Extracellular Hypothalamic γ-Aminobutyric Acid (GABA) and L-Glutamic Acid Concentrations in Response to Bicuculline in a Genetic Absence Epilepsy Rat Model (original) (raw)
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Epilepsia, 2002
Summary: Purpose: γ-Aminobutyric acid (GABA) plays a vital role in both central cardiovascular homeostasis and pathogenesis of epilepsy. Epilepsy affects autonomic nervous system functions. In this study, we aimed to clarify the role of GABAA receptors in hypothalamic cardiovascular regulation in a genetically determined animal model of absence epilepsy.Methods: Nonepileptic Wistar rats and genetic absence epilepsy rats from Strasbourg (GAERS) were instrumented with a guide cannula for drug injection and extradural electrodes for EEG recording. After a recovery period, iliac arterial catheters were inserted for direct measurement of mean arterial pressure and heart rate. Bicuculline, a GABAA-receptor antagonist, was injected into the dorsomedial (DMH) or posterior (PH) hypothalamic nuclei of nonepileptic control rats or GAERS. Blood pressure, heart rate, and EEG recordings were performed in conscious unrestrained animals.Results: Bicuculline injections into the hypothalamus produced increases in blood pressure and heart rate of both control rats and GAERS. The DMH group of GAERS showed a twofold increase in the blood pressure and the heart rate compared with those of control rats. Pressor responses to bicuculline, when microinjected into the PH, were similar in the nonepileptic animals and GAERS. Conversely, the amplitude of tachycardic responses to the administration of bicuculline into the PH was significantly higher in GAERS compared with those of control rats.Conclusions: The bicuculline-induced increases in blood pressure and heart rate were more prominent when given in the DMH of GAERS. These results indicate an increased GABAA receptor–mediated cardiovascular response through the DMH in conscious rats with absence epilepsy.
Excitatory amino acid antagonists protect mice against seizures induced by bicuculline
Brain Research, 1990
The effects of excitatory amino acid antagonists on convulsions induced by intracerebroventricular (i.c.v.) or systemic (s.c.) administration of the ),-aminobutyric acid A (GABAA) antagonist bicucuUine (BIC) were tested in mice. 3-((+)-2-Carboxypiperazin-4-yl)-propyl-1-phosphonate (CPP), 2-amino-7-phosphonoheptanoate (AP7) and (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate (MK-801) were used as representatives of N-methyl-D-aspartate (NMDA) antagonists, y-D-Glutamylaminomethylsulphonate (~,-D-GAMS) typified a preferential kainate (KA) antagonist, 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) represented a preferential quisqualate (QA) antagonist, and kynurenic acid (KYNA) was used as a mixed NMDA/KA antagonist. Bicuculline methiodide (BMI) induced clonic convulsions following i.c.v, administration with a CDso of 0.183 nmol (range 0.164-0.204). The excitatory amino acid antagonists blocked clonic seizures induced by BMI in the dose of 0.224 nmol (approximately CD97) when coinjected into the lateral ventricle. CPP (EDs0 0.0075 nmol) was the most potent anticonvulsant and was followed by AP7 (0.182 nmol), MK-801 (0.22 nmol), ?'-o-GAMS (0.4 nmol), KYNA (1.7 nmol) and CNQX (5.17 nmol). Muscimol (MSC), the GABA A agonist, blocked BMI-induced seizures with an EDso of 0.25 nmol. Systemic (s.c.) administration of BIC induced in mice generalized seizures with a CDso of 2.2 mg/kg (range 1.9-2.5) for clonus and CDso of 2.4 mg/kg (range 2.2-2.7) for tonus. The seizures induced by s.c. injection of BIC in the dose of 3.2 mg/kg (approximately CD97 ) were blocked by pretreatment (i.p.) with the NMDA antagonists MK-801 (EDso 0.075 mg/kg for clonus and 0.044 mg/kg for tonus), CPP (7.743 mg/kg for clonus and 0.032 mg/kg for tonus) and CGS 19755 (> 10 mg/kg for clonus and 3.01 mg/kg for tonus). The GABA A agonist MSC had no effect on clonus (> 2.5 mg/kg) and prevented mice from tonus with an EDso of 1.77 mg/kg. These results suggest an important role of excitation mediated by dicarboxylic amino acids in the pathogenesis of seizures triggered by bicucuiline in mice.
Synapse, 1991
Bicuculline methiodide (BMI), a y-aminobutyrate (GABA) antagonist, is a powerful convulsant agent when injected into the cerebral ventricles, amygdala, hippocampus, thalamus, neocortex, and deep prepiriform cortex in rats. In contrast, bilateral microinjection of BMI into the rat striatum confers protection against seizures induced by the cholinergic agonist pilocarpine (380 mgkg, i.p.1, with an ED,, of 94 fmol (range 45-195 fmol). No topographical variation in the anticonvulsant action of BMI was detected throughout rostrocaudal and dorsoventral aspects of the striatum. The anticonvulsant action of BMI in the striatum was reversed by coadministration of the GABA agonist muscimol or by blocking GABA-mediated inhibition in either the substantia nigra pars reticulata or in the entopeduncular nucleus. The results show that blockade of GABA-mediated inhibition in the striatum has a powerful anticonvulsant effect in the pilocarpine model, suggesting that GABAergic transmission in the striatum modulates the seizure propagation in the forebrain.
Cardiovascular effects of intracerebroventricular bicuculline in rats with absence seizures
Epilepsy Research, 1999
administration of CDP-choline (0.25, 0.5, 1 and 2 µmol) induced prompt, dose-and time-dependent increase in blood pressure in normotensive rats. Equimolar dose of CDP-choline (1 µmol; i.c.v.) and choline (1 µmol; i.c.v.) caused similar increases in blood pressure while cytidine (1 µmol; i.c.v.) failed to produce any pressor effect. In haemorrhagic shock, CDPcholine (0.1, 0.25, 0.5 and 1 µmol; i.c.v.) increased blood pressure dose-and time-dependently. The complete reversal of hypotension was observed with the i.c.v. injection of CDP-choline (1 µmol) and choline (1 µmol). Cytidine (1 µmol; i.c.v.) produced small, but significant (P<0.05) increase in blood pressure in haemorrhaged rats. Dose-related bradycardia was observed with the injection of CDP-choline in normotensive rats, but the changes in heart rate were not significantly different (P>0.05) in hypotensive conditions. Choline levels in lateral cerebral ventricle and hypothalamus increased about nine-and fivefold, respectively, after CDP-choline (1 µmol) administration in normotensive rats. In haemorrhagic shock extracellular choline levels in hypothalamus increased sevenfold after an i.c.v. administration of CDP-choline (1 µmol). Hemicholinium-3 (20 µg; i.c.v.), a neuronal high affinity choline uptake blocker, and mecamylamine (50 µg; i.c.v.), nicotinic receptor antagonist, pretreatment abolished the pressor effect of CDP-choline in normal rats. The increase in blood pressure was also attenuated by atropine (10 µg; i.c.v.) pretreatment. Atropine blocked the bradycardic response observed after CDP-choline. In haemorrhaged rats, the pressor effect of CDP-choline was attenuated by hemicholinium-3 and mecamylamine while atropine failed to alter the pressor response to CDP-choline. I.c.v. CDPcholine increased plasma adrenaline and vasopressin levels in normal rats. Haemorrhage, itself, increased plasma tinic cholinergic receptors is solely involved in the pressor effect. Increase in plasma vasopressin and adrenaline mediates the pressor response of CDP-choline in both normotensive and hypotensive conditions.
Brain Research, 1983
The objective of the present study was to explore if lesions of the ascending noradrenergic pathways, originating in the locus coeruleus, modulate the cerebral metabolic response to bicuculline-induced seizures in rats. Bilateral noradrenergic lesions were performed by 6-hydroxydopamine injections in the caudal mesencephalon, 12-22 days before seizures were induced in animals ventilated on N20:02 (75:25). After 5 min of seizures the brain was frozen in situ and cerebral cortex and hippocampus were sampled for analysis. Labile phosphates, glycolytic metabolites, cyclic nucleotides, and free fatty acids were measured. In another series, lesioned animals wele used for measurements of cerebral oxygen consumption. The noradrenergic lesions neither modified the electroencephalographically recorded seizure discharge, nor did they alter cerebral oxygen consumption or cerebral energy state. However, when compared to sham-operated animals, those with noradrenergic lesions had significantly higher (115 ~ and 68 ~o) glycogen concentrations and lower (50 ~ and 52 ~) cyclic AMP concentrations in cerebral cortex and hippocampus, respectively, demonstrating the marked influence of noradrenergic activity on adenylate cyclase activity and glycogenolysis. The lesions failed to modulate the rise in free fatty acids in the cerebral cortex, or the cyclic GMP concentrations in the cerebral cortex and hippocampus. Thus, increased noradrenergic activity during status epilepticus does not seem responsible for lipolysis or for activation of guanylate eyclase.
Brain Research, 1996
y-Aminobutyric acid (GABA) is known to play an important role in the central control of cardiovascular functions. GABAergic agonists and antagonists elicit blood pressure and heart rate changes when injected into the brain. It was demonstrated here that bicuculline methiodide (BMI), a GABA A antagonist, caused dose-dependent increases in both blood pressure and heart rate in conscious rats when injected intracerebroventricularly. The roles of the central nucleus of the amygdala (CeA), the paraventricular nucleus (PVN) and the dorsomedial nucleus (DMH) of the hypothalamus in BMI-induced blood pressure and heart rate changes were investigated in this study. The pressor effect of BMI was significantly attenuated by the electrolytic ablation of DMH and PVN, whereas it was only slightly, but insignificantly reduced by CeA lesions. The microinjection of BMI into the DMH and the PVN elicited significant pressor and tachycardic responses whereas only a slight increase was observed in rats injected BMI into the CeA. The BMI-induced increases in both blood pressure and heart rate were more prominent when given into the DMH. These results indicate that the DMH plays an important role in GABAergic control of cardiovascular functions. The PVN and CeA seem to have a minor part in this respect.
Neuroscience letters, 2002
The aim of this study was to demonstrate the effect of administration of gamma-aminobutyric acid (GABA)A receptor antagonist, bicuculline, into the reticular nucleus of the thalamus (nRt) on spike and wave discharges (SWD) and cardiovascular regulation in conscious rats with genetic absence epilepsy. Rats were instrumented with guide cannulas for drug injection and extradural electrodes for electroencephalogram recording. After a 1 week recovery period, iliac arterial catheters were inserted for direct measurement of blood pressure and heart rate. Administration of bicuculline into the nRt produced increases in spontaneous SWD and failed to alter blood pressure and heart rate. These data suggest that GABAA receptors located within the nRt are involved in the incidence of SWD, whereas they do not seem to be involved in cardiovascular regulation of rats with genetic absence epilepsy.
Proceedings of the National Academy of Sciences, 1989
The y-aminobutyric acid antagonist, bicuculline methiodide (BMI), induces myoclonic seizures in rats when injected into the deep prepyriform cortex at concentrations lower than those that induce convulsions from the amygdala, hippocampus, or neocortex. This observation prompted the suggestion that the deep prepyriform cortex was responsible for seizure generation regardless of the neurotransmitter and neuronal circuits involved. Bilateral intrastriatal application of BMI protects rats against seizures induced by (i) local application of BMI into the deep prepyriform cortex and (ii) systemic application of bicuculline, pilocarpine (a cholinergic agonist), or kainic acid (a glutamate receptor agonist). The region of the striatum sensitive to the previously unknown anticonvulsant action of BMI is located in the immediate
Brain Research, 1976
It is well known that during generalized seizures induced by antivitamin B6 agents, such as hydrazides, as well as by direct antagonists of pyridoxine, such as desoxypyridoxine, the GABA concentration is reduced in the whole brain2, 23. The same is true in the vicinity of the human epileptic focus z2. However, previous studies have not established if the GABA reduction is the primary cause of the seizure, i.e. whether the decrease in GABA content occurs prior to the onset of the seizure or in the course of the seizure. Comparing the changes taking place during the preictal period of drug induced seizures with those of the ictal period may answer this problem. A thorough study of the preictal alterations necessitates a regional investigation for two reasons. First, the GABA level differs among brain regions 6,16 --in this respect the substantia nigra with its high GABA content is very interesting --and second, the susceptibility towards seizure discharges differs among brain regions --in this respect the hippocampus, one of the most seizure prone regions of the brain 1°,2°, earns special regard.