title: Effect of ganaxolone and THIP on operant and limited-access ethanol self-administration.
abstract: Recent evidence suggests that GABA(A) receptor ligands may regulate ethanol intake via effects at both synaptic and extrasynaptic receptors. For example, the endogenous neurosteroid, allopregnanolone (ALLO) has a similar pharmacological profile as ethanol, and it alters ethanol intake in rodent models. Additionally, recent evidence suggests that δ-subunit-containing extrasynaptic GABA(A) receptors may confer high sensitivity to both ethanol and neurosteroids. The purpose of the present study was to determine the effects of ganaxolone (GAN; an ALLO analog) and gaboxadol (THIP; a GABA(A) receptor agonist with selectivity for the extrasynaptic δ-subunit) on ethanol intake, drinking patterns, and bout characteristics in operant and limited-access self-administration procedures. In separate studies, the effects of GAN (0-10 mg/kg) and THIP (2-16 mg/kg) were tested in C57BL/6J male mice provided with 2-h access to a two-bottle choice of water or 10% ethanol or trained to respond for 30 min of access to 10% ethanol. GAN had no overall significant effect on operant ethanol self-administration, but tended to decrease the latency to consume the first bout. In the limited-access procedure, GAN dose-dependently decreased ethanol intake. THIP dose-dependently decreased ethanol intake in both paradigms, altering both the consummatory and appetitive processes of operant self-administration as well as shifting the drinking patterns in both procedures. These results add to literature suggesting time-dependent effects of neurosteroids to promote the onset, and to subsequently decrease, ethanol drinking behavior, and they support a role for extrasynaptic GABA(A) receptor activation in ethanol reinforcement.
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA. ramakerm@ohsu.edu
authors.forename: Marcia J
authors.initials: MJ
authors.lastname: Ramaker
authors.forename: Moriah N
authors.initials: MN
authors.lastname: Strong
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ford
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Finn
mesh_terms: D000427:Alcohol Deterrents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000428:Alcohol Drinking / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000431:Ethanol / Q000097:blood; D058785:GABA-A Receptor Agonists / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D007555:Isoxazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D018697:Nootropic Agents / Q000494:pharmacology*; D011280:Pregnanolone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D021122:Protein Subunits / Q000819:agonists / Q000378:metabolism; D011963:Receptors, GABA-A / Q000737:chemistry / Q000378:metabolism; D012054:Reinforcement, Psychology; D012646:Self Administration; D013997:Time Factors
chemical_list: D000427:Alcohol Deterrents; D015507:Drugs, Investigational; D058785:GABA-A Receptor Agonists; D007555:Isoxazoles; D018697:Nootropic Agents; D021122:Protein Subunits; D011963:Receptors, GABA-A; D000431:Ethanol; C105051:ganaxolone; D011280:Pregnanolone; C015542:gaboxadol