Evidence for central benzodiazepine receptor heterogeneity from behavior tests.
To explore behavioral selectivity as a consequence of multiple receptor subtypes, four benzodiazepine receptor ligands, flunitrazepam, CGS 9896, zolpidem, and AHR 11797, were tested at five in vivo endpoints: anticonvulsant action, anxiolysis/anxiogenesis as determined in the plus-maze test, locomotor activity, changes in food consumption, and hypothermia. All compounds produced hypothermia. In the plus-maze test, flunitrazepam, CGS 9896, and a low dose of zolpidem (0.05 mg/kg) increased the time spent in the open arms, although AHR 11797 and higher doses of zolpidem decreased time spent in the open arms. Flunitrazepam and zolpidem greatly reduced, CGS 9896 slightly reduced, and AHR 11797 did not affect locomotor activity. Flunitrazepam and CGS 9896 increased food consumption, but AHR 11797 and zolpidem had no effect. Only flunitrazepam fully protected the animals from pentylenetetrazol-induced seizures. The qualitative differences in the effects of these compounds observed are difficult to explain by activation of a single benzodiazepine receptor subtype. As Ro15-1788 antagonized all the observed effects, these compounds act through multiple central benzodiazepine receptors.
Davies
M F
MF
Molecular Research Institute, Palo Alto, CA 94304.
Onaivi
E S
ES
Chen
S W
SW
Maguire
P A
PA
Tsai
N F
NF
Loew
G H
GH
D000818:Animals; D001007:Anxiety / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects*; D001569:Benzodiazepines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005247:Feeding Behavior / Q000187:drug effects; D005442:Flumazenil / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects*; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control
D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005442:Flumazenil; D010433:Pentylenetetrazole