Activation of peripheral mitochondrial benzodiazepine receptors in the hippocampus stimulates allopregnanolone synthesis and produces anxiolytic-likeeffects in the rat

Rationale and objectives: Stimulation of the mitochondrial benzodiazepine r eceptor (MBR) in the brain activates the synthesis of neurosteroids that ca n act as positive modulators of the GABA, receptor complex. Allopregnanolon e is a potent anxiolytic, anticonvulsant, sedative and hypnotic GABAergic n eurosteroid. The anxiolytic-like effects of FGIN 1-27, an MBR agonist, were determined after microinjection into the dorsal hippocampus. Methods: Beha vior in the elevated plus-maze was assessed in adult male rats after bilate ral injections of 0, 1.25, 2.5, or 5 mu g FGIN 1-27. The behavioral effects of FGIN 1-27 were also determined in animals receiving intrahippocampal co -administration of 20 ng picrotoxin, 5 mu g flumazenil, or 200 ng PK 11195. The effects of FGIN 1-27 on behavior in the elevated plus-maze and shock-p robe burying test were measured in animals pretreated systemically with 10 mg/kg 4-MA, a 5 alpha-reductase inhibitor. Hippocampal and blood plasma lev els of allopregnanolone were measured in separate groups of animals pretrea ted with 4-MA and receiving an intrahippocampal injection of FGIN 1-27. Res ults: Intrahippocampal injections of FGIN 1-27 produced anxiolytic-like eff ects in the plus-maze and in the shock-probe burying test. Hippocampal and blood levels of allopregnanolone were also increased by FGIN 1-27. The anxi olytic-like effects of FGIN 1-27 were attenuated by PK 11195 and were block ed by picrotoxin and 4-MA pretreatment, but remained unaffected by flumazen il pretreatment. The neurosteroidogenic effect of FGIN 1-27 was also elimin ated by 4-MA. Conclusion: Activation of the MBR in the hippocampus leads to the synthesis of allopregnanolone, an anxiolytic neurosteroid that potenti ates GABAA receptor function.