van Nieuwenhuijzen P S, McGregor I S, Hunt G E
School of Psychology, Griffith Taylor Building (A19), University of Sydney, Sydney, NSW 2006, Australia.
Neuroscience. 2009 Jan 23;158(2):441-55. doi: 10.1016/j.neuroscience.2008.10.011. Epub 2008 Oct 17.
gamma-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 GABA(B) 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 GABA(B) 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 GABA(B) 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.
γ-羟基丁酸（GHB）是一种能产生欣快感、促进社交且诱导睡眠的药物，它与自身的GHB受体位点具有高亲和力结合，与γ-氨基丁酸B（GABA(B)）受体的结合则较弱。GHB在发作性睡病和酒精中毒的治疗中有效，但大量使用会导致依赖和戒断反应。GHB的许多作用（镇静、体温过低、僵住症）可被GABA(B)受体激动剂（如巴氯芬）模拟。然而，其他作用（欣快和促进社交作用以及对发作性睡病的治疗作用）则不然。本研究采用Fos免疫组织化学法，评估中高剂量的GHB（250、500和1000毫克/千克）以及高剂量的巴氯芬（10毫克/千克，其产生的镇静作用与500毫克/千克GHB相似）在大鼠脑中产生的神经激活情况。结果显示，这两种药物激活的共同区域众多，包括下丘脑的视上核、室旁核、视前正中核和腹侧乳头前核、杏仁核中央核、动眼神经副核、外侧臂旁核、蓝斑以及孤束核。GHB（500毫克/千克）而非巴氯芬（10毫克/千克）在中缝正中核和外侧缰核诱导了显著的Fos表达，而更高剂量的GHB（1000毫克/千克）在Calleja岛、齿状回（多形层）和弓状核以及与快速眼动和非快速眼动睡眠相关的各个区域（外侧背盖核、结节乳头体核以及腹外侧和前背侧视前核）诱导了额外的Fos表达。令人惊讶的是，在伏隔核、纹状体和腹侧被盖区等与奖赏相关的区域，未观察到GHB或巴氯芬诱导的Fos免疫反应性。总体而言，这些结果表明GHB引起的脑激活具有独特特征，这可能仅部分归因于GABA(B)受体效应。这证实了GHB独特的神经药理学特征，并指出了可能是其对睡眠、体温、社交能力和内分泌功能产生特征性影响基础的关键神经底物。
