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The Journal of Neuroscience, December 10, 2003, 23(36):11469-11478

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Cellular/Molecular
Pathway-Specific Action of -Hydroxybutyric Acid in Sensory Thalamus and Its Relevance to Absence Seizures

Nicolas Gervasi,^1 * Zohreh Monnier,^1 * Pierre Vincent,¹ Danièle Paupardin-Tritsch,¹ Stuart W. Hughes,² Vincenzo Crunelli,² and Nathalie Leresche¹

¹Neurobiologie des Processus Adaptatifs, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 7102-Université Pierre et Marie Curie, F-75005 Paris, France, and ²School of Biosciences, Cardiff University, Cardiff CF10 3US, United Kingdom

The systemic injection of -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 µM-10 mM) reversibly decreased the amplitude of electrically evoked EPSCs and GABA_A IPSCs via activation of GABA_B receptors; however, 60% of the IPSCs were insensitive to low (250 µM-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 µM) 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.

Key words: GABA_B receptors; inhibition; excitation; sleep; intrathalamic oscillations; abuse

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Received July 10, 2003; revised October 14, 2003; accepted October 28, 2003.

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