title: Alteration of ethanol drinking in mice via modulation of the GABA(A) receptor with ganaxolone, finasteride, and gaboxadol.
abstract: BACKGROUND
  Neurosteroids and other γ-aminobutyric acid(A) (GABA(A) ) receptor-modulating compounds have been shown to affect ethanol intake, although their mechanism remains unclear. This study examined how patterns of 24-hour ethanol drinking in mice were altered with the synthetic GABAergic neurosteroid ganaxolone (GAN), with an inhibitor of neurosteroid synthesis (finasteride [FIN]), or a GABA(A) receptor agonist with some selectivity at extrasynaptic receptors (gaboxadol HCL [THIP]).
  
  
  METHODS
  Male C57BL/6J mice had continuous access to a 10% v/v ethanol solution (10E) or water. Using lickometer chambers, drinking patterns were analyzed among mice treated in succession to GAN (0, 5, and 10 mg/kg), FIN (0 or 100 mg/kg), and THIP (0, 2, 4, 8, and 16 mg/kg).
  
  
  RESULTS
  GAN shifted drinking in a similar but extended manner to previous reports using low doses of the neurosteroid allopregnanolone (ALLO); drinking was increased in hour 1, decreased in hours 2 and 3, and increased in hours 4 and 5 postinjection. THIP (8 mg/kg) and FIN both decreased 10E drinking during the first 5 hours postinjection by 30 and 53%, respectively, while having no effect on or increasing water drinking, respectively. All 3 drugs altered the initiation of drinking sessions in a dose-dependent fashion. FIN increased and GAN decreased time to first lick and first bout. THIP (8 mg/kg) decreased time to first lick but increased time to first bout and attenuated first bout size.
  
  
  CONCLUSIONS
  The present findings support a role for the modulation of ethanol intake by neurosteroids and GABA(A) receptor-acting compounds and provide hints as to how drinking patterns are shifted. The ability of THIP to alter 10E drinking suggests that extrasynaptic GABA(A) receptors may be involved in the modulation of ethanol intake. Further, the consistent results with THIP to that seen previously with high doses of ALLO suggest that future studies should further examine the relationship between neurosteroids and extrasynaptic GABA(A) receptors, which could provide a better understanding of the mechanism by which neurosteroids influence ethanol intake.
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon, USA. ramakerm@ohsu.edu
authors.forename: Marcia J
authors.initials: MJ
authors.lastname: Ramaker
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ford
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Fretwell
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Finn
mesh_terms: D000428:Alcohol Drinking / Q000503:physiopathology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004327:Drinking Behavior / Q000187:drug effects* / Q000502:physiology; D018120:Finasteride / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D011280:Pregnanolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology
chemical_list: D058785:GABA-A Receptor Agonists; D007555:Isoxazoles; D011963:Receptors, GABA-A; D018120:Finasteride; C105051:ganaxolone; D011280:Pregnanolone; C015542:gaboxadol