Kamal Rama M, van Noorden Martijn S, Franzek Ernst, Dijkstra Boukje A G, Loonen Anton J M, De Jong Cornelius A J
Nijmegen Institute for Scientist-Practitioners in Addiction (NISPA), Nijmegen, The Netherlands.
Neuropsychobiology. 2016;73(2):65-80. doi: 10.1159/000443173. Epub 2016 Mar 23.
x03B3;-Hydroxybutyrate (GHB) has gained popularity as a drug of abuse. In the Netherlands the number of patients in treatment for GHB dependence has increased sharply. Clinical presentation of GHB withdrawal can be life threatening. We aim, through this overview, to explore the neurobiological pathways causing GHB dependency and withdrawal, and their implications for treatment choices.
In this work we review the literature discussing the findings from animal models to clinical studies focused on the neurobiological pathways of endogenous but mainly exogenous GHB.
Chronic abuse of GHB exerts multifarious neurotransmitter and neuromodulator effects on x03B3;-aminobutyric acid (GABA), glutamate, dopamine, serotonin, norepinephrine and cholinergic systems. Moreover, important effects on neurosteroidogenesis and oxytocin release are wielded. GHB acts mainly via a bidirectional effect on GABAB receptors (GABABR; subunits GABAB1 and GABAB2), depending on the subunit of the GIRK (G-protein-dependent ion inwardly rectifying potassium) channel involved, and an indirect effect of the cortical and limbic inputs outside the nucleus accumbens. GHB also activates a specific GHB receptor and β1-subunits of α4-GABAAR. Reversing this complex interaction of neurobiological mechanisms by the abrupt cessation of GHB use results in a withdrawal syndrome with a diversity of symptoms of different intensity, depending on the pattern of GHB abuse.
The GHB withdrawal symptoms cannot be related to a single mechanism or neurological pathway, which implies that different medication combinations are needed for treatment. A single drug class, such as benzodiazepines, gabapentin or antipsychotics, is unlikely to be sufficient to avoid life-threatening complications. Detoxification by means of titration and tapering of pharmaceutical GHB can be considered as a promising treatment that could make polypharmacy redundant.
γ-羟基丁酸（GHB）作为一种滥用药物已日益流行。在荷兰，接受GHB依赖治疗的患者数量急剧增加。GHB戒断的临床表现可能危及生命。我们旨在通过本综述探讨导致GHB依赖和戒断的神经生物学途径及其对治疗选择的影响。
在这项工作中，我们回顾了从动物模型到临床研究的文献，这些研究聚焦于内源性但主要是外源性GHB的神经生物学途径。
长期滥用GHB对γ-氨基丁酸（GABA）、谷氨酸、多巴胺、5-羟色胺、去甲肾上腺素和胆碱能系统产生多种神经递质和神经调质作用。此外，对神经甾体生成和催产素释放也有重要影响。GHB主要通过对GABAB受体（GABABR；亚基GABAB1和GABAB2）的双向作用发挥作用，这取决于所涉及的GIRK（G蛋白依赖性内向整流钾离子）通道的亚基，以及伏隔核外皮质和边缘输入的间接作用。GHB还激活特定的GHB受体和α4-GABAAR的β1亚基。突然停止使用GHB来逆转这种复杂的神经生物学机制相互作用会导致戒断综合征，其症状强度各异，这取决于GHB的滥用模式。
GHB戒断症状不能归因于单一机制或神经通路，这意味着治疗需要不同的药物组合。单一药物类别，如苯二氮卓类、加巴喷丁或抗精神病药物，不太可能足以避免危及生命的并发症。通过滴定和逐渐减少药用GHB进行解毒可被视为一种有前景的治疗方法，这可能使联合用药变得多余。
