Modulation of anxiety by beta-carbolines and other benzodiazepine receptor ligands: relationship of pharmacological to biochemical measures of efficacy.
Several beta-carbolines and other benzodiazepines (BZ) receptor ligands have been investigated for anxiolytic or anxiogenic action in 4 unrelated animal models of anxiety using rats. The substances could be grouped into essentially 2 groups. The first, anxiolytics, exhibited antipunishment activity in a lick-suppression test, antagonised the discriminative stimulus provided by pentylenetetrazol, resembled chlordiazepoxide (CDP) in a drug discrimination test, and reduced the rise in plasma corticosterone levels following swim stress. Such substances included several benzodiazepines, the beta-carboline ZK 93 423, and the triazolapyridazine CL 218 872. A subgroup of anxiolytics were active in only some of these tests. They included two beta-carbolines, ZK 91 296 and ZK 95 962, and the pyrazoloquinoline CGS 9896, and these 3 substances were also distinguishable in not producing rate-decreasing effects in any of the 3 operant tests. The second group were anxiogenic in that they produced a discriminative stimulus resembling that of PTZ, they antagonised the CDP cue, exhibited propunishment effects in the lick-suppression test, and themselves caused increases in plasma corticosterone in otherwise unstressed animals. Such substances included the beta-carbolines DMCM, FG 7142 and ZK 90 886, and the pyrazoloquinoline CGS 8216. Two substances, Ro 15-1788 and ZK 93 426 had little or only weak activity in any test. The classification of these substances into anxiolytics or anxiogenics could be predicted qualitatively both by their ability to enhance (anxiolytics) or decrease the binding of 35S-TBPS to rat brain membranes and by whether their own binding was increased (anxiolytics) by adding the GABA agonist muscimol to the in vitro incubation medium. For the limited number of substances for which full data was available, there was also a quantitative relationship between the degree of enhancement of 35S-TBPS binding by a substance and its potency in the CDP cue test when such potency was expressed as numbers of BZ receptors occupied at the ED50 value in the pharmacological test. Furthermore, for the anxiolytics, activity in the CDP cue correlated significantly with potency in 2 other tests. Otherwise, surprisingly weak correlations existed between potencies in the different tests. In particular, the beta-carboline ZK 95 962 was highly potent in antagonising the PTZ cue but inactive in both a conflict test and in protecting against stress. These results are discussed in terms of differences in the neuropharmacologies of the 4 tests and in selectivity of the BZ receptor ligands for subtypes of BZ receptor.
Stephens
D N
DN
Research Laboratories of Schering AG, Berlin, F.R.G.
Schneider
H H
HH
Kehr
W
W
Jensen
L H
LH
Petersen
E
E
Honore
T
T
D000818:Animals; D001007:Anxiety / Q000187:drug effects*; D001569:Benzodiazepines / Q000008:administration & dosage / Q000378:metabolism*; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002243:Carbolines / Q000008:administration & dosage / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D013312:Stress, Physiological / Q000378:metabolism
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002243:Carbolines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C037476:tert-butylbicyclophosphorothionate; D003345:Corticosterone