title: Regional Fos-expression induced by γ-hydroxybutyrate (GHB): comparison with γ-butyrolactone (GBL) and effects of co-administration of the GABAB antagonist SCH 50911 and putative GHB antagonist NCS-382.
abstract: γ-Hydroxybutyrate (GHB) has a complex array of neural actions that include effects on its own high-affinity GHB receptor, the release of neuroactive steroids, and agonist actions at GABAA and GABAB receptors. We previously reported partial overlap in the c-Fos expression patterns produced by GHB and the GABAB agonist, baclofen in rats. The present study extends these earlier findings by examining the extent to which GHB Fos expression and behavioral sedation are prevented by (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911), a GABAB antagonist, and NCS-382, a putative antagonist at the high-affinity GHB receptor. We also compare Fos expression caused by GHB and its precursor γ-butyrolactone (GBL), which is a pro-drug for GHB but lacks the high sodium content of the parent GHB molecule. Both GHB (1,000 mg/kg) and GBL (600 mg/kg) induced rapid sedation in rats that lasted over 90 min and caused similar Fos expression patterns, albeit with GBL causing greater activation of the nucleus accumbens (core and shell) and dentate gyrus (granular layer). Pretreatment with SCH 50911 (100mg/kg) partly reversed the sedative effects of GHB and significantly reduced GHB-induced Fos expression in only four regions: the tenia tecta, lateral habenula, dorsal raphe and laterodorsal tegmental nucleus. NCS-382 (50mg/kg) had no effect on GHB-induced sedation or Fos expression. When given alone, both NCS-382 and SCH 50911 increased Fos expression in the bed nucleus of the stria terminalis, central amygdala, parasubthalamic nucleus and nucleus of the solitary tract. SCH 50911 alone affected the Islands of Calleja and the medial, central and paraventricular thalamic nuclei. Overall, this study shows a surprising lack of reversal of GHB-induced Fos expression by two relevant antagonists, both of which have marked intrinsic actions. This may reflect the limited doses tested but also suggests that GHB Fos expression reflects mechanisms independent of GHB and GABAB receptors.
authors.affiliation: Faculty of Pharmacy, University of Sydney, Camperdown, NSW 2006, Australia. Electronic address: pieternel.vannieuwenhuijzen@sydney.edu.au.
authors.forename: P S
authors.initials: PS
authors.lastname: van Nieuwenhuijzen
authors.affiliation: School of Psychology, University of Sydney, Camperdown, NSW 2006, Australia. Electronic address: iain.mcgregor@sydney.edu.au.
authors.forename: I S
authors.initials: IS
authors.lastname: McGregor
authors.affiliation: Faculty of Pharmacy, University of Sydney, Camperdown, NSW 2006, Australia. Electronic address: mary.collins@sydney.edu.au.
authors.forename: M
authors.initials: M
authors.lastname: Chebib
authors.affiliation: Discipline of Psychiatry, University of Sydney, Concord Hospital, NSW 2139, Australia. Electronic address: glenn.hunt@sydney.edu.au.
authors.forename: G E
authors.initials: GE
authors.lastname: Hunt
mesh_terms: D015107:4-Butyrolactone / Q000494:pharmacology; D000818:Animals; D001567:Benzocycloheptenes / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000502:physiology*; D002452:Cell Count; D002491:Central Nervous System Agents / Q000494:pharmacology; D058788:GABA-B Receptor Antagonists / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D011897:Random Allocation; D017208:Rats, Wistar; D012978:Sodium Oxybate / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: C095804:(+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid; D001567:Benzocycloheptenes; D002491:Central Nervous System Agents; D058788:GABA-B Receptor Antagonists; D006993:Hypnotics and Sedatives; D009025:Morpholines; D016760:Proto-Oncogene Proteins c-fos; C066471:NCS 382; D012978:Sodium Oxybate; D015107:4-Butyrolactone
keywords: GABA(B); GHB; NCS-382; SCH 50911; c-Fos; gamma-butyrolactone