The effect of chronic treatment with peripheral benzodiazepine receptor ligands on behavior and GABAA/benzodiazepine receptors in rat.
Rats were twice daily (2 x 10 mg/kg, i.p.) treated for three weeks with the peripheral benzodiazepine (BZ) receptor ligands Ro 5-4864 (4'-chlorodiazepam) and PK 11,195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carbox ami de). After the first injection there were no differences between the drug-treated and control animals in behavioral tests. After 10 days treatment, the number of sniffings was increased in Ro 5-4864-treated rats. After the last injection, sniffings and ambulations were decreased in PK 11,195-treated animals. The number of rearings and groomings remained unchanged throughout the treatment, and there were no changes in the results in the elevated plus-maze test. Apparently these compounds are devoid of anxiolytic and anxiogenic effects at moderate doses. The effect of 72 a h withdrawal from the above mentioned chronic treatment on peripheral and central BZ receptors as well as on GABAA receptors was studied with receptor binding techniques using 3H-Ro 5-4864, 3H-flumazenil and 3H-muscimol, respectively, as ligands. The number of GABAA and central BZ receptors was lower after Ro 5-4864 treatment, as was the effect of progesterone-induced stimulation of 3H-muscimol binding. The number of peripheral BZ receptors was decreased after Ro 5-4864 and PK 11,195 treatments in the olfactory bulb but not in the cerebral cortex. The chronic treatment with peripheral BZ receptor ligands Ro 5-4864 and PK 11,195 produced only little behavioral effects. Ro 5-4864, often presented as an agonist of peripheral BZ receptors, was behaviorally inactive.(ABSTRACT TRUNCATED AT 250 WORDS)
Rägo
L
L
Department of Pharmacology and Toxicology, University of Kuopio, Finland.
Saano
V
V
Auvinen
T
T
Adojaan
A
A
Holma
R
R
Airaksinen
M M
MM
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001570:Benzodiazepinones / Q000009:adverse effects / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003292:Convulsants / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007546:Isoquinolines / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D009118:Muscimol / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D013375:Substance Withdrawal Syndrome
D001570:Benzodiazepinones; D003292:Convulsants; D007546:Isoquinolines; D011963:Receptors, GABA-A; D009118:Muscimol; C028513:4'-chlorodiazepam; C037850:PK 11195