GHB for cataplexy: Possible mode of action.
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.
Developmental Psychiatry, University of Nottingham, Nottingham, UK elemer.szabadi@nottingham.ac.uk.
Elemer
E
Szabadi
D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D002385:Cataplexy / Q000188:drug therapy* / Q000378:metabolism; D004644:Emotions / Q000187:drug effects; D006801:Humans; D006885:Hydroxybutyrates / Q000494:pharmacology*; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018080:Receptors, GABA-B / Q000378:metabolism; D012890:Sleep / Q000187:drug effects; D012978:Sodium Oxybate / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D006885:Hydroxybutyrates; D018080:Receptors, GABA-B; C111420:4-hydroxybutyric acid; D005680:gamma-Aminobutyric Acid; D012978:Sodium Oxybate
Cataplexy; alpha-2 adrenoceptors; autoinhibition; locus coeruleus; narcolepsy; noradrenaline; γ-aminobutyric acid; γ-hydroxybutyric acid