Biomaterial Database

Chronic benzodiazepine administration. VIII. Receptor upregulation produced by chronic exposure to the inverse agonist FG-7142. 1991

G A Pritchard, and W R Galpern, and M Lumpkin, and L G Miller

Department of Psychiatry, Tufts University School of Medicine and New England Medical Center, Boston, Massachusetts.

Treatment with benzodiazepine agonists is associated with the development of behavioral tolerance and receptor downregulation, whereas antagonist administration has been reported to lead to increased activity and receptor upregulation. To determine the effects of chronic inverse agonist administration, mice were treated with FG-7142 (20 mg/kg/day) by implanted s.c. osmotic pumps for 1 to 14 days. No seizures were observed in FG-7142-exposed animals. Open-field activity was unchanged as compared to controls at days 1 and 2, but was elevated significantly at days 4 and 7. Activity was reduced below control values at day 14. Benzodiazepine receptor binding determined in vivo was unchanged for days 1, 4 and 7 within the hippocampus but was elevated at day 14. Binding remained unchanged in the cortex, cerebellum, hypothalamus and pons-medulla for the duration of drug exposure. Cortical benzodiazepine binding assessed in vitro was unchanged at days 1 and 2 but increased at days 4, 7 and 14 vs. vehicle treated controls. Binding at the gamma-aminobutyric acid site was increased at day 7 whereas binding of t-[35S]butylbicyclophosphoro-thionate was increased at days 7 and 14 of FG-7142 exposure. Maximal muscimol-slimulated [36Cl-] uptake was elevated at days 4, 7 and 14 compared to day 1 of exposure. These results demonstrate that chronic continuous exposure to FG-7142 is associated with an absence of kindled seizures and with behavioral and neurochemical changes indicative of gamma-aminobutyric acidA receptor upregulation.

UI	MeSH Term	Description	Entries
D007275	Injections, Intravenous	Injections made into a vein for therapeutic or experimental purposes.	Intravenous Injections,Injection, Intravenous,Intravenous Injection
D008297	Male		Males
D009043	Motor Activity	Body movements of a human or an animal as a behavioral phenomenon.	Activities, Motor,Activity, Motor,Motor Activities
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
D002243	Carbolines	A group of pyrido-indole compounds. Included are any points of fusion of pyridine with the five-membered ring of indole and any derivatives of these compounds. These are similar to CARBAZOLES which are benzo-indoles.	Carboline,Pyrido(4,3-b)Indole,Beta-Carbolines,Pyrido(4,3-b)Indoles,Beta Carbolines
D005442	Flumazenil	A potent benzodiazepine receptor antagonist. Since it reverses the sedative and other actions of benzodiazepines, it has been suggested as an antidote to benzodiazepine overdoses.	Flumazepil,Anexate,Lanexat,Ro 15-1788,Romazicon,Ro 15 1788,Ro 151788
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
D001067	Appetite Depressants	Agents that are used to suppress appetite.	Anorectic,Anorectic Agent,Anorectics,Anorexic Drug,Anorexigenic Drug,Appetite Depressant,Appetite Suppressant,Appetite Suppressants,Appetite-Depressing Drug,Appetite-Suppressant Drug,Anorectic Agents,Anorexic Drugs,Anorexigenic Drugs,Appetite-Depressing Drugs,Appetite-Suppressant Drugs,Agent, Anorectic,Agents, Anorectic,Appetite Depressing Drug,Appetite Depressing Drugs,Appetite Suppressant Drug,Appetite Suppressant Drugs,Depressant, Appetite,Depressants, Appetite,Drug, Anorexic,Drug, Anorexigenic,Drug, Appetite-Depressing,Drug, Appetite-Suppressant,Drugs, Anorexic,Drugs, Anorexigenic,Drugs, Appetite-Depressing,Drugs, Appetite-Suppressant,Suppressant, Appetite,Suppressants, Appetite
D001569	Benzodiazepines	A group of two-ring heterocyclic compounds consisting of a benzene ring fused to a diazepine ring.	Benzodiazepine,Benzodiazepine Compounds
D001665	Binding Sites	The parts of a macromolecule that directly participate in its specific combination with another molecule.	Combining Site,Binding Site,Combining Sites,Site, Binding,Site, Combining,Sites, Binding,Sites, Combining