title: Activation of peripheral mitochondrial benzodiazepine receptors in the hippocampus stimulates allopregnanolone synthesis and produces anxiolytic-like effects in the rat.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  Activation of the MBR in the hippocampus leads to the synthesis of allopregnanolone, an anxiolytic neurosteroid that potentiates GABA(A) receptor function.
authors.affiliation: Department of Psychology, College of the Holy Cross, Worcester, MA 01602, USA. dbitran@holycross.edu
authors.forename: D
authors.initials: D
authors.lastname: Bitran
authors.forename: M
authors.initials: M
authors.lastname: Foley
authors.forename: D
authors.initials: D
authors.lastname: Audette
authors.forename: N
authors.initials: N
authors.lastname: Leslie
authors.forename: C A
authors.initials: CA
authors.lastname: Frye
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001007:Anxiety / Q000378:metabolism*; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007210:Indoleacetic Acids / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010852:Picrotoxin / Q000494:pharmacology; D011280:Pregnanolone / Q000096:biosynthesis* / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*
chemical_list: D018756:GABA Antagonists; D007210:Indoleacetic Acids; D007546:Isoquinolines; D010852:Picrotoxin; D011280:Pregnanolone; D011963:Receptors, GABA-A; C081306:N,N-di-n-hexyl-2-(4-fluorophenyl)indole-3-acetamide; C037850:PK 11195