Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GABA(B) agonists inhibit excitatory transmission to hippocampal CA3 neurons during low frequency stimulation. We examined whether GABA(B) receptor activation can also enhance synaptic efficacy, when investigated at an input with high initial release probability. Short-term depression of field excitatory postsynaptic potential (EPSP) amplitude was observed during trains of stimuli applied to associational/commissural inputs (10-50 Hz; 22 degrees C). Baclofen (10 microM) reduced the amplitude of initial EPSPs in a train, and also reduced the degree of short-term depression. EPSPs recorded late in a train were significantly larger in baclofen than those recorded in control solution. These dual effects were mimicked by another selective GABA(B) agonist (SKF 97541, 10 microM), and abolished by a GABA(B)-selective antagonist (SCH 50911, 20 microM). The effects of baclofen were similar at a higher recording temperature (32 degrees C), where short-term depression was observed at higher stimulation frequencies. These results are consistent with the idea that a reduction of transmitter release probability could increase the fidelity of high-frequency transmission at this input, an effect that could help account for excitatory effects of GABA(B) agonists in some seizure models.
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PMID:GABA(B)-receptor modulation of short-term synaptic depression at an excitatory input to murine hippocampal CA3 pyramidal neurons. 1523 71

The present study was performed to determine whether the effects induced by GABA(B) receptor-acting drugs would be related with the alteration in GABA(B) receptor expression in the hippocampus using Mongolian gerbil, a genetic epilepsy model. The distribution patterns of both GABA(B) receptor 1A/B and GABA(B)receptor 2 immunoreactivities were similarly detected in the hippocampi of normal and seizure-prone gerbils. Following baclofen (GABA(B) receptor agonist) or phaclofen (GABA(B) receptor antagonist) treatment, GABA(B) receptor immunoreactivities were decreased or increased by dose-dependent manners, respectively. Vigabatrin (GABA transaminase inhibitor) or 3-mercaptopropionic acid (GAD inhibitor) treatment did not affect GABA(B) receptor expressions. These findings suggest that GABA(B) receptor expression in the gerbil hippocampus may be altered by baclofen or phaclofen treatment.
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PMID:Altered GABAB receptor immunoreactivity in the gerbil hippocampus induced by baclofen and phaclofen, not seizure activity. 1523 66

gamma-Hydroxybutyric acid (GHB) is a short-chain fatty acid that occurs naturally in mammalian brain where it is derived metabolically from gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain. GHB was synthesised over 40 years ago and its presence in the brain and a number of aspects of its biological, pharmacological and toxicological properties have been elucidated over the last 20-30 years. However, widespread interest in this compound has arisen only in the past 5-10 years, primarily as a result of the emergence of GHB as a major recreational drug and public health problem in the US. There is considerable evidence that GHB may be a neuromodulator in the brain. GHB has multiple neuronal mechanisms including activation of both the gamma-aminobutyric acid type B (GABA(B)) receptor, and a separate GHB-specific receptor. This complex GHB-GABA(B) receptor interaction is probably responsible for the protean pharmacological, electroencephalographic, behavioural and toxicological effects of GHB, as well as the perturbations of learning and memory associated with supra-physiological concentrations of GHB in the brain that result from the exogenous administration of this drug in the clinical context of GHB abuse, addiction and withdrawal. Investigation of the inborn error of metabolism succinic semialdehyde deficiency (SSADH) and the murine model of this disorder (SSADH knockout mice), in which GHB plays a major role, may help dissect out GHB- and GABA(B) receptor-mediated mechanisms. In particular, the mechanisms that are operative in the molecular pathogenesis of GHB addiction and withdrawal as well as the absence seizures observed in the GHB-treated animals.
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PMID:Gamma-hydroxybutyric acid: neurobiology and toxicology of a recreational drug. 1529 89

The globus pallidus occupies a critical position in the 'indirect' pathway of the basal ganglia and, as such, plays an important role in the modulation of movement. In recent years, the importance of the globus pallidus in the normal and malfunctioned basal ganglia is emerging. However, the function and operation of various transmitter systems in this nucleus are largely unknown. GABA is the major neurotransmitter involved in the globus pallidus. By means of electrophysiological recording, immunohistochemistry and behavioral studies, new information on the distribution and functions of the GABAergic neurotransmission in the rat globus pallidus has been generated. Morphological studies revealed the existence of GABA(A) receptor, including its benzodiazepine binding site, and GABA(B) receptor in globus pallidus. At subcellular level, GABA(A) receptors are located at the postsynaptic sites of symmetric synapses (putative GABAergic synapses). However, GABA(B) receptors are located at both pre- and postsynaptic sites of symmetric, as well as asymmetric synapses (putative excitatory synapses). Consistent with the morphological results, functional studies showed that activation of GABA(B) receptors in globus pallidus reduces the release of GABA and glutamate by activating presynaptic auto- and heteroreceptors, and hyperpolarizes pallidal neurons by activating postsynaptic receptors. In addition to GABA(B) receptor, activation of GABA(A) receptor benzodiazepine binding site and blockade of GABA uptake change the activity of globus pallidus by prolonging the duration of GABA current. In agreement with the in vitro effect, activation of GABA(B) receptor, GABA(A) receptor benzodiazepine binding site and blockade of GABA uptake cause rotation in behaving animal. Furthermore, the GABA system in the globus pallidus is involved in the etiology of Parkinson's disease and regulation of seizures threshold. It has been demonstrated that the abnormal hypoactivity and synchronized rhythmic discharge of globus pallidus neurons associate with akinesia and resting tremor in parkinsonism. Recent electrophysiological and behavioral studies indicated that the new anti-epileptic drug, tiagabine, is functional in globus pallidus, which may present more information to understand the involvement of globus pallidus in epilepsy.
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PMID:GABAergic neurotransmission in globus pallidus and its involvement in neurologic disorders. 1532 74

Fast oscillations at approximately 200 Hz, termed ripples, occur in the hippocampus and cortex of several species, including humans, and are thought to play a role in physiological (e.g., sensory information processing or memory consolidation) and pathological (e.g., seizures) processes. Blocking gamma-aminobutyric acid type A (GABA(A)) receptor-mediated inhibition represents one of the most often used models of epileptiform discharge. Here we found that bath application of the GABA(A) receptor antagonist picrotoxin (50 microM) to mouse hippocampus-entorhinal cortex slices induced spontaneous epileptiform activity (duration 536.6 +/- 146.1 msec, mean +/- SD; interval of occurrence 14.8 +/- 3.3 sec, n = 12) with two distinct phases of discharge; the first was characterized, in the dentate gyrus only, by high-frequency, field oscillations (ripples) at 206.3 +/- 23.4 Hz (n = 12), whereas the second component corresponded to afterdischarges in the theta range frequency. Ripples, which were also recorded in "minislices" only of the dentate gyrus, were unaffected by application of the mu-opioid receptor agonist (D-Ala2-N-Me-Phe,Gly-ol)enkephalin (10 microM; n = 6) or the N-methyl-D-aspartate (NMDA) receptor antagonist 3-(2-carboxy-piperazine-4-yl)-propyl-l-phosphonate (10 microM; n = 5). In contrast, the non-NMDA glutamatergic receptor antagonist 6-cyano-7-nitro-quinoxaline-2,3-dione (10 microM; n = 5) completely blocked all picrotoxin-induced activities. In addition, application of the GABA(B) receptor agonist baclofen (0.01-0.5 microM; n = 6) dose dependently and reversibly abolished all picrotoxin-induced activities. We also found that application of the gap-junction decouplers carbenoxolone (0.2-0.5 mM; n = 6) or octanol (0.2-0.5 mM; n = 3) blocked the second phase while leaving ripples unchanged. These findings demonstrate that the disinhibited dentate gyrus can generate ripple activity at approximately 200 Hz that is contributed by ionotropic glutamatergic mechanisms and is not dependent on either GABA(A) receptor-mediated or gap-junction mechanisms.
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PMID:Ripple activity in the dentate gyrus of dishinibited hippocampus-entorhinal cortex slices. 1574 60

Although reduced calcium binding protein (CBP) immunoreactivities in the epileptic hippocampus have been well established, it has been controversial that these changes may directly indicate neuronal degeneration. In the present study, therefore, we investigated CBP expressions in the gerbil hippocampus following treatment with gamma-aminobutyric acid (GABA) receptor antagonists in order to assess whether altered CBP expressions are the result of either abnormal excitation or indicative of neuronal damage/degeneration. Seizure-sensitive (SS) gerbils showed a loss/decline of CBP immunoreactivities in some hippocampal neurons as compared with seizure-resistant (SR) gerbils. In muscimol (GABA(A) receptor agonist) treated SS gerbils, expression levels of CBP were enhanced as compared with saline-treated SS gerbils. Bicuculline (a GABA(A) receptor antagonist) treatment markedly reduced CBP immunoreactivities in hippocampal neurons of the SR gerbil. Baclofen (a GABA(B) receptor agonist) treatment increased CBP immunoreactivities in the hippocampus of SS gerbils, although its effect was lower than that of muscimol treatment. Moreover, phaclofen (GABA(B) receptor antagonist) treated SR gerbil showed reduction in calbindin D-28K immunoreactivity, not parvalbumin immunoreactivity, in the hippocampus. These findings therefore suggest that reduced CBP immunoreactivities may be the consequence of abnormal discharge caused by loss of GABAergic inhibition rather than an indication of the neuronal damage/degeneration.
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PMID:Effects of GABAergic transmissions on the immunoreactivities of calcium binding proteins in the gerbil hippocampus. 1577 49

Gamma-hydroxybutyric acid (GHB) and its precursors, 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL), are recreational drugs widely abused in the US, Europe and Australasia. A severe withdrawal syndrome from GHB, 1,4-BD and GBL has been increasingly documented over the last years, necessitating the development of a reliable animal model for investigations of potential therapeutic approaches. The present study describes the induction and occurrence of audiogenic seizures as a sign of withdrawal from GHB and 1,4-BD in selectively bred Sardinian alcohol-preferring (sP) rats, treated with escalating doses of GHB (1.5-3.5 g/kg, twice daily; i.g.) or 1,4-BD (500-1000 mg/kg, twice daily; i.g.) for 9 consecutive days. Acute administration of the selective GABA(B) receptor antagonist, SCH 50911, dramatically increased seizure occurrence. We propose that the inherent sensitivity of sP rats to different GHB-associated responses may have contributed to the unraveling of a phenomenon which was otherwise not recognizable in other rat strains.
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PMID:Withdrawal syndrome from gamma-hydroxybutyric acid (GHB) and 1,4-butanediol (1,4-BD) in Sardinian alcohol-preferring rats. 1588 53

Enaminones are a novel group of compounds that have been shown to possess anticonvulsant activity in in vivo animal models of seizures. The cellular mechanism by which these compounds produce their anticonvulsant effects is not yet known. This study examined the effects of enaminones on excitatory synaptic transmission. We studied the effects of 3-(4'-chlorophenyl)aminocyclohex-2-enone (E118), methyl 4-(4'-bromophenyl)aminocyclohex-3-en-6-methyl-2-oxo-1-oate (E139) and ethyl 4-(4'-hydroxyphenyl)aminocyclohex-3-en-6-methyl-2-oxo-1-oate (E169) on isolated evoked, glutamate-mediated excitatory synaptic responses by recording whole-cell currents and potentials in cells of the nucleus accumbens (NAc) contained in forebrain slices. The anticonvulsant enaminones (E118 and E139), but not E169, depressed NMDA and non-NMDA receptor-mediated synaptic responses. The inhibition of the non-NMDA response was concentration-dependent (1.0-100 microM) with a maximal depression of approximately -30%. E118 and E139 had similar potencies (EC(50)=3.0 and 3.5 microM, respectively) in depressing this response but E139 was more efficacious (E(max)=-31.3+/-3.8%) than E118 (E(max)=-22.6+/-1.6%). The excitatory postsynaptic current (EPSC) depression caused by 10 microM E139 (-27.7+/-3.8%) was blocked by 1 microM CGP55845 (6.3+/-8.1%), a potent GABA(B) receptor antagonist. Pretreatment of slices with gamma-vinylGABA and 1-(2-(((diphenylmethylene)imino)oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridine-carboxylic acid (NO-711), an irreversible GABA transaminase (GABA-T) inhibitor and a GABA reuptake blocker, respectively, like the anticonvulsant enaminones, also caused a depression of the evoked EPSC (-38.1+/-14.1 and -24.1+/-8.9%, respectively). In the presence of these compounds, E139 did not cause a further depression of the EPSC. Our data suggest that anticonvulsant enaminones cause EPSC depression by enhancing extracellular GABA levels possibly through the inhibition of either GABA reuptake or GABA-T enzyme, or both.
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PMID:Anticonvulsant enaminones depress excitatory synaptic transmission in the rat brain by enhancing extracellular GABA levels. 1591 38

Epilepsy may result from altered transmission of the principal inhibitory transmitter GABA in the brain. Using in situ hybridization in two animal models of epileptogenesis, we investigated changes in the expression of nine major GABA(A) receptor subunits (alpha1, alpha2, alpha4, alpha5, beta1-beta3, gamma2 and delta) and of the GABA(B) receptor species GABA(B)R1a, GABA(B)R1b and GABA(B)R2 in 1) hippocampal kindling and 2) epilepsy following electrically-induced status epilepticus (SE). Hippocampal kindling triggers a decrease in seizure threshold without producing spontaneous seizures and hippocampal damage, whereas the SE model is characterized by spontaneous seizures and hippocampal damage. Changes in the expression of GABA(A) and GABA(B) receptor mRNAs were observed in both models, and compared with those seen in other models and in human temporal lobe epilepsy. The most prominent changes were a relatively fast (24 h after kindling and electrically-induced SE) and lasting (7 and 30 days after termination of kindling and SE, respectively) reduction of GABA(A) receptor subunit delta mRNA levels (by 43-78%) in dentate granule cells, accompanied by increases in mRNA levels of all three beta-subunits (by 8-79%) and subunit gamma2 (by 11-43%). Levels of the minor subunit alpha4 were increased by up to 60% in dentate granule cells in both animal models, whereas those of subunit alpha5 were decreased 24 h and 30 days after SE, but not after kindling. In cornu ammonis 3 pyramidal cells, downregulation of subunits alpha2, alpha4, alpha5, and beta1-3 was observed in the ventral hippocampus and of alpha2, alpha5, beta3 and gamma2 in its dorsal extension 24 h after SE. Similar but less pronounced changes were seen in sector cornu ammonis 1. Persistent decreases in subunit alpha2, alpha4 and beta2 transcript levels were presumably related to SE-induced cell loss. GABA(B) receptor expression was characterized by increases in GABA(B)R2 mRNA levels at all intervals after kindling and SE. The observed changes suggest substantial and cell specific rearrangement of GABA receptors. Lasting downregulation of subunits delta and alpha5 in granule cells and transient decreases in subunit alpha2 and beta1-3 mRNA levels in cornu ammonis 3 pyramidal cells are suggestive of impaired GABA(A) receptor-mediated inhibition. Persistent upregulation of subunits beta1-3 and gamma2 of the GABA(A) receptor and of GABA(B)R2 mRNA in granule cells, however, may result in activation of compensatory anticonvulsant mechanisms.
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PMID:Altered expression of GABA(A) and GABA(B) receptor subunit mRNAs in the hippocampus after kindling and electrically induced status epilepticus. 1595 Nov 23

GABA(B) receptor (GABA(B)R)-mediated presynaptic inhibition regulates neurotransmitter release from synaptic terminals. In the neonatal hippocampus, GABA(B)R activation reduces GABA release and terminates spontaneous network discharges called giant depolarizing potentials (GDPs). Blocking GABA(B)Rs transforms GDPs into longer epileptiform discharges. Thus, GABA(B)R-mediated presynaptic inhibition of GABA release (GABA auto-inhibition) controls both spontaneous network activity and excitability in the developing hippocampus. Here we show that extensive release of endogenous GABA during epileptiform activity impairs GABA auto-inhibition, but not GABA(B)R-mediated inhibition of glutamate release, leading to hyperexcitability of the neonatal hippocampal network. Paired-pulse depression of GABA release (PPD) and heterosynaptic depression of glutamate release were used to monitor the efficacy of presynaptic GABA(B)R-mediated inhibition in slices. PPD, but not heterosynaptic depression, was dramatically reduced after potassium (K+)-induced ictal-like discharges (ILDs), suggesting a selective impairment of GABA(B)R-dependent presynaptic inhibition of GABAergic terminals. Impairing GABA auto-inhibition induced a 44% increase in GDP width and the appearance of pathological network discharges. Preventing GABA-induced activation of GABA(B)Rs during ILDs avoided PPD loss and most modifications of the network activity. In contrast, a partial block of GABA(B)Rs induced network discharges strikingly similar to those observed after K+-driven ILDs. Finally, neither loss of GABA auto-inhibition nor network hyperexcitability could be observed following synchronous release of endogenous GABA in physiological conditions (during GDPs at 1 Hz). Thus, epileptiform activity was instrumental to impair GABA(B)R-dependent presynaptic inhibition of GABAergic terminals. In conclusion, our results indicate that endogenous GABA released during epileptiform activity can reduce GABA auto-inhibition and trigger pathological network discharges in the newborn rat hippocampus. Such functional impairment may play a role in acute post-seizure plasticity.
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PMID:Epileptiform activity triggers long-term plasticity of GABA(B) receptor signalling in the developing rat hippocampus. 1609 37


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