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

Abstract

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.

γ-Hydroxybutyrate Increases a Potassium Current and Decreases the H-Current in Hippocampal Neurons via GABAB Receptors

“…Notably, GHB is reportedly a weak (but selective) GABA B receptor agonist (Mathivet et al, 1997), which explains the incomplete occlusion of the baclofen effect by GHB. The implication of GABA B receptors to mediate GHB effects is in agreement with most electrophysiological studies (Xie and Smart, 1992a,b;Engberg and Nissbrandt, 1993;Williams et al, 1995;Emri et al, 1996;Madden and Johnson, 1998;Jensen and Mody, 2001;Gervasi et al, 2003). Still, GHB is believed to be a neurotransmitter with its own binding site different from GABA B receptors (Feigenbaum and Fig.…”

“…GHB also inhibited neurons in the ventral tegmental area and neocortex (Madden and Johnson, 1998;Jensen and Mody, 2001) and concomitantly promoted oscillatory activity in sub-stantia nigra and thalamocortical neurons (Engberg and Nissbrandt, 1993;Williams et al, 1995;Gervasi et al, 2003). These effects were prevented by a GABA B receptor antagonist.…”

Baclofen and Gamma-Hydroxybutyrate Withdrawal

“…Originally manufactured as a GABA analog, GHB mediates its major effects as a GABA B agonist [16,17]. Endogenous GHB, which is both a GABA precursor and metabolite, also activates GHB receptors and increases endogenous GABA levels [18].…”

Synthesis and Catabolism of γ-Hydroxybutyrate in SH-SY5Y Human Neuroblastoma Cells

“…It has been shown to transport across the blood-brain barrier by a carrier-mediated mechanism (20) and acts through both a specific GHB receptor (21) and the GABA type B receptor (22). It is believed that large increases in brain GHB concentration following external administration hyperstimulates the GHB receptor(s) (23), and this mechanism is likely to be the basis of the major pharmacological effects of GHB.…”