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At least 19 recordsLinked to original sources
PubMed1994

Morphological correlates of altered neuronal activity in organotypic cerebellar cultures chronically exposed to anti-GABA agents.

Organotypic cerebellar cultures derived from newborn mice were chronically exposed to medium containing picrotoxin or bicuculline from explanation until they were recorded from extracellularly or fixed for morphological studies. Cultures exposed to anti-GABA agents for 13-18 days in vitro had decreased spontaneous cortical discharge rates when compared with sister control cultures and prolonged inhibitory responses to cortical stimulation. Electron microscopic examination of exposed cultures after 14-16 days in vitro revealed a hyperinnervation of Purkinje cell somata by inhibitory terminals predominantly of basket cell origin. The sprouted terminals penetrated otherwise intact Purkinje cell astrocytic sheaths. These changes represent a departure from the usual developmental pattern, a departure induced by exposure to anti-GABA agents that increased neuronal activity early in the development of the cerebellar circuitry in vitro. The precise signals that initiated the changes are unknown, but the altered development is most likely in response to increased Purkinje cell activity.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1996

The effect on maximal electroshock seizures induced by GABA agents and antiepileptic drugs microinfused into the nucleus reticularis pontis oralis.

The nucleus reticularis pontis oralis (RPO) is necessary for the expression of tonic hindlimb extension (THE) in maximal electroshock seizures (MES) of rats. Previous work in this laboratory has demonstrated that focal RPO microinfusion of NMDA antagonists inhibited THE while focal RPO microinfusion of NMDA induced convulsive activity similar to the audiogenic seizure response of rats. The purpose of the present study was to identify other receptors in the RPO that influence THE or induce convulsive activity. Bilateral microinfusion of bicuculline had no effect on the THE component of MES except when the bicuculline induced wild-running convulsions in which case the subsequent THE response to the MES stimulus was inhibited. The GABAergic agents muscimol, baclofen or 2-hydroxysaclofen neither altered the THE response nor induced convulsions. In addition, bilateral RPO microinfusion of the clinically effective antiepileptic drugs phenytoin, phenobarbital, valproate, ethosuximide or felbamate had no effect on the THE component of MES. These results indicate that the role of GABAergic receptors in the anticonvulsant activity mediated by the RPO is not prominent and that the RPO is unlikely to be the site of antiepileptic drug action in MES.

Animals↗
PubMed1991

Antinociceptive action of GABA-mimetic agent--N-phthaloyl GABA.

N-phthaloyl GABA (P-GABA), a nonselective GABA-ergic drug, showed positive analgesic response in four different models in mice, viz-tail immersion, tail clip, hot plate and writhing-induced by acetic acid. Antinociceptive ED50 (ip in mice) of P-GABA was lowest in tail immersion method (ED50 = 24.27, mg/kg). Though pethidine (10 mg/kg, ip) significantly potentiated the antinociceptive action of P-GABA (20 mg/kg, ip), pretreatment of naloxone (5 mg/kg, im) did not influence the same. Pretreatment with atropine (10 mg/kg, im), picrotoxin (0.08 mg/kg) and 3-mercaptopropionic acid (2 mg/kg) reduced the antinociceptive action of P-GABA significantly. But pretreatment with bicuculline (0.4 mg/kg), a specific GABA antagonist, did not reduce the antinociceptive action of P-GABA.

Analgesics↗
PubMed1999

The GABA paradox: multiple roles as metabolite, neurotransmitter, and neurodifferentiative agent.

GABA, which is present in the brain in large amounts, is distributed among distinctly different cellular pools, possibly reflecting its multiple functions as metabolite, neurotransmitter, and neurotrophin. Its metabolic enzymes also exhibit heterogeneity, because glutamate decarboxylase exists in two isoforms with different subcellular distribution and regulatory properties. Moreover, recent evidence points to a more pronounced regulatory role of the tricarboxylic acid cycle than hitherto anticipated in the biosynthetic machinery responsible for formation of GABA from glutamine. Additionally, GABAergic neurons may contain distinct populations of mitochondria having different turnover rates of the tricarboxylic acid cycle with different levels of association with GABA synthesis from 2-oxoglutarate via glutamate. These aspects are discussed in relation to the different functional roles of GABA and its prominent involvement in epileptogenic activity.

Animals↗
PubMed1988

GABA-ergic mechanisms in the anticonvulsive activity of newly synthesized barbiturates. II. Correlation of HB-7 with GABA-ergic agents.

The effect of the newly synthesized barbiturate HB-7 (2-hydroxylamino-5-ethyl-5-sec. pentylbarbituric acid) was investigated in experiments on mice in comparison with the effect of pentobarbital (PB), as well as their correlations with agents potentiating GABA-ergic transmission: GABA, aminooxyacetic acid, nipecotic acid, di-n-propylacetate (depakin, DPA), muscimol and baclofen. After the test applied (electroshock convulsions) 50 per cent of the animals in the control group had a tonic convulsion. HB-7 and all the other agents were administered in threshold doses. GABA-ergic agents were found to have a different effect on the anticonvulsive action of HB-7 and of pentobarbital. The anticonvulsive effect of HB-7 was potentiated when it was applied in combination with baclofen and AOAA, and partially with depakin (DPA). The anticonvulsive action of pentobarbital is potentiated when it is administered in combination with DPA and AOAA. The results obtained suggest that the GABA-ergic transmission in the brain participates in the anticonvulsive effects of the barbiturates investigated (HB-7 and PB).

Animals↗
PubMed1990

Antiulcer activity of N-phthaloyl GABA--a new GABA mimetic agent.

N-phthaloyl GABA (P. GABA) inhibited gastric ulceration induced by 3 hr restraint stress at 4 degrees C (CRS) in albino rats. Antiulcer activity of P. GABA was compared with sodium valproate and cimetidine. P. GABA, sodium valproate and cimetidine showed a dose dependent reduction of gastric ulceration. Pretreatment with GABA antagonists-bicuculline methiodide (0.5 mg/kg, im) or 3 mercaptopropionic acid (2 mg/kg, im) reversed the antiulcerogenic activity of both the drugs (P. GABA and sodium valproate). GABA antagonists as such did not induce gastric ulceration in normal rats.

3-Mercaptopropionic Acid↗
PubMed2002

Effect of intracerebroventricular injection of GABA receptor agents on morphine-induced antinociception in the formalin test.

In the present study, the effects of gamma-aminobutyric acid (GABA) receptor agonists and antagonists on antinociception induced by morphine in the formalin test were investigated in rats. Intraperitoneal (i.p.) injection of different doses of morphine (1, 3, 6 and 9 mg/kg) and intracerebroventricular (i.c.v.) injection of different doses of muscimol (0.5, 1 and 2 microg per rat) or baclofen (0.25, 0.5 and 1 microg per rat) induced a dose-related antinociception in the both first and second phases of the formalin test. The responses induced by muscimol or baclofen in both phases were reduced by bicuculline or CGP35348 [p-(3-aminopropyl)-p-diethoxymethyl-phosphinic acid], respectively. Bicuculline alone has produced antinociception in the second phase and CGP35348 alone has had antinociception in both phases of the formalin test. Morphine in combination with different doses of muscimol or baclofen did not elicit potentiation. The opioid receptor antagonist naloxone reduced the response induced by muscimol in the second phase and baclofen in both phases of the formalin test. It may be concluded that central GABA(A) and GABA(B) receptor stimulation induces antinociception in the formalin test. However, the antinociception induced by GABA receptor agonists may be mediated partly through supraspinal opioid receptor mechanisms and, for the GABA(B) receptor agonist, through spinal and supraspinal opioid receptor mechanisms.

Analgesics, Opioid↗
PubMed1996

Anti-ulcerogenic activity of GABA and GABA mimetic agents in rats.

To elucidate the involvement of peripheral gamma- aminobutyric acid (GABA) and some GABA-mimetic agents in different models of gastric and duodenal ulcerations in rats and guinea pigs, effects of GABA, baclofen (GABAB agonist), diazepam, gamma-butyrolactone (GABA receptor agonist), sodium valproate, isoniazid (GABA-T inhibitor) and glycine (an inhibitory neurotransmitter), given po or ip were studied. All the drugs significantly reduced the ulcer index, incidence and number of ulcer in various models of gastric ulcers except glycine which failed to protect in reserpine-induced ulcers in rats. None of the drugs, except diazepam, had any protective effect on histamine-induced gastric ulcers in guinea pigs. Similarly, no protection was observed by any drug against cysteamine-induced duodenal ulcers in rats, while sodium valproate, isoniazid and glycine significantly decreased number of ulcers against histamine-induced duodenal ulcer in guinea pigs. The results suggest that GABA and GABA-mimetic agents, and glycine, an inhibitory neurotransmitter, afforded protection against some experimental models of peptic ulcer in rats. The effects appear to be due to their inhibitory effect on mucosal defensive factors.

Animals↗
PubMed1980

Ketamine activation of experimental corticoreticular epilepsy.

Generalized corticoreticular epilepsy was established in adult cats by parenteral penicillin, and electroencephalographic monitoring was carried out. Ketamine HCl was injected intravenously in doses of 2.5 to 20 mg per kilogram. If doses of penicillin were inadequate to establish typical spike-wave activity, ketamine induced the spike-wave pattern typical of much higher doses of penicillin. At doses of penicillin that established the spike-wave pattern, ketamine potentiated the spike-wave activity and sometimes induced spike-and-wave status. These findings suggest caution in the clinical use of ketamine in patients with corticoreticular epilepsy. Because analogous effects have been observed upon administration of GABA-mimetic agents, GABA systems may play a role in ketamine anesthesia and corticoreticular epilepsy. Precollicular brain transections failed to modify ketamine effects, excluding a possible influence of mesencephalic centers on the observed potentiation.

Animals↗
PubMed1996

Protective effects of GABAergic drugs and other anticonvulsants in lithium-pilocarpine-induced status epilepticus.

Administration of subconvulsive dose of pilocarpine (30 mg/kg s.c.) to rats pretreated with lithium chloride (3 meq/kg i.p.) produced a state of status epilepticus in animals. The animals showed characteristic symptoms of generalized convulsions, wet dog shakes (WDS), forelimb clonus and falling back. The symptoms of status epilepticus (SE) developed within 26.8 +/- 3.6 min after administering pilocarpine and these symptoms continued uninterrupted. The phenomenon was totally reproducible, with a consistent latency of onset of seizures and a high mortality rate. The symptoms were blocked by atropine, scopolamine and the GABAergic agents GABA, sodium valproate, (+)-baclofen and clonazepam when given prior to pilocarpine, but not when administered 30 min after pilocarpine administration.

Animals↗
PubMedDate not supplied

Relative anticonvulsant effects of GABAmimetic and GABA modulatory agents.

Anticonvulsant properties of compounds that enhance GABA-mediated inhibition through modulatory sites on the GABAA receptor [phenobarbital (PB), clonazepam (CZP), alpha-ethyl-alpha-methyl-gamma-thiobutyrolactone (alpha-EMTBL)] were compared with anticonvulsant effects of compounds believed to be antagonists at these modulatory sites (Ro15-1788 and alpha-isopropyl-alpha-methyl-gamma-butyrolactone gamma-IMGBL)] and to 4,5,6,7-tetrahydroisoxazolo-[4,5-c]-pyridin-3-ol (THIP, GABAA receptor agonist), (+/-) baclofen (GABAB receptor agonist), and gamma-vinyl GABA, a compound that increases endogenous GABA. The compounds were tested for their ability to block experimental seizures caused by maximal electroshock, pentylenetetrazol, picrotoxin, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), bicuculline (BIC), aminophylline, strychnine, and t-butyl-bicyclophosphorothionate (TBPS) in mice. CZP blocked all but strychnine seizures. PB was also highly effective, blocking all but TBPS seizures. alpha-EMTBL, representing a new class of experimental anticonvulsant drugs, prevented all seizures except strychnine (STR)- and aminophylline-induced seizures. The antagonists are effective only against one convulsant stimulus. Ro15-1788 and alpha-IMGBL prevented only DMCM- and pentylenetetrazol (PTZ)-induced seizures, respectively. THIP and gamma-vinyl GABA both blocked only BIC and picrotoxin seizures. Baclofen had no anticonvulsant activity. These data demonstrate that compounds that increase neuronal inhibition by potentiating the action of GABA have a broader spectrum of anticonvulsant action than either antagonists or GABAmimetic agents or compounds that increase endogenous GABA.

4-Butyrolactone↗
PubMed1981

Differential effects of gamma-aminobutyric acid (GABA)-elevating agents on the neuroleptic-induced activation of striatal tyrosine-hydroxylase: evidence that di-n-propylacetate augments GABAergic neurotransmission.

Di-n-propylacetate (DPA), in contrast to many other agents which elevate brain gamma-aminobutyric acid (GABA) content, appears to increase GABA selectively in a compartment that is associated with nerve terminals. In order to determine whether the DPA-induced increase in nerve-terminal GABA could augment GABAergic transmission in substantia nigra, we examined the ability of DPA to influence nigrostriatal dopamine function. For this purpose, the neuroleptic-induced activation of striatal tyrosine hydroxylase (TH) was selected as a model system. Neuroleptic drugs, such as haloperidol, cause an allosteric activation of striatal TH which can be measured in vitro as a decrease in the Km of TH for cofactor (2-amino-4-hydroxy-6,7-dimethyl-5,6,7,8-tetrahydropterine). This effect can be reversed by treatment with GABA-receptor agonists. We therefore examined the ability of DPA to reverse the activation of striatal TH induced by haloperidol. DPA was able to reverse the haloperidol-induced activation of striatal TH in doses which caused a 30 to 50% increase in GABA in substantia nigra. The action of DPA was completely antagonized by treatment with bicuculline, a GABA-receptor antagonist, indicating that the effect of DPA is mediated via GABA receptors. The effect of amino-oxyacetic acid was also examined, since our previous evidence suggested that the GABA increase after this agent was largely associated with compartments of GABA other than nerve terminals. Amino-oxyacetic acid was less effective than DPA in preventing the haloperidol-induced activation of TH, despite the fact that nigral GABA was increased by 30 to 100%.

Aminooxyacetic Acid↗
PubMed1979

Effects of GABA-mimetic agents on the cat spinal cord.

Muscimol, ibotenic acid, isoguvacine, 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridin-3-ol (THIP) and gamma-aminobutyric acid (GABA) injected intravenously exerted the following dose-dependent effects on the lumbosacral spinal cord of spinal cats: 1. The excitability of primary afferents and the amplitude of dorsal root reflexes were enhanced; segmental monosynaptic ventral root reflexes and dorsal root potentials as well as the spontaneous gamma-fibre activity and, to a smaller extent, the excitability of motoneurons and polysynaptic reflexes, were depressed. 2. Muscimol was the most potent compound (0.3-1 mg/kg produced significant effects), followed by ibotenic acid (3-10 mg/kg), isoguvacine and THIP (10-30 mg/kg) and GABA (100 mg/kg). 3. Most effects were reversibly antagonized by bicuculline, but not by strychnine, indicating that they were due to a specific interaction with GABA-receptors. 4. These results suggest that the systemic injection of GABA-mimetic agents affects spinal cord activities by actions related to GABA-receptors located on primary afferent endings, intrinsic spinal neurons, and motoneurons.

Animals↗
PubMedDate not supplied

The effect of beta-adrenoceptor antagonists alone and in combination with a GABA-elevating agent on isoniazid-induced convulsions in rats.

A delay in the onset of isoniazid-induced convulsions was found in rats pretreated with the beta 2-adrenoceptor blocker, butoxamine and the nonspecific beta-blocker, propranolol. In these animals the convulsive responses were inhibited in a dose dependent manner. These compounds were found to be effective even after the induction of convulsions. The beta 1-blocker, acebutolol was able to protect rats only when injected prior to the challenge. The anticonvulsant effect of acebutolol and propranolol but not that of butoxamine was found to be enhanced in animals pretreated with a gamma-aminobutyric acid (GABA) elevating agent, aminooxyacetic acid (AOAA). The findings indicate that the GABA-mediated anticonvulsant action of AOAA seems to be additive with that resulting from beta 1 but not beta 2-blockade.

Acebutolol↗
PubMed1994

Antinociceptive action of N-octanoyl GABA--a new GABA mimetic agent.

A new derivative of gamma-aminobutyric acid (GABA) was synthesized. The compound, N-octanoyl GABA (O-GABA), exhibited positive analgesic response in four different models in mice--tail immersion, hot plate, tail clip and acetic acid induced writhing. The antinociceptive activity was significantly blocked by picrotoxin but not by bicuculline or 3-mercaptopropionic acid. Naloxone failed to reverse the antinociceptive response of O-GABA but a synergistic action was observed with pethidine. Pretreatment with atropine significantly reduced the antinociceptive action of O-GABA. Biochemical tests revealed that O-GABA significantly increased brain GABA levels.

Analgesics↗
PubMedDate not supplied

[The effect of GABA-ergic agents on the electrolyte balance under hypokinesia].

The effect of hypokinesia on the blood electrolyte balance was studied. In restricted motor activity marked deviations of the type of hypokalemia and hypercalcemia were encountered, which could promote the development of various pathological processes, including disorder of central and regional hemodynamics. GABA and piracetam had no effect on the blood serum electrolyte content in the early periods of hypokinesia. In later periods of hypokinesia both drugs under examination corrected the disorders of blood electrolyte balance induced by prolonged restriction of motor activity.

Animals↗
PubMedDate not supplied

[Neurophysiological mechanisms of the action of GABA-tropic agents on brain structures].

The effect of systemic administration of agonists and antagonists of GABA system on excitability and intracentral relationships of the brain structures was found during chronic experiments on rabbits with bipolar electrodes implanted in the region of the frontal cortex, dorsal hippocampus, midbrain reticular formation and central gray matter. The changes of the functional state of the cerebral formations were suggested to be related to a different degree of the involvement of GABA receptors of types A and B.

Aminooxyacetic Acid↗
PubMed1986

Interactions of angiotensin II and GABA-ergic agents at the threshold of convulsive reactions.

The effects of angiotensin II (AT II), GABA, muscimol (administered i.c.v.) and of amino-oxiacetic acid (AOAA) and baclofen (administered i.p.), as well as of the combinations of AT II with these substances and bicuculline, were studied with respect to the threshold of the convulsive seizures induced by timed intravenous infusion of pentylenetetrazol (PTZ) in mice. It was found in the experiments that the threshold-increasing effect of GABA, muscimol and AOAA was potentiated by AT II (applied in a dose which did not change essentially the convulsive threshold). The potentiated effect of GABA, muscimol and AOAA on the convulsive threshold, when applied in combination with AT II, was antagonized by bicuculline. The threshold-increasing effect of baclofen was not affected substantially by AT II; in this case bicuculline had no effect. On the basis of the results obtained it may be assumed that AT II performs the functions of an antocoid predominantly for the GABA-A receptors in the central nervous system.

Aminooxyacetic Acid↗