Discriminative stimulus effects of omega (BZ) receptor ligands: correlation with in vivo inhibition of [3H]-flumazenil binding in different regions of the rat central nervous system.
Rats can be trained to discriminate benzodiazepines (BZ) from vehicle and there is considerable evidence that the stimulus effects of these drugs are mediated by activity at omega (BZ) modulatory sites of the GABAA receptor complex. A number of recent studies, however, have indicated that differences may exist between the discriminative stimulus effects of benzodiazepines and those of certain non-benzodiazepine ligands for the omega (BZ) receptors (e.g. zolpidem, abecarnil). As it is known that several subtypes of omega (BZ) sites are found in the central nervous system, and that drugs such as zolpidem have selectivity for certain subtypes, it is possible that differential stimulus effects may be associated with receptor selectivity. In the present study, correlations were calculated between the potencies of nine compounds with affinity for omega receptors (diazepam, lorazepam, triazolam, clonazepam, alprazolam, zopiclone, suriclone, CL 218, 872 and zolpidem) to substitute for chlordiazepoxide in rats trained to discriminate a dose (5 mg/kg) of this benzodiazepine and the ability of the same compounds to inhibit the binding of [3H]-flumazenil from different structures in the rat central nervous system in vivo. The correlations obtained were: cerebellum 0.46, cortex 0.39, striatum 0.78 (P < 0.05), hippocampus 0.79 (P < 0.05) and spinal cord 0.95 (P < 0.001). These different structures are known to contain different relative concentrations of omega 1 (BZ1) and omega 2 (BZ2) sites with the spinal cord containing the greatest (80%) and cerebellum the lowest (5%) concentration of omega 2 (BZ2) sites.(ABSTRACT TRUNCATED AT 250 WORDS)
Sanger
D J
DJ
Synthélabo Recherche (L.E.R.S.), Bagneux, France.
Benavides
J
J
D000818:Animals; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D004193:Discrimination Learning / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D005442:Flumazenil / Q000493:pharmacokinetics*; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D008024:Ligands; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
D014151:Anti-Anxiety Agents; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D008024:Ligands; D011963:Receptors, GABA-A; D005442:Flumazenil