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

Rationale and objectives: Stimulation of the mitochondrial benzodiazepine receptor (MBR) in the brain activates the synthesis of neurosteroids that can act as positive modulators of the GABAA receptor complex. Allopregnanolone is a potent anxiolytic, anticonvulsant, sedative and hypnotic GABAergic neurosteroid. The anxiolytic-like effects of FGIN 1-27, an MBR agonist, were determined after microinjection into the dorsal hippocampus. Methods: Behavior in the elevated plus-maze was assessed in adult male rats after bilateral injections of 0, 1.25, 2.5, or 5 µg FGIN 1-27. The behavioral effects of FGIN 1-27 were also determined in animals receiving intrahippocampal co-administration of 20 ng picrotoxin, 5 µg flumazenil, or 200 ng PK 11195. The effects of FGIN 1-27 on behavior in the elevated plus-maze and shock-probe burying test were measured in animals pretreated systemically with 10 mg/kg 4-MA, a 5α-reductase inhibitor. Hippocampal and blood plasma levels of allopregnanolone were measured in separate groups of animals pretreated with 4-MA and receiving an intrahippocampal injection of FGIN 1-27. Results: Intrahippocampal injections of FGIN 1-27 produced anxiolytic-like effects 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 anxiolytic-like effects of FGIN 1-27 were attenuated by PK 11195 and were blocked by picrotoxin and 4-MA pretreatment, but remained unaffected by flumazenil pretreatment. The neurosteroidogenic effect of FGIN 1-27 was also eliminated by 4-MA. Conclusion: Activation of the MBR in the hippocampus leads to the synthesis of allopregnanolone, an anxiolytic neurosteroid that potentiates GABAA receptor function.