title: A single acute pharmacological dose of γ-hydroxybutyrate modifies multiple gene expression patterns in rat hippocampus and frontal cortex.
abstract: γ-Hydroxybutyrate (GHB) is a natural brain neuromodulator that has its own enzymatic machinery for synthesis and degradation, release, and transport systems and several receptors that belong to the G protein-coupled receptor (GPCR) family. Targeting of this system with exogenous GHB is used in therapy to induce sleep and anesthesia and to reduce alcohol withdrawal syndrome. GHB is also popular as a recreational drug for its anxiolytic and mild euphoric effects. However, in both cases, GHB must be administered at high doses in order to maintain GHB concentrations in brain of ∼800-1,000 μM. These high concentrations are thought to be necessary for interactions with low-affinity sites on GABA(B) receptor, but the molecular targets and cellular mechanisms modulated by GHB remain poorly characterized. Therefore, to provide new insights into the elucidation of GHB mechanisms of action and open new tracks for future investigations, we explored changes of GHB-induced transcriptomes in rat hippocampus and prefrontal cortex by using DNA microarray studies. We demonstrate that a single acute anesthetic dose of 1 g/kg GHB alters a large number of genes, 121 in hippocampus and 53 in prefrontal cortex; 16 genes were modified simultaneously in both brain regions. In terms of molecular functions, the majority of modified genes coded for proteins or nucleotide binding sites. In terms of Gene Ontology (GO) functional categories, the largest groups were involved in metabolic processing for hippocampal genes and in biological regulation for prefrontal cortex genes. The majority of genes modified in both structures were implicated in cell communication processes. Western blot and immunohistochemical studies carried out on eight selected proteins confirmed the microarray findings.
authors.affiliation: Equipe Stéroïdes, Neuromodulateurs et Neuropathologies, EA 4438, Faculté de Médecine, 67085 Strasbourg, France. kemmel@unistra.fr
authors.forename: Véronique
authors.initials: V
authors.lastname: Kemmel
authors.forename: Christian
authors.initials: C
authors.lastname: Klein
authors.forename: Doulaye
authors.initials: D
authors.lastname: Dembélé
authors.forename: Bernard
authors.initials: B
authors.lastname: Jost
authors.forename: Omar
authors.initials: O
authors.lastname: Taleb
authors.forename: Dominique
authors.initials: D
authors.lastname: Aunis
authors.forename: Ayikoe G
authors.initials: AG
authors.lastname: Mensah-Nyagan
authors.forename: Michel
authors.initials: M
authors.lastname: Maitre
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002491:Central Nervous System Agents / Q000494:pharmacology*; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012978:Sodium Oxybate / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D002491:Central Nervous System Agents; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D012978:Sodium Oxybate