Biomaterial Database

Electrophysiological characterization of potent agonists and antagonists at pre- and postsynaptic GABAB receptors on neurones in rat brain slices. 1990

G R Seabrook, and W Howson, and M G Lacey

Department of Pharmacology, Smith Kline and French Research Limited, Frythe Welwyn, Hertfordshire.

1. Intracellular recordings were made from neurons in striatum (caudate-putamen) and substantia nigra pars compacta in rat brain slices. Three GABAB agonists, baclofen, 3-aminopropylphosphinic acid (3-APPA) and 3-aminopropyl(methyl)phosphinic acid (SK&F 97541), depressed excitatory postsynaptic potentials (e.p.s.ps) mediated by glutamate in the striatum, and hyperpolarized neurones in the substantia nigra. The ability of 3-aminopropyl(diethyoxymethyl)phosphinic acid (CGP 35348), 3-aminopropyl (hexyl)phosphinic acid (3-APHPA) and phaclofen to antagonize these responses was assessed. 2. Striatal e.p.s.ps, studied in the presence of bicuculline (30 microns), were reduced in amplitude by 92% with 6,7-dinitroquinoxaline-2,3-dione (DNQX; 30 microns). These e.p.s.ps were depressed by up to 95% by SK&F 97541 and baclofen with EC50s of 0.092 microns and 1.25 microns respectively. The maximal effect of 3-APPA was 67% with an EC50 of 0.83 microns. Agonist concentration-effect data fitted a single-site logistic model. GABAB agonists were without effect on striatal neurone membrane potential, input resistance or depolarizations induced by applied glutamate. 3. The depression of striatal e.p.s.ps by SK&F 97541 was reversibly antagonized by CGP 35348, 3-APHPA and phaclofen with estimated equilibrium dissociation constants (KB) of 11.2 +/- 1.7 microns (n = 4), 13.3 +/- 0.4 microM (n = 3) and 405 +/- 43 microM (n = 3) respectively. CGP 35348 and 3-APHPA appeared to act competitively (Schild plot slopes of 0.99 and 1.01 respectively). 4. Nigral neurones were hyperpolarized by up to 25 mV by SK&F 97541 and baclofen with EC50s of 0.15 microns and 3.6 microns respectively. The maximum hyperpolarization by 3-APPA was only 84% that of the other agonists, with an EC50 of 9.0 microM. Agonist concentration-effect data fitted a single-site logistic model. 5. The SK&F 97541-induced hyperpolarization was reversibly antagonized by CGP 35348, 3-APHPA and phaclofen with estimated KBS of 17.6 + 4.4 (n = 3), 14.0 + 1.5 (n = 4), and >400 microM (n = 1) respectively. CGP 35348 appeared competitive (Schild plot slope of 0.99). Antagonists were also tested with baclofen as agonist, yielding similar KB estimates as for SK&F 97541. 6. It is concluded that at both the presynaptic and postsynaptic sites examined, SK&F 97541 was about 10 fold more potent than baclofen or 3-APPA. The antagonists CGP 35348 and 3-APHPA (KB 1O-20 microM) were about 20 fold more potent than phaclofen. The similarities in relative agonist potency and estimated antagonist affinity between these two functionally distinct GABAB receptors renders them pharmacologically indistinguishable at present.

UI	MeSH Term	Description	Entries
D008564	Membrane Potentials	The voltage differences across a membrane. For cellular membranes they are computed by subtracting the voltage measured outside the membrane from the voltage measured inside the membrane. They result from differences of inside versus outside concentration of potassium, sodium, chloride, and other ions across cells' or ORGANELLES membranes. For excitable cells, the resting membrane potentials range between -30 and -100 millivolts. Physical, chemical, or electrical stimuli can make a membrane potential more negative (hyperpolarization), or less negative (depolarization).	Resting Potentials,Transmembrane Potentials,Delta Psi,Resting Membrane Potential,Transmembrane Electrical Potential Difference,Transmembrane Potential Difference,Difference, Transmembrane Potential,Differences, Transmembrane Potential,Membrane Potential,Membrane Potential, Resting,Membrane Potentials, Resting,Potential Difference, Transmembrane,Potential Differences, Transmembrane,Potential, Membrane,Potential, Resting,Potential, Transmembrane,Potentials, Membrane,Potentials, Resting,Potentials, Transmembrane,Resting Membrane Potentials,Resting Potential,Transmembrane Potential,Transmembrane Potential Differences
D009474	Neurons	The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM.	Nerve Cells,Cell, Nerve,Cells, Nerve,Nerve Cell,Neuron
D009943	Organophosphorus Compounds	Organic compounds that contain phosphorus as an integral part of the molecule. Included under this heading is broad array of synthetic compounds that are used as PESTICIDES and DRUGS.	Organophosphorus Compound,Organopyrophosphorus Compound,Organopyrophosphorus Compounds,Compound, Organophosphorus,Compound, Organopyrophosphorus,Compounds, Organophosphorus,Compounds, Organopyrophosphorus
D011963	Receptors, GABA-A	Cell surface proteins which bind GAMMA-AMINOBUTYRIC ACID and contain an integral membrane chloride channel. Each receptor is assembled as a pentamer from a pool of at least 19 different possible subunits. The receptors belong to a superfamily that share a common CYSTEINE loop.	Benzodiazepine-Gaba Receptors,GABA-A Receptors,Receptors, Benzodiazepine,Receptors, Benzodiazepine-GABA,Receptors, Diazepam,Receptors, GABA-Benzodiazepine,Receptors, Muscimol,Benzodiazepine Receptor,Benzodiazepine Receptors,Benzodiazepine-GABA Receptor,Diazepam Receptor,Diazepam Receptors,GABA(A) Receptor,GABA-A Receptor,GABA-A Receptor alpha Subunit,GABA-A Receptor beta Subunit,GABA-A Receptor delta Subunit,GABA-A Receptor epsilon Subunit,GABA-A Receptor gamma Subunit,GABA-A Receptor rho Subunit,GABA-Benzodiazepine Receptor,GABA-Benzodiazepine Receptors,Muscimol Receptor,Muscimol Receptors,delta Subunit, GABA-A Receptor,epsilon Subunit, GABA-A Receptor,gamma-Aminobutyric Acid Subtype A Receptors,Benzodiazepine GABA Receptor,Benzodiazepine Gaba Receptors,GABA A Receptor,GABA A Receptor alpha Subunit,GABA A Receptor beta Subunit,GABA A Receptor delta Subunit,GABA A Receptor epsilon Subunit,GABA A Receptor gamma Subunit,GABA A Receptor rho Subunit,GABA A Receptors,GABA Benzodiazepine Receptor,GABA Benzodiazepine Receptors,Receptor, Benzodiazepine,Receptor, Benzodiazepine-GABA,Receptor, Diazepam,Receptor, GABA-A,Receptor, GABA-Benzodiazepine,Receptor, Muscimol,Receptors, Benzodiazepine GABA,Receptors, GABA A,Receptors, GABA Benzodiazepine,delta Subunit, GABA A Receptor,epsilon Subunit, GABA A Receptor,gamma Aminobutyric Acid Subtype A Receptors
D001921	Brain	The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM.	Encephalon
D003342	Corpus Striatum	Striped GRAY MATTER and WHITE MATTER consisting of the NEOSTRIATUM and paleostriatum (GLOBUS PALLIDUS). It is located in front of and lateral to the THALAMUS in each cerebral hemisphere. The gray substance is made up of the CAUDATE NUCLEUS and the lentiform nucleus (the latter consisting of the GLOBUS PALLIDUS and PUTAMEN). The WHITE MATTER is the INTERNAL CAPSULE.	Lenticular Nucleus,Lentiform Nucleus,Lentiform Nuclei,Nucleus Lentiformis,Lentiformis, Nucleus,Nuclei, Lentiform,Nucleus, Lenticular,Nucleus, Lentiform,Striatum, Corpus
D004594	Electrophysiology	The study of the generation and behavior of electrical charges in living organisms particularly the nervous system and the effects of electricity on living organisms.
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D001418	Baclofen	A GAMMA-AMINOBUTYRIC ACID derivative that is a specific agonist of GABA-B RECEPTORS. It is used in the treatment of MUSCLE SPASTICITY, especially that due to SPINAL CORD INJURIES. Its therapeutic effects result from actions at spinal and supraspinal sites, generally the reduction of excitatory transmission.	Baclophen,Chlorophenyl GABA,Apo-Baclofen,Atrofen,Ba-34,647,Ba-34647,Baclofen AWD,Baclofène-Irex,Baclospas,CIBA-34,647-BA,Clofen,Gen-Baclofen,Genpharm,Lebic,Lioresal,Liorésal,Nu-Baclo,PCP-GABA,PMS-Baclofen,beta-(Aminomethyl)-4-chlorobenzenepropanoic Acid,beta-(p-Chlorophenyl)-gamma-aminobutyric Acid,AWD, Baclofen,Apo Baclofen,ApoBaclofen,Ba34,647,Ba34647,Baclofène Irex,BaclofèneIrex,CIBA34,647BA,GABA, Chlorophenyl,Gen Baclofen,GenBaclofen,Nu Baclo,NuBaclo,PMS Baclofen,PMSBaclofen
D001640	Bicuculline	An isoquinoline alkaloid obtained from Dicentra cucullaria and other plants. It is a competitive antagonist for GABA-A receptors.	6-(5,6,7,8-Tetrahydro-6-methyl-1,3-dioxolo(4,5-g)isoquinolin-5-yl)furo(3,4-e)1,3-benzodioxol-8(6H)one