COMPARISON OF SEVERAL BENZODIAZEPINE RECEPTOR LIGANDS IN 2 MODELS OF ANXIOLYTIC ACTIVITY IN THE MOUSE - AN ANALYSIS BASED ON FRACTIONAL RECEPTOR OCCUPANCIES

This study compared the effects of the beta-carboline anxiolytic, abec arnil, with other benzodiazepine receptor (BZR) ligands, including the full agonists diazepam and alprazolam, and the partial agonists ZK 95 962 and bretazenil (Ro 16-6028), and alpidem, in the mouse four-plate test and plus-maze. The efficacy and potency of each compound was rela ted to the fraction of BZR occupied by the drug. Abecarnil was efficac ious in both tests and showed anxiolytic effects comparable with alpra zolam and diazepam. In the four-plate test, abecarnil, bretazenil, and ZK 95962 had selective effects on releasing exploratory locomotor act ivity suppressed by footshock (punished crossings). None of these comp ounds significantly altered non-punished crossings. In contrast, diaze pam and alprazolam increased both unpunished and punished crossings at low to medium doses (receptor occupancies of approximately 20-60%). T he number of punished and unpunished crossings fell to control levels or below at higher, more sedative doses (approximately 80% receptor oc cupancy. Alpidem had very weak anxiolytic-like effects in this test an d markedly reduced unpunished crossings at relatively low receptor occ upancies (>15%). In the plus-maze, abecarnil increased the time spent in the open arms and the percentage open arm entries to an extent equa l to that observed following diazepam or alprazolam administration. Br etazenil and ZK 95962 had weak effects on the measures of anxiolytic a ctivity in this test. Alpidem also had little anxiolytic-like activity in the plus-maze but markedly reduced the total number of arm entries . The fractional BZR occupancies required to increase the time spent i n the open arms of the maze to 250% of control levels were approximate ly 45% for abecarnil and alprazolam, 60% for diazepam, and 100% for ZK 95962. Bretazenil did not reach this potentiation at the doses tested (up to 89% receptor occupancy). Abecarnil appeared to act as a full a gonist on the measures of anxiolytic activity in both. tests (i.e. req uired low fractional BZR occupancies) but on the measures of stimulati on or sedation was more similar to the BZR partial agonists (i.e. had no significant effects even at receptor occupancies approaching 100%). On this basis abecarnil could be described as a ''selective agonist'' . In general, the four-plate test was more sensitive than the plus-maz e. For example, lower BZR occupancies were needed to produce significa nt anxiolytic effects in the four-plate test than in the plus-maze. In addition, the partial agonists bretazenil and ZK 95962, which both pr oduced weak effects in the plus-maze, had similar anxiolytic potencies to the full BZR agonists, diazepam and alprazolam, in the four-plate test.