title: Central and peripheral metabolic changes induced by gamma-hydroxybutyrate.
abstract: OBJECTIVE
  Gamma-hydroxybutyrate (GHB) was originally introduced as an anesthetic but was first abused by bodybuilders and then became a recreational or club drug.1 Sodium salt of GHB is currently used for the treatment of cataplexy in patients with narcolepsy. The mode of action and metabolism of GHB is not well understood. GHB stimulates growth hormone release in humans and induces weight loss in treated patients, suggesting an unexplored metabolic effect. In different experiments the effect of GHB administration on central (cerebral cortex) and peripheral (liver) biochemical processes involved in the metabolism of the drug, as well as the effects of the drug on metabolism, were evaluated in mice.
  
  
  METHODS
  C57BL/6J, gamma-aminobutyric acid B (GABAB) knockout and obese (ob/ob) mice were acutely or chronically treated with GHB at 300 mg/kg.
  
  
  RESULTS
  Respiratory ratio decreased under GHB treatment, independent of food intake, suggesting a shift in energy substrate from carbohydrates to lipids. GHB-treated C57BL/6J and GABAB null mice but not ob/ob mice gained less weight than matched controls. GHB dramatically increased the corticosterone level but did not affect growth hormone or prolactin. Metabolome profiling showed that an acute high dose of GHB did not increase the brain GABA level. In the brain and the liver, GHB was metabolized into succinic semialdehyde by hydroxyacid-oxoacid transhydrogenase. Chronic administration decreased glutamate, s-adenosylhomocysteine, and oxidized gluthathione, and increased omega-3 fatty acids.
  
  
  CONCLUSIONS
  Our findings indicate large central and peripheral metabolic changes induced by GHB with important relevance to its therapeutic use.
authors.affiliation: Center for Integrative Genomics (CIG), University of Lausanne, Lausanne, Switzerland.
authors.forename: Gianina
authors.initials: G
authors.lastname: Luca
authors.affiliation: Department of Biology, Brandeis University, Waltham, MA.
authors.forename: Julie
authors.initials: J
authors.lastname: Vienne
authors.affiliation: Center for Integrative Genomics (CIG), University of Lausanne, Lausanne, Switzerland.
authors.forename: Angélique
authors.initials: A
authors.lastname: Vaucher
authors.affiliation: Center for Integrative Genomics (CIG), University of Lausanne, Lausanne, Switzerland.
authors.forename: Sonia
authors.initials: S
authors.lastname: Jimenez
authors.affiliation: Center for Integrative Genomics (CIG), University of Lausanne, Lausanne, Switzerland.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Tafti
mesh_terms: D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000818:Animals; D001823:Body Composition / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism*; D003345:Corticosterone / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D013006:Growth Hormone / Q000378:metabolism; D006885:Hydroxybutyrates / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D024101:Mitochondrial Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D011388:Prolactin / Q000378:metabolism; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000172:deficiency / Q000378:metabolism
chemical_list: D015525:Fatty Acids, Omega-3; D006885:Hydroxybutyrates; D024101:Mitochondrial Proteins; C111420:4-hydroxybutyric acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D011388:Prolactin; D013006:Growth Hormone; D012435:S-Adenosylhomocysteine; D000429:Alcohol Oxidoreductases; C072878:hydroxyacid-oxoacid transhydrogenase; C009338:succinic semialdehyde; D019803:Glutathione Disulfide; D003345:Corticosterone
keywords: GHB; antioxidant; brain; liver; metabolomics