Extrasynaptic site of action for γ-hydroxybutyrate

Enna, S.J.

doi:10.1073/pnas.1210290109

Cited by 4 publications

(2 citation statements)

References 25 publications

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“…9 Recently it was discovered that at least some of the pharmacological effects of GHB are due to the activation of extrasynaptic GABA-A receptors. 16 It is possible that, while GABA-B receptors mediate most of the behavioral and inhibitory effects of GBL/GHB at high doses, other mechanisms are more relevant at lower doses, which is consistent with effects that have been observed clinically. Benzodiazepines are GABA-A agonists: since crosstolerance between benzodiazepines and GBL/GHB is partial, some patients experiencing withdrawal will not respond to the administration of standard doses of benzodiazepines and appear to require, and may not fully respond to, unusually high doses.…”

Section: Discussionsupporting

confidence: 57%

Management and Treatment of Gamma Butyrolactone Withdrawal Syndrome

Ghio

Cervetti

Respino

et al. 2014

Journal of Psychiatric Practice

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Gamma butyrolactone (GBL) is an increasingly popular drug of abuse that is readily available in most countries, and it is often purchased over the Internet. In addition to the acute hazards of intoxication and overdose, users who are dependent on GBL can also experience severe withdrawal reactions, including hallucinations, agitation, confusion, delusions, delirium, rhabdomyolysis, and seizures. Most of the existing literature suggests the use of a high-dose benzodiazepine as a first-line treatment for GBL withdrawal. However, several cases of resistance to benzodiazepines have been observed, which likely reflect some pharmacological differences between benzodiazepines and GBL. Specifically, the effects of benzodiazepines are primarily mediated by gamma-aminobutyric acid (GABA)-A receptors, while GBL and its analogues act mainly at GABA-B receptors, with possible additional effects via the ionotropic GABA-A receptors. In this regard, recent studies have found that GBL and its analogues possess a high affinity for a specific form of extrasynaptic GABA-A receptors that are strongly activated by barbiturates, such as phenobarbital, but that are insensitive to benzodiazepines. Taken together, these findings suggest that barbiturates could be evaluated as first-choice agents for the treatment of GBL/gamma hydroxybutyrate (GHB) withdrawal instead of benzodiazepines. In support of this view, we describe a clinical case of difficult to manage GBL withdrawal symptoms in a 42-year-old male. We also review the literature on treatment options for GBL/GHB withdrawal, including benzodiazepine-resistant withdrawal.

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Section: Discussionsupporting

confidence: 57%

Management and Treatment of Gamma Butyrolactone Withdrawal Syndrome

Ghio

Cervetti

Respino

et al. 2014

Journal of Psychiatric Practice

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“…Recently it has been proposed that the GHB receptor is in fact a subtype of the GABA A receptor (Absalom et al, 2012; Bay et al, 2014; Enna, 2012). However, the importance of the interaction of GHB with GABA A receptors has been questioned (Connelly et al, 2013a).…”

Section: Ghbmentioning

confidence: 99%

GHB for cataplexy: Possible mode of action

Szabadi

2015

J Psychopharmacol

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The sleep disorder narcolepsy is caused by the loss of orexinergic neurones in the lateral hypothalamus. A troublesome symptom of narcolepsy is cataplexy, the sudden loss of muscle tone in response to strong emotions. It can be alleviated by antidepressants and sodium oxybate (γ-hydroxybutyric acid (GHB)). It is likely that the noradrenergic nucleus locus coeruleus (LC) is involved since it is essential for the maintenance of muscle tone, and ceases to fire during cataplectic attacks. Furthermore, alpha-2 adrenoceptors proliferate in the LC in cataplexy, probably due to 'heterologous denervation supersensitivity' resulting from the loss/weakening of the orexinergic input to the LC. This would lead to the sensitization of the autoinhibition mechanism of LC neurones mediated by inhibitory alpha-2 adrenoceptors ('autoreceptors'). Thus the excitatory input from the amygdala to the LC, activated by an emotional stimulus, would lead to the 'switching off' of LC activity via the supersensitive auto-inhibition mechanism. GHB is an agonist at both γ-aminobutyric acid (GABA) GABA (B) and GHB receptors that may be a subtype of an extrasynaptic GABA(A) receptor. GHB may prevent a cataplectic attack by dampening the tone of LC neurones via the stimulation of inhibitory extrasynaptic GABA receptors in the LC, and thus increasing the threshold for autoinhibition.

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Trp266 determines the binding specificity of a porcine aflatoxin B1 aldehyde reductase for aflatoxin B1-dialdehyde

Zhang

et al. 2013

Biochemical Pharmacology

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Extrasynaptic site of action for γ-hydroxybutyrate

Cited by 4 publications

References 25 publications

Management and Treatment of Gamma Butyrolactone Withdrawal Syndrome

Management and Treatment of Gamma Butyrolactone Withdrawal Syndrome

GHB for cataplexy: Possible mode of action

Trp266 determines the binding specificity of a porcine aflatoxin B1 aldehyde reductase for aflatoxin B1-dialdehyde

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