Cerebral-activating (EEG) properties of two inverse agonists and of an antagonist at the benzodiazepine receptor in the rat.
In order to assess the effects of inverse benzodiazepine agonists and antagonists on brain function, computerized EEG (CEEG) analysis was performed in rats following the i.p. administration of SR 95195 (7-phenyl-3-methyl-1,2,4 triazolo-[4,3-b]pyridazine) and CGS 8216 (2-phenylpyrazolo-[4,3c]-quinoline-3-[5H]-one) two benzodiazepine receptor inverse agonists (BRIAGs) and of flumazepil (Ro 15-1788), a benzodiazepine receptor antagonist (BRANT). The EEG effects of SR 95195 (3, 10, 30 and 60 mg/kg), CGS 8216 (10 and 30 mg/kg) and flumazepil (3, 10, 30 and 60 mg/kg) were compared to those of the psychostimulant drugs DL-amphetamine (0.1, 0.3 and 1 mg/kg), and caffeine (10 and 30 mg/kg) and those of aniracetam (100 and 300 mg/kg), a nootropic pyrrolidone derivative. The CEEG profiles of SR 95195, CGS 8216 and flumazepil were mainly characterized by a power increase in the 20-32 Hz frequency range and by a power reduction in the 8-16 Hz range. These effects were quite similar to those of the psychostimulants DL-amphetamine and caffeine as well as to those of the nootropic aniracetam. Other psychotropic drugs with CNS-depressant properties, namely diazepam (10 mg/kg p.o.), pentobarbital (30 mg/kg p.o.), chlorpromazine (10 mg/kg i.p.) and imipramine (10 mg/kg i.p.) induced quite different EEG power modifications. These results show that BRIAGs and BRANTs possess a marked intrinsic activity at the central level and suggest that this activity is CNS-activating in nature.
Santucci
V
V
Department of Neuropsychiatry, Sanofi Recherche, Montpellier, France.
Fournier
M
M
Worms
P
P
Keane
P
P
Bizière
K
K
D000818:Animals; D014151:Anti-Anxiety Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D002746:Chlorpromazine / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D004569:Electroencephalography; D005442:Flumazenil / Q000494:pharmacology; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D010424:Pentobarbital / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology
D014151:Anti-Anxiety Agents; D000697:Central Nervous System Stimulants; D011720:Pyrazoles; D011724:Pyridazines; D011760:Pyrrolidinones; D011963:Receptors, GABA-A; C051712:7-phenyl-3-methyl-1,2,4-triazolo-(4,3b)pyridazine; D005442:Flumazenil; C036466:aniracetam; C033830:2-phenylpyrazolo(4,3-c)quinolin-3(5H)-one; D010424:Pentobarbital; D007099:Imipramine; D003975:Diazepam; D002746:Chlorpromazine