TY - JOUR
T1 - Learning and memory-enhancing effects of Ro 15-4513
T2 - A comparison with flumazenil
AU - Prather, P. L.
AU - Forster, M. J.
AU - Lal, H.
PY - 1992/3
Y1 - 1992/3
N2 - Synthetic benzodiazepines produce an anterograde amnesia, which can be reversed by selective benzodiazepine antagonists or inverse agonists. It has therefore been suggested that the memory-enhancing effects of the antagonists are due to antagonism of an endogenous "benzodiazepine-like" endocoid. If the memory-enhancing effects of the benzodiazepine antagonists are determined predominantly by the antagonism of such endogenous benzodiazepine-ligands, then it could be hypothesized that administration of an inverse agonist, which produces effects functionally opposite to those of benzodiazepine agonists, may also mimic the effects of benzodiazepine antagonists but not produce effects greater than those of the pure antagonists. The purpose of the present study was therefore to investigate the memory-enhancing effects of the benzodiazepine inverse agonist, ethyl-8-amido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5a] [1,4] benzodiazepine-3-carboxylate (Ro 15-4513) in young HSD:(ICR)BR mice and to compare these effects with those of the benzodiazepine antagonist, flumazenil. Pretraining injections of flumazenil and Ro 15-4513 (2.5 and 10.0 mg/kg) enhanced equally, both the acquisition and the retention of a task for 1 week requiring mice to discriminate the correct arm of a T-maze, to avoid a mild electric shock. Pretreatment with Ro 15-4513 also dose-dependently protected the animals from experimental amnesia, induced by the cholinergic receptor antagonist, scopolamine in a second model of memory, in which mice were required to passively avoid a dark chamber after shock. In contrast, Ro 15-4513, injected prior to daily active avoidance sessions, failed to significantly improve either the acquisition or retention performance. Taken collectively, these results suggest that the benzodiazepine inverse agonist, Ro 15-4513 possessed memory-enhancing effects, approximately equivalent to that of the antagonist, flumazenil. It is therefore concluded that these memory-enhancing effects are related to the ability of these drugs to antagonize the agonistic actions of an endogenous benzodiazepine-like ligand, rather than to any intrinsic activity of their own.
AB - Synthetic benzodiazepines produce an anterograde amnesia, which can be reversed by selective benzodiazepine antagonists or inverse agonists. It has therefore been suggested that the memory-enhancing effects of the antagonists are due to antagonism of an endogenous "benzodiazepine-like" endocoid. If the memory-enhancing effects of the benzodiazepine antagonists are determined predominantly by the antagonism of such endogenous benzodiazepine-ligands, then it could be hypothesized that administration of an inverse agonist, which produces effects functionally opposite to those of benzodiazepine agonists, may also mimic the effects of benzodiazepine antagonists but not produce effects greater than those of the pure antagonists. The purpose of the present study was therefore to investigate the memory-enhancing effects of the benzodiazepine inverse agonist, ethyl-8-amido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5a] [1,4] benzodiazepine-3-carboxylate (Ro 15-4513) in young HSD:(ICR)BR mice and to compare these effects with those of the benzodiazepine antagonist, flumazenil. Pretraining injections of flumazenil and Ro 15-4513 (2.5 and 10.0 mg/kg) enhanced equally, both the acquisition and the retention of a task for 1 week requiring mice to discriminate the correct arm of a T-maze, to avoid a mild electric shock. Pretreatment with Ro 15-4513 also dose-dependently protected the animals from experimental amnesia, induced by the cholinergic receptor antagonist, scopolamine in a second model of memory, in which mice were required to passively avoid a dark chamber after shock. In contrast, Ro 15-4513, injected prior to daily active avoidance sessions, failed to significantly improve either the acquisition or retention performance. Taken collectively, these results suggest that the benzodiazepine inverse agonist, Ro 15-4513 possessed memory-enhancing effects, approximately equivalent to that of the antagonist, flumazenil. It is therefore concluded that these memory-enhancing effects are related to the ability of these drugs to antagonize the agonistic actions of an endogenous benzodiazepine-like ligand, rather than to any intrinsic activity of their own.
KW - antagonist
KW - benzodiazepines
KW - inverse agonist
KW - learning
KW - memory
KW - mouse
UR - http://www.scopus.com/inward/record.url?scp=0026586895&partnerID=8YFLogxK
U2 - 10.1016/0028-3908(92)90180-W
DO - 10.1016/0028-3908(92)90180-W
M3 - Article
C2 - 1630596
AN - SCOPUS:0026586895
SN - 0028-3908
VL - 31
SP - 299
EP - 306
JO - Neuropharmacology
JF - Neuropharmacology
IS - 3
ER -