The distribution of γ-hydroxybutyrate-induced Fos expression in rat brain: Comparison with baclofen

• Published in: Neuroscience Vol. 158; no. 2; pp. 441 - 455
• Main Authors: van Nieuwenhuijzen, P.S, McGregor, I.S, Hunt, G.E
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 23.01.2009
• Subjects: Anesthetics, Intravenous - pharmacology; Animals; Area Under Curve; Baclofen - pharmacology; Brain - anatomy & histology; Brain - drug effects; c-Fos; Cell Count - methods; Dose-Response Relationship, Drug; GABA Agonists - pharmacology; GABAB; gamma-hydroxybutyrate; Gene Expression Regulation - drug effects; locomotor activity; Male; Motor Activity - drug effects; Neurology; Oncogene Proteins v-fos - genetics; Oncogene Proteins v-fos - metabolism; Rats; Rats, Wistar; reward; sleep; Sodium Oxybate - pharmacology; GHB; slow wave sleep; 3,4-methylenedioxymethamphetamine; VTA; LHB; c-Fos; MFB; NREM; phosphate buffer; PVN; phosphate-buffered saline; NTS; rapid eye movement; THC; AUC; MDMA; sleep; GBL; analysis of variance; ANOVA; non-rapid eye movement; PBH; VLPO; lateral habenula; delta 9-tetrahydrocannabinol; GABA B; reward; PBS; MnPO; median raphe; nucleus of the solitary tract; area under the curve; ventrolateral preoptic nucleus; paraventricular nucleus of the hypothalamus; SWS; MnR; phosphate-buffered horse serum; γ-butyrolactone; median preoptic nucleus; PB; SON; medial forebrain bundle; ventral tegmental area; gamma-hydroxybutyrate; supraoptic nucleus; locomotor activity; REM; γ-hydroxybutyrate; GABAB
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2008.10.011

Abstract γ-Hydroxybutyrate (GHB) is a euphoric, prosocial and sleep inducing drug that binds with high affinity to its own GHB receptor site and also more weakly to GABAB receptors. GHB is efficacious in the treatment of narcolepsy and alcoholism, but heavy use can lead to dependence and withdrawal. Many effects of GHB (sedation, hypothermia, catalepsy) are mimicked by GABAB receptor agonists (e.g. baclofen). However other effects (euphoric and prosocial effects and a therapeutic effect in narcolepsy) are not. The present study used Fos immunohistochemistry to assess the neural activation produced in rat brain by medium to high doses of GHB (250, 500 and 1000 mg/kg) and a high dose of baclofen (10 mg/kg) that produced similar sedation to 500 mg/kg GHB. Results showed many common regions of activation with these two drugs including the supraoptic, paraventricular, median preoptic and ventral premammillary nuclei of the hypothalamus, the central nucleus of the amygdala, Edinger-Westphal nucleus, lateral parabrachial nucleus, locus coeruleus, and nucleus of the solitary tract. GHB (500 mg/kg), but not baclofen (10 mg/kg), induced significant Fos expression in the median raphe nucleus and lateral habenula, while a higher dose of GHB (1000 mg/kg) induced additional Fos expression in the islands of Calleja, dentate gyrus (polymorphic layer) and arcuate nucleus, and in various regions implicated in rapid and non-rapid eye movement sleep (laterodorsal tegmental nucleus, tuberomammillary nucleus and the ventrolateral and anterodorsal preoptic nuclei). Surprisingly, Fos immunoreactivity was not observed with either GHB or baclofen in reward-relevant regions such as the nucleus accumbens, striatum and ventral tegmental area. Overall these results indicate a distinctive signature of brain activation with GHB that may be only partly due to GABAB receptor effects. This confirms a unique neuropharmacological profile for GHB and indicates key neural substrates that may underlie its characteristic influence on sleep, body temperature, sociability and endocrine function.