title: The Neurobiological Mechanisms of Gamma-Hydroxybutyrate Dependence and Withdrawal and Their Clinical Relevance: A Review.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Nijmegen Institute for Scientist-Practitioners in Addiction (NISPA), Nijmegen, The Netherlands.
authors.forename: Rama M
authors.initials: RM
authors.lastname: Kamal
authors.forename: Martijn S
authors.initials: MS
authors.lastname: van Noorden
authors.forename: Ernst
authors.initials: E
authors.lastname: Franzek
authors.forename: Boukje A G
authors.initials: BA
authors.lastname: Dijkstra
authors.forename: Anton J M
authors.initials: AJ
authors.lastname: Loonen
authors.forename: Cornelius A J
authors.initials: CA
authors.lastname: De Jong
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D012978:Sodium Oxybate / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy / Q000378:metabolism*; D019966:Substance-Related Disorders / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D012978:Sodium Oxybate