GHB for cataplexy: Possible mode of action

Abstract

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.

Mechanisms for the Specific Properties of γ‐Hydroxybutyrate in Brain

“…The anticataplexy effect of GHB has been proposed to act via a GABAergic effect at multiple sites (some GABA-A receptors; but also GABA-B and GHB receptors) that may regulate the muscle tone through the modulation of the locus coeruleus activity. 153 Other psychopharmacological properties reported for GHB (anxiolysis, euphoria, prosocial facilitation) have apparently never been reported for pure GABA-B agonists. 154 Baclofen is not a drug of abuse like GHB, which is self-administered in monkeys and laboratory animals, with low reinforcing effects compared to benzodiazepines.…”

“…Presently, only GHB simultaneously alleviates cataplexy, excessive daytime sleepiness, and nocturnal sleep disruption while pure GABA‐B agonists have no indication in this domain. The anticataplexy effect of GHB has been proposed to act via a GABAergic effect at multiple sites (some GABA‐A receptors; but also GABA‐B and GHB receptors) that may regulate the muscle tone through the modulation of the locus coeruleus activity . Other psychopharmacological properties reported for GHB (anxiolysis, euphoria, prosocial facilitation) have apparently never been reported for pure GABA‐B agonists .…”

FRET-Based Sensors Unravel Activation and Allosteric Modulation of the GABAB Receptor

“…The pharmacological manipulation of GABA B receptors is of interest for the treatment of a wide variety of neurological diseases and psychiatric disorders (Bowery, 2006;Filip et al, 2015). Two agonists are actually used for therapeutic intervention: (R)-Baclofen (Lioresal) used as an antispastic agent and now also prescribed to decrease alcohol self-administration (Agabio and Colombo, 2014), and g-hydroxybutyrate (GHB, Xyrem) used for the treatment of narcolepsy (Szabadi, 2015). Alternatively, positive allosteric modulators (PAMs) offer the possibility of fine tuning GABA B receptor activity with better therapeutic effects (Kalinichev et al, 2014;Pin and Pré zeau, 2007).…”

Pharmacologic, Pharmacokinetic, and Clinical Assessment of Illicitly Used γ‐Hydroxybutyrate

“…Before discussing the pharmacology and application of GHB for illicit purposes, a brief overview of its use for cataplexy (the sudden loss of muscle tone in response to strong emotions) in narcolepsy (a syndrome characterized by excessive daytime sleepiness) is warranted. The exact mechanism for this purpose not been elucidated, but a theory of action has recently been proposed . Noradrenergic neurons in the locus coeruleus region of the pons maintain muscle tone but cease to fire during cataplexy.…”

“…This predisposes to switching off of locus coeruleus activity via a supersensitive autoinhibition mechanism when the amygdala is activated by an emotional stimulus. GHB may prevent cataplexy by dampening the tone of locus coeruleus neurons via the stimulation of inhibitory extrasynaptic GABA receptors and thereby increasing the threshold for autoinhibition . In addition, GHB is a central nervous system depressant that can enhance nighttime sleep, resulting in daytime wakefulness in patients with cataplexy in narcolepsy .…”