Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.19 (GABA transaminase)
 808 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Because of its abundance in the brain, its ability to produce hyperpolarizing inhibition of almost all neurons, its association with benzodiazepines, and the discovery that many convulsants inhibited its synthesis, gamma-aminobutyric acid (GABA) has often appeared to be the key to epilepsy. Many assumed that "primary" or "genetic" epilepsy must be a disorder of GABA synapses and that GABA agonists would be universal anticonvulsants if permeability and drug metabolism were controlled. The GABA synthetic gene was a logical "candidate gene" for epilepsy. However, the GABA-deficiency theory of epilepsy is less convincing today. GABA agonists were found to intensify seizures in some rodent and human cases. Absence and other generalized seizures in humans often worsened when treated with GABA transaminase inhibitors such as gamma-vinyl-GABA. Surprisingly, the GABA transaminase inhibitors appear to be more useful in partial than in generalized epilepsies. Neuronal GABA uptake blockers are proconvulsant. GABA agonists aggravate seizures in several mutants, ranging from the photosensitive baboon to the genetically epilepsy-prone rat. How can this be understood? Muscimol injections into the pedunculopontine nucleus increase seizures due to systematically administered convulsants, while the receptor blocker bicuculline suppresses seizures after injection into several brain regions, including the striatum. The result of inhibiting inhibitory circuits is excitation. Studies with GABA uptake blockers and the GABAB agonist baclofen are presented in which their combined administration provoked seizures in rats. Baclofen was shown also to increase the incidence of seizures evoked by pentylenetetrazole without increasing seizures due to local injections of excitatory amino acids. Baclofen antagonized the myoclonic effect of 5-hydroxytryptophan in rats with serotonin lesions. Baclofen augments some seizures and inhibits others. Selective inhibition of a particular tract, whether GABAergic or not, may have convulsant or anticonvulsant effects, depending on its connections and the state of the organism. GABAA receptor stimulation is usually but not always anticonvulsant. GABAB receptor stimulation may facilitate absence seizures and related primary generalized seizures. GABAB receptors may be abnormal in some forms of nonfocal epilepsy seen in childhood. It is likely that mutations of GABA transporter and GABAA receptor genes will be found in humans but they will probably not be patients with "pure epilepsy."
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PMID:GABA and epilepsy: their complex relationship and the evolution of our understanding. 131 57

Pretreatment with 5-hydroxytryptophan (5-HTP), a precursor of 5-HT, antagonised while pretreatment with p-chlorophenylalanine (PCPA), a 5-HT depletor, potentiated the myoclonus induced by picrotoxin, a GABA antagonist. Pretreatment with aminooxyacetic acid (AOAA), a GABA transaminase inhibitor, antagonised picrotoxin-induced myoclonus. The combined effect of the least protective doses of AOAA and 5-HTP was greater than the sum of their individual inhibitory effects on picrotoxin-induced myoclonus. Further, AOAA failed to inhibit picrotoxin-induced myoclonus in PCPA pretreated rats. These findings suggest that the central 5-HT-ergic system exerts a facilitatory influence on the GABA-ergic system and thus it is involved in the antimyoclonic action of GABA.
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PMID:A functional interaction between GABA and 5-HT in inhibiting picrotoxin-induced myoclonus in rats. 214 69

The purpose of this paper was to study the relationship between different neurotransmitter systems and seizure susceptibility in Mongolian gerbils with genetically determined epilepsy. In these animals, generalized tonic-clonic seizures were induced by stimulation with a blast of compressed air. A variety of drugs that specifically manipulate inhibitory or excitatory neurotransmitter systems proved capable of dose dependently blocking these seizures, i.e., the anticholinergic drug biperiden (ED50 12 mg/kg i.p.), the excitatory amino acid antagonist (+/-)-2-amino-7-phosphonoheptanoic acid (120 mg/kg), the gamma-aminobutyric acid (GABA) agonists muscimol (0.66 mg/kg), 4,5,6,7-tetrahydroisoxazolo(5,4-c) pyridine-3-ol (1.3 mg/kg), progabide (50 mg/kg) and its acidic metabolite SL 75102 (45 mg/kg), the GABA aminotransferase inhibitors aminooxyacetic acid (0.9 mg/kg), gamma-acetylenic GABA (2.1 mg/kg) and ethanolamine-O-sulfate (1000 mg/kg), the GABA uptake inhibitor (-)-nipecotic acid ethyl ester (21 mg/kg), the dopamine agonist apomorphine (approximately 5 mg/kg), the dopamine precursor 3,4-dihydroxy-L-phenylalanine (34 mg/kg), and the alpha-adrenoceptor agonists clonidine (0.38 mg/kg) and xylazine (approximately 10 mg/kg). The anticonvulsant effect of 3,4-dihydroxyl-L-phenylalanine was not significantly affected by pretreatment with the dopamine-beta-hydroxylase inhibitors disulfiram and diethyldithiocarbamate, thus strongly indicating that 3,4-dihydroxyl-L-phenylalanine was acting through increase in dopamine rather than noradrenaline levels in the brain. The (+)-isomer of nipecotic acid ethyl ester, the glycineamide derivative milacemide, the indirect 5-hydroxytryptamine agonist fenfluramine and the 5-hydroxytryptamine antagonist ketanserin exerted no anticonvulsant action. The 5-hydroxytryptamine precursor L-5-hydroxytryptophan and the dopamine agonist lisuride were only weakly active but exerted pronounced side effects in the animals. Weak anticonvulsant effects were also determined for atropine, the noradrenaline precursor DL-threo-3,4-dihydroxyphenylserine and the excitatory amino acid antagonist (+/-)-2-amino-5-phosphonopentanoic acid. Comparison of anticonvulsant potencies of the various drugs in gerbils with potencies reported in other genetic animal models of epilepsy, such as audiogenic seizure-susceptible mice, indicated that drugs that increase GABA and dopamine levels in the brain are strikingly more effective in gerbils than in other species in blocking generalized seizures.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Influence of pharmacological manipulation of inhibitory and excitatory neurotransmitter systems on seizure behavior in the Mongolian gerbil. 285 79

ACB is one of the sites containing nerve terminals of the mesolimbic dopamine system. We have found that all the male Sprague-Dawley rats with electrolytic lesions of bilateral ACB showed locomotor hyperactivity and hyperemotionality. Muricide was also observed in about 40% of these lesioned rats. Hyperemotionality and muricide were maximum during the first 2-3 days after the lesioning, then gradually declined. Locomotor hyperactivity lasted invariably for over 30 days. Hyperemotionality and muricide were both inhibited by the following drugs given i.p., chlorpromazine; haloperidol; diazepam; estazolam; aminooxyacetic acid (GABA transaminase inhibitor); phenoxybenzamine. However, imipramine, atropine and L-5-hydroxytryptophan inhibited selectively the muricidal behavior. Lesioning of the catecholaminergic (CA) system by administration of 6-hydroxydopamine into bilateral ACB-produced only moderate hyperemotionality with no evidence of locomotor hyperactivity and muricide. These results suggest that lesioning of the CA system plus other neural mechanisms in ACB are required for development of these three forms off hyperemotional behavior. Cholinergic, serotonergic, GABAergic and CA mechanisms may also be involved in hyperemotionality and muricide in ACB lesioned rats.
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PMID:[Behavioral changes following lesioning of the nucleus accumbens (ACB) and effects of centrally acting drugs in rats (author's transl)]. 610 6

Using male hooded Lister rats the effects of GABAergic and serotonergic treatments alone and with chlordiazepoxide (CDP) were compared with the behavioral effects of CDP in a conditioned conflict procedure with three components; Reward, Time Out, and Conflict. CDP (2.5, 5.0, and 10.0 mg/kg ip) dose- relatedly increased punished and time out responding, but increased rewarded responding in an inversely dose-related manner. Punished responding was enhanced by chronic treatment to a rate which remained stable between 9 and 19 injections. The GABA transaminase inhibitor ethanolamine-O-sulfate (EOS), given chronically in drinking water (5.0 mg/ml), increased punished responding linearly to a high stable level after 2-3 weeks. Rewarded and time out responding were less substantially increased. CDP given with EOS dose- relatedly increased time out and punished responding substantially above the rates found with either treatment alone. The GABA antagonist picrotoxin blocked the increase in punished and time out responding found with EOS and CDP alone. The tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA; 100 mg/kg x 3) linearly increased punished responding for the first week of treatment. CDP with PCPA selectively and significantly increased punished responding above the rates for either treatment alone, but the increases were not as substantial as those with EOS + CDP. The serotonin reuptake inhibitor Wy 25093 reduced increases in time out and punished responding under CDP, and the precursor 5-hydroxytryptophan (5-HTP) counteracted increases in punished responding under PCPA but also substantially reduced rewarded responding. These results provide evidence that both increased GABA and decreased serotonin transmission are involved in the anticonflict effects of CDP, as EOS and PCPA both mimicked and potentiated effects of CDP, while picrotoxin, Wy 25093, and 5-HTP counteracted them.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evidence for the involvement of brain GABA and serotonin systems in the anticonflict effects of chlordiazepoxide in rats. 632 60