From the street to the brain: neurobiology of the recreational drug γ-hydroxybutyric acid

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Abstract

γ-Hydroxybutyric acid (GHB) is a short-chain fatty acid that occurs naturally in the mammalian brain and is formed primarily from the precursor γ-aminobutyric acid (GABA). The properties of GHB suggest that it has a neuromodulatory role in the brain and has the ability to induce several pharmacological and behavioral effects. GHB has been used clinically as an anesthetic and to treat alcoholism and narcolepsy. Furthermore, GHB has emerged recently as a major recreational drug of abuse. GHB appears to have dual mechanisms of action in the brain. Biochemical data suggest that the intrinsic neurobiological activity of GHB might be mediated through the GHB receptor, which is separate and distinct from the GABAB receptor. However, many of the pharmacological and clinical effects of exogenously administered GHB, including the properties of addiction, tolerance, withdrawal and intoxication, are probably mediated via the GABAB receptor, where GHB might act both directly as a partial agonist and indirectly through GHB-derived GABA.

Section snippets

Endogenous GHB in the brain

GHB is a short-chain fatty acid that occurs naturally in the mammalian brain at a concentration of 1–4 μM [7]. The primary precursor of GHB in the brain is γ-aminobutyric acid (GABA). GHB is formed in the brain from GABA-derived succinic semialdehyde (SSA) via a specific succinic semialdehyde reductase (SSR). GHB can be reconverted back to SSA via GHB dehydrogenase, and the GHB-derived SSA can be converted back to GABA [7]. SSA can also be metabolized by succinic semialdehyde dehydrogenase

GHB addiction and withdrawal

The recent surge in the use of GHB as a major recreational drug has led to reports of addictive properties of this compound in humans 4, 12. In addition, GHB withdrawal symptoms similar to those observed in ethanol withdrawal have been reported in humans 13, 14. In the majority of these cases, tolerance to GHB occurred. Studies in rodents are in concordance with the clinical data. Thus, rats treated chronically with GHB exhibit tolerance and withdrawal 15, 16, and develop conditioned place

Distinct GHB and GABAB receptors

The GABAB receptor is a heterodimer in which the GABAB(1) receptor dimerizes with the GABAB(2) receptor to form a functional GABAB receptor [26]. The GABAB receptor couples to various effector systems through a signal-transducing G protein. Presynaptically, activation of GABAB receptor autoreceptors (located on GABA-containing neurons) and heteroreceptors (located on other neurotransmitter-releasing neurons) has been reported to inhibit neurotransmitter release through inhibition of Ca2+

Dose response of GHB

Given the low KD of GHB for the GHB receptor and the high median inhibitory concentration (IC50) of GHB for the GABAB receptor relative to the physiological concentration of GHB in brain, the determination of the relationship between dose and response is crucial to understanding the mechanism of action of endogenous versus exogenously administered GHB. The clinical and experimental effects of GHB are dose dependent (Table 2). In humans, low doses (10 mg kg−1) induce short-term anterograde

Neuromodulatory effects of GHB

GHB concentrations in the brain that exceed the physiological levels of GHB by 2–3 orders of magnitude both saturate GHB receptors and produce GABAB receptor-mediated functional perturbations in the brain. Hence, the GHB–GABAB receptor interaction has potential relevance for mechanisms of GHB addiction, tolerance, abuse, toxicity and other effects of exogenously administered high doses of GHB. However, GABAB receptor-mediated mechanisms cannot explain the specific properties of endogenous GHB

GHB and dopamine

GHB has long been known to have an effect on dopamine systems in the brain. Chronic treatment with GHB results in upregulation of dopamine D1 and D2 receptor mRNA expression in brain regions rich in GHB receptors [53]. Acute treatment with GHB inhibits dopamine release [54]. The attenuation of dopamine neurotransmission that follows GHB administration might underlie the loss of locomotor activity that can occur in humans and experimental animals. Rodent studies have shown that GHB given in

GHB and reward

The mechanism of the addictive properties of GHB is not clear. At a molecular level, chronic GHB exposure would probably desensitize GHB and GABAB receptors, as has been demonstrated in vitro 59, 60, thus reducing their ability to inhibit neurotransmitter release. Hence, under conditions of chronic GHB intake, it is possible that compensatory mechanisms could occur that offset the inhibition of dopamine release and could in fact result in an increase in dopamine, GABA and/or glutamate release.

GHB and progesterone

Evidence from microdialysis studies in rats suggests that exogenous administration of GHB elevates brain concentrations of the hormone progesterone in a dose-dependant fashion [61]. However, again, large doses of GHB were required for this effect, which was blocked by a GABAB receptor antagonist but not by a GHB receptor antagonist. Furthermore, the GHB-induced increase in progesterone levels was mimicked by baclofen. The ability of GHB to elevate levels of progesterone has relevance to

Therapeutic intervention for GHB intoxication

The data reviewed above suggest that high concentrations of GHB can result in activation of the GABAB receptor and that the resultant effect can be blocked by GABAB receptor antagonists, but not by GHB receptor antagonists. Because levels of GHB are inordinately high during GHB intoxication, it would seem logical that blockade of the GABAB receptor might be an effective acute treatment for GHB overdose. However, studies of mice that lack the gene encoding SSADH (SSADH−/−) suggest that GHB

Acknowledgements

This work was supported in part by the Canadian Institutes of Health Research (grant # 14329 MOP), the National Institute of Health (grant# NS40270), an endowment from the Bloorview Childrens Hospital Foundation, a personal award to C.G.T.W. from the Heart and Stroke Foundation of Canada, and members of the Partnership for Pediatric Epilepsy Research (including the American Epilepsy Society, the Epilepsy Foundation, Anna and Jim Fantaci, Fight Against Childhood Epilepsy and Seizures

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