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

Psychopharmacology (Berl). 2000 Jul;151(1):64-71. doi: 10.1007/s002130000471.


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 GABA(A) 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 microg FGIN 1-27. The behavioral effects of FGIN 1-27 were also determined in animals receiving intrahippocampal co-administration of 20 ng picrotoxin, 5 microg 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 5alpha-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 GABA(A) receptor function.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Analysis of Variance
  • Animals
  • Anxiety / metabolism*
  • GABA Antagonists / pharmacology
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Indoleacetic Acids / pharmacology
  • Isoquinolines / pharmacology
  • Male
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Picrotoxin / pharmacology
  • Pregnanolone / biosynthesis*
  • Pregnanolone / physiology
  • Rats
  • Rats, Long-Evans
  • Receptors, GABA-A / drug effects
  • Receptors, GABA-A / metabolism*


  • GABA Antagonists
  • Indoleacetic Acids
  • Isoquinolines
  • Receptors, GABA-A
  • Picrotoxin
  • N,N-di-n-hexyl-2-(4-fluorophenyl)indole-3-acetamide
  • Pregnanolone
  • PK 11195