Role of cholinergic mechanisms in the mechanism of action of bicuculline (original) (raw)
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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.
Studies on the neuropharmacological activity of bicuculline and related compounds
Brain Research, 1976
Bicuculline and 3 chemical derivatives were assayed on a variety of biological systems. Consistent with reports of studies on other animals, some of these compounds caused convulsions in insects and blocked inhibitory postsynaptic potentials in insect muscle. They all potently inhibited mouse brain acetylcholinesterase. Bicuculline and its analogs inhibited the binding of GABA in vitro to sites in crayfish muscle membranes which have properties of receptor sites; this site of action could explain the activity of bicuculline at arthropod neuromuscular junctions. These compounds, at high concentrations (over 100/~M), also inhibited GABA uptake by mouse brain homogenates at 0 °C apparently non-competitively. Bicucine methyl ester inhibited GABA transport by brain at 37 °C, consistent with non-specific membrane effects at high concentrations of drug. These and other observations cast doubt upon the specificity of bicuculline-like compounds for action on GABA synapses, especially for in vitro studies at high drug concentrations (over 10 #M). The neuroactivity of low doses of bicuculline is apparently not explained by these in vitro effects, and could very well be due to inhibition of GABA synapses at either receptor or ionophore sites. At physiological conditions of pH and temperature, bicuculline is hydrolyzed at its lactone moiety to the less active compound bicucine; this could lead to underestimates of the biological activity of bicuculline. More stable analogs studied so far are not more potent, however.
General Pharmacology: The Vascular System, 1990
Some new pharmacological activities of bicuculline were found in isolated rat atria, mouse vas deferens and guinea-pig ileum. 2. In isolated rat atria bicuculline (10-300#M) induced potent positive inotropic and negative chronotropic effects which were not antagonized by propranolol (1 gM), 6-hydroxydopamine pretreatment (50 mg/kg i.v. twice), ranitidine (3 #M) or atropine (1 #M). Bicuculline (10-300 #M) potentiated electrically evoked contractions in mouse vas deferens and inhibited them (30-500 pM) in guinea-pig ileum. It was inactive on unstimulated mouse vas deferens. 3. The above effects were completely reproduced by the bicuculline related-substance, fl-hydrastine, but not by the bicuculline N-methyl derivative, bicuculline methiodide (BMI), on the isolated rat atria. BMI inhibited instead of potentiating the mouse vas deferens twitches and potentiated instead of inhibiting the guinea-pig ileum twitches. 4. Picrotoxin, the other classic non-competitive GABA A antagonist, was completely devoid of the effects reported for bicuculline. 5. We concluded that, on the three preparations studied, bicuculline possesses some effects which are unrelated to its GABA A receptor blocking activity.
Experimental Neurology, 1975
The interaction of N-methyl-bicuculline and Y-aminobutyric acid (GABA) on a synaptosomal fraction of rat cerebral cortex was examined at 0 C in a balanced bicarbonate-buffered medium using differential centrifugation and double-isotope scintillation spectrometry. The drug, at lo-' M, produced a significant decrease in the binding of ["H]GABA (lo-', lo-' M) to the particles. Further experiments revealed that N-methyl-bicuculline, at concentrations of lo-'-lo-" M, significantly decreased the "binding" of GABA (4.8 X 10." M) to the particles. This bicuculline-induced reduction in GABA binding exhibited linear characteristics over a 10-'"-10-3 M concentration range of the drug, and when present at 10d3 M, the drug decreased GABA binding by about 23%. This demonstration of a bicucullinesensitive component of GABA binding to synaptosomal particles adds support to neurophysiological studies which have indicated that bicuculline may serve as an antagonist to the GABA receptor in zjie'o.
GABA and bicuculline actions on mouse spinal cord and cortical neurons in cell culture
Brain Research, 1982
The neutral amino acid 7-aminobutyric acid (GABA) produced membrane hyperpolarization and increased membrane chloride ion conductance of spinal cord (SC) and cortical (CTX) neurons in cell culture. GABA dose response curves were obtained for SC neurons by pressure applying known concentrations of GABA from micropipettes with large tips (miniperfusion pipettes). GABA response threshold was about 2 #M and large responses were elicited at GABA concentrations greater than 10/tM. Bicuculline (B1CUC) (0.1-10/~M) reversibly antagonized GABA responses on both SC and CTX neurons with a half maximal inhibitory concentration of about 1 ttM. BICUC antagonism of GABA responses was competitive (Lineweaver-Burke analysis). These results are compared with data on GABA and BICUC displacement of [aH]GABA binding to membranes of SC and CTX neurons in cell culture. It is suggested that high affinity GABA receptors are likely to be relevant for postsynaptic GABA responses while low affinity GABA receptors may be presynaptic. 0006-8993/82/0000-0000/$02.75
Journal of Pharmacological Sciences, 2008
The posterior part of the hypothalamus plays a vital role in the homeostatic processes of the internal environment, including blood pressure and heart rate regulation, by means of γaminobutyric acid (GABA)ergic and glutamatergic neurotransmission. In this study we measured the extracellular levels of GABA and L-glutamic acid in the dorsomedial hypothalamic nucleus (DMH) and posterior hypothalamus (PH), following intracerebroventricular (i.c.v.) administration of bicuculline, a GABA A-receptor antagonist, in genetic absence epileptic rats from Strasbourg (GAERS), where heart rate, blood pressure, and EEG recordings were also collected simultaneously. The i.c.v. injection of bicuculline (0.3 nmol) produced no response in nonepileptic Wistar rats but caused an increase in mean arterial pressure in GAERS (P<0.01). Microdialysis experiments showed that L-glutamic acid increased in the DMH in GAERS after bicuculline administration (P<0.01). Additionally, extracellular GABA concentration decreased in the PH (P<0.05). Bicuculline suppressed the spike-and-wave discharges, the characteristic sign of absence seizures. All these results suggest that the bicuculline-induced blood pressure response is accompanied by changes in L-glutamic acid levels in the DMH and GABA levels in the PH, indicating a bicuculline hypersensitivity in the DMH and PH of GAERS that may make the GAERS display an altered mode of central cardiovascular regulation. These results suggest that the circuits affected in GAERS are not only restricted to the regions responsible for seizure generation but also present in the hypothalamus.