Biomaterial Database

Reversible modification of GABAA receptor subunit mRNA expression during tolerance to diazepam-induced cognition dysfunction. 1996

P Longone, and F Impagnatiello, and A Guidotti, and E Costa

Department of Psychiatry, University of Illinois at Chicago 60612, USA.

Benzodiazepines (BZs) that are endowed with full positive allosteric modulatory (FAM) activity on GABAA receptors cause anterograde amnesia in both animals and humans. In rats subjected to a delayed object recognition test, diazepam, endowed with FAM activity, exerted an amnesic action, whereas BZs endowed with partial allosteric modulatory (PAM) activity on GABAA receptors, such as imidazenil, failed to induce amnesia, even if administered at doses five times higher than those equipotent to a standard anticonvulsant dose of diazepam (17.6 mumol/kg/os). After discontinuation of 14 days' treatment with vehicle, diazepam, or imidazenil (three times daily with increasing doses starting from 17.6 mumol/kg/os for diazepam and 2.5 mumol/kg/os for imidazenil), we compared the persistence of tolerance to the amnesic effect of diazepam with the persistence of the changes in the context of four (alpha 1, alpha 5, gamma 2L, gamma 2S) GABAA receptor subunit mRNAs in the fronto-parietal motor (FrPaM) cortex and the hippocampus. Rats receiving the long-term treatment with diazepam developed a tolerance to the amnesic effect of this drug and showed a decrease (30-50%) in the expression of mRNAs encoding for alpha 1 gamma 2L, gamma 2S GABAA receptor subunits, an increase, by approximately 30%, of the expression of mRNA of the alpha 5 subunit in the FrPaM cortex and a decrease, by approximately 25%, in the expression of mRNA, of the alpha 1 subunit in the hippocampus. These changes of subunit mRNA expression and the tolerance to the amnesic effect of diazepam returned to control values 72 hr after termination of the long-term treatment with diazepam. No tolerance to the amnesic effect of diazepam and no changes in GABAA receptor subunit mRNA expression were found in rats undergoing long-term treatment with imidazenil.

UI	MeSH Term	Description	Entries
D007093	Imidazoles	Compounds containing 1,3-diazole, a five membered aromatic ring containing two nitrogen atoms separated by one of the carbons. Chemically reduced ones include IMIDAZOLINES and IMIDAZOLIDINES. Distinguish from 1,2-diazole (PYRAZOLES).
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
D003072	Cognition Disorders	Disorders characterized by disturbances in mental processes related to learning, thinking, reasoning, and judgment.	Overinclusion,Disorder, Cognition,Disorders, Cognition
D003975	Diazepam	A benzodiazepine with anticonvulsant, anxiolytic, sedative, muscle relaxant, and amnesic properties and a long duration of action. Its actions are mediated by enhancement of GAMMA-AMINOBUTYRIC ACID activity.	7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,Apaurin,Diazemuls,Faustan,Relanium,Seduxen,Sibazon,Stesolid,Valium
D004361	Drug Tolerance	Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from DRUG RESISTANCE wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from MAXIMUM TOLERATED DOSE and NO-OBSERVED-ADVERSE-EFFECT LEVEL.	Drug Tolerances,Tolerance, Drug,Tolerances, Drug
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
D000927	Anticonvulsants	Drugs used to prevent SEIZURES or reduce their severity.	Anticonvulsant,Anticonvulsant Drug,Anticonvulsive Agent,Anticonvulsive Drug,Antiepileptic,Antiepileptic Agent,Antiepileptic Agents,Antiepileptic Drug,Anticonvulsant Drugs,Anticonvulsive Agents,Anticonvulsive Drugs,Antiepileptic Drugs,Antiepileptics,Agent, Anticonvulsive,Agent, Antiepileptic,Agents, Anticonvulsive,Agents, Antiepileptic,Drug, Anticonvulsant,Drug, Anticonvulsive,Drug, Antiepileptic,Drugs, Anticonvulsant,Drugs, Anticonvulsive,Drugs, Antiepileptic
D001569	Benzodiazepines	A group of two-ring heterocyclic compounds consisting of a benzene ring fused to a diazepine ring.	Benzodiazepine,Benzodiazepine Compounds