Involvement of neurosteroids in the anxiolytic-like effects of AC-5216 in mice.
AC-5216, a ligand for the translocator protein (18 kDa) (TSPO), previously called the peripheral benzodiazepine receptor (PBR), produces anxiolytic-like effects mediated by TSPO in animal models of anxiety. Since stimulation of TSPO is considered to promote the synthesis of neurosteroids, we investigated the possible role of endogenous neurosteroids that positively act on the GABA(A) receptor in the anxiolytic-like effects of AC-5216. In our experiments, the effects of trilostane and finasteride, two inhibitors of steroidogenic enzymes, and picrotoxin, a GABA(A) receptor-gated Cl(-) channel blocker, on the anxiolytic-like effects of AC-5216 were examined in the social interaction test in mice. Also, the anxiolytic-like effects of allopregnanolone and progesterone were examined. The anxiolytic-like effects of AC-5216 (0.1 mg/kg, p.o.) were inhibited by trilostane (10-30 mg/kg, s.c.), finasteride (10-30 mg/kg, s.c.), and picrotoxin (0.03-0.3 mg/kg, s.c.), while those of diazepam (0.1 mg/kg, p.o.) were inhibited by picrotoxin only. The anxiolytic-like effects of progesterone (1-3 mg/kg, s.c.) were inhibited by finasteride (3-30 mg/kg) and picrotoxin (0.1-0.3 mg/kg), although those of allopregnanolone (10 mg/kg, s.c.) were inhibited by picrotoxin only. These results demonstrate that the anxiolytic-like effects of AC-5216 are due to newly synthesized neurosteroids that enhance GABA(A) receptor function.
Kita
Atsuko
A
Discovery Pharmacology II, Pharmacology Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Enoki 33-94, Suita, Osaka 564-0053, Japan. atsuko-kita@ds-pharma.co.jp
Furukawa
Kiyoshi
K
D000818:Animals; D014151:Anti-Anxiety Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology; D013196:Dihydrotestosterone / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018120:Finasteride / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D007398:Interpersonal Relations; D008297:Male; D051379:Mice; D010852:Picrotoxin / Q000494:pharmacology; D011280:Pregnanolone / Q000494:pharmacology*; D011374:Progesterone / Q000494:pharmacology*; D011687:Purines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000187:drug effects
D014151:Anti-Anxiety Agents; D003975:Diazepam; D013196:Dihydrotestosterone; D004791:Enzyme Inhibitors; D018120:Finasteride; D018756:GABA Antagonists; D010852:Picrotoxin; D011280:Pregnanolone; D011374:Progesterone; D011687:Purines; D011963:Receptors, GABA-A; C502525:N-benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide; C009954:trilostane