates the accumulation of (3)H-GABA by isolated retina, not by increasing the exchange of (3)H-GABA with the endogenous GABA pools, but by reducing the metabolism of the amino acid and hence reducing the loss of radioactivity from the tissue in the form of tritiated metabolites.

Acetates↗
PubMed1978

Gamma-aminobutyric acid (GABA) in the CSF of schizophrenic patients before and after neuroleptic treatment.

Gamma-aminobutyric acid (GABA) levels in the CSF were measured in 9 normal individuals, 17 drug-free schizophrenic patients and 10 of these same schizophrenic patients after neuroleptic treatment. There was no significant difference between CSF level of GABA in the control group compared to those in schizophrenic patients; however, 6 of the 7 lowest GABA levels were from schizophrenic patients. There was a significant decline of 12 per cent in mean GABA levels in the CSF after a mean of two months of neuroleptic treatment.

Adult↗
PubMed1983

Effects of glial uptake and desensitization on the activity of gamma-aminobutyric acid (GABA) and its analogs at the cat dorsal root ganglion.

Responses to gamma-aminobutyric acid (GABA) and 13 structurally related analogs were recorded under voltage clamp conditions from isolated cat dorsal root ganglia (DRG). All of the analogs were applied by superfusion at a concentration of 1 mM. Of the 13 structurally related compounds, only muscimol was more effective than GABA in its ability to produce an inward current at the DRG membrane. Complete (1 microM-10 mM) concentration-response relationships were obtained for muscimol, GABA and 3-aminopropane sulfonic acid. Muscimol was most potent at all concentrations, however, the relative order of potency for GABA and 3-aminopropane sulfonic acid was concentration-dependent. In addition to producing differences in their peak currents, the various agonists demonstrated different time courses in their respective rates of decay. When the glial uptake system for GABA in cat DRG was inhibited by substituting lithium for sodium or by the addition of 1 mM nipecotic acid to the normal Krebs' solution, the membrane responses to GABA, SL-75102 and isoguvacine were facilitated, whereas the responses induced by the other analogs remained unchanged. Although the process of uptake altered significantly the decay phase of GABA responses when GABA was applied by superfusion or by iontophoresis, nipecotic acid inhibition of uptake did not appear to affect GABA-induced desensitization that was apparent when GABA was applied either by superfusion or with long iontophoretic pulses. GABA and all of the analogs in this study demonstrated cross-desensitization, each being able to depress the action of the other. Our results suggest that all of the active GABA analogs appear to be acting at a similar GABA receptor on cat DRG and this GABA receptor is coupled to a chloride channel.

Animals↗
PubMed1981

Effect of freezing on gamma-aminobutyric acid levels in human cerebrospinal fluid.

Using a radioreceptor assay, the concentration of gamma-aminobutyric acid (GABA) in human cerebrospinal fluid (CSF) was found to be elevated significantly following a single deep-freeze to --70 degrees C and thaw. Mean CSF GABA (+/- SD) in unfrozen CSF was 173 +/0 73 pmol/ml (n = 24). After a single deep-freeze, the mean level was 243 +/- 106 pmol/ml (p less than 0.02). Subsequent freeze-thaw cycles resulted in further irregular and unpredictable elevations in CSF GABA. Mean level after two freezes was 379 +/- 125 pmol/ml and after three freezes 654 +/- 411 pmol/ml. These changes could result in the incorrect interpretation of results in patients suffering from neurological diseases.

Adult↗
PubMed1985

An unusual effect of gamma-aminobutyric acid on synaptic transmission of frog tectal neurones in vitro.

Bath-applied gamma-aminobutyric acid (GABA) enhanced, in a dose-dependent fashion, the amplitude of optic nerve-evoked monosynaptic excitatory responses of the frog optic tectum superfused in vitro at 7 degrees C. Muscimol was more potent than GABA in eliciting similar effects. GABA-induced responses were antagonized by picrotoxin and were insensitive to bicuculline or strychnine. Raising the bath temperature to 20 degrees C reduced the potency of GABA on these preparations. No significant effect of GABA on the compound action potential of the whole optic nerve was found. These data indicate that GABA can amplify visual inputs to the tectum through bicuculline-insensitive mechanisms.

Action Potentials↗