Pathway-specific action of gamma-hydroxybutyric acid in sensory thalamus and its relevance to absence seizures.
The systemic injection of gamma-hydroxybutyric acid (GHB) elicits spike and wave discharges (SWDs), the EEG hallmark of absence seizures, and represents a well established, widely used pharmacological model of this nonconvulsive epilepsy. Despite this experimental use of GHB, as well as its therapeutic use in narcolepsy and its increasing abuse, however, the precise cellular mechanisms underlying the different pharmacological actions of this drug are still unclear. Because sensory thalamic nuclei play a key role in the generation of SWDs and sleep rhythms, and because direct injection of GHB in the ventrobasal (VB) thalamus elicits SWDs, we investigated GHB effects on corticothalamic EPSCs and GABAergic IPSCs in VB thalamocortical (TC) neurons. GHB (250 microm-10 mm) reversibly decreased the amplitude of electrically evoked EPSCs and GABAA IPSCs via activation of GABAB receptors; however, approximately 60% of the IPSCs were insensitive to low (250 microm-1.0 mm) GHB concentrations. The putative GHB receptor antagonist NSC 382 applied alone had a number of unspecific effects, whereas it either had no action on, or further increased, the GHB-elicited effects on synaptic currents. Low GHB concentrations (250 microm) were also effective in increasing absence-like intrathalamic oscillations evoked by cortical afferent stimulation. These results indicate that low concentrations of GHB, similar to the brain concentrations that evoke SWDs in vivo, differentially affect excitatory and inhibitory synaptic currents in TC neurons and promote absence-like intrathalamic oscillations. Furthermore, the present data strengthen previous suggestions on the GHB mechanism of sleep promotion and will help focus future studies on the cellular mechanisms underlying its abuse.
Gervasi
Nicolas
N
Neurobiologie des Processus Adaptatifs, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 7102-Université Pierre et Marie Curie, F-75005 Paris, France.
Monnier
Zohreh
Z
Vincent
Pierre
P
Paupardin-Tritsch
Daniele
D
Hughes
Stuart W
SW
Crunelli
Vincenzo
V
Leresche
Nathalie
N
D000344:Afferent Pathways; D000818:Animals; D001567:Benzocycloheptenes / Q000494:pharmacology; D002478:Cells, Cultured; D004553:Electric Conductivity; D004832:Epilepsy, Absence / Q000139:chemically induced; D005071:Evoked Potentials; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D058786:GABA-B Receptor Agonists; D006885:Hydroxybutyrates / Q000494:pharmacology* / Q000633:toxicity; D009433:Neural Inhibition; D009475:Neurons, Afferent / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000502:physiology; D018080:Receptors, GABA-B / Q000145:classification / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D013788:Thalamus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology
C039403:4-hydroxybutyric acid receptor; D001567:Benzocycloheptenes; D058786:GABA-B Receptor Agonists; D006885:Hydroxybutyrates; D011956:Receptors, Cell Surface; D018080:Receptors, GABA-B; C066471:NCS 382; C111420:4-hydroxybutyric acid; C035142:4-hydroxy-2-butenoic acid