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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on May 19, 2004; DOI: 10.1124/jpet.104.069534

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Received for publication April 7, 2004.
Revised May 18, 2004.
Accepted for publication May 19, 2004.

Gamma-Hydroxybutyrate Increases a Potassium Conductance and Decreases the H-current in Hippocampal Neurons via GABAB Receptors

Paul Schweitzer 1*, Marisa Roberto 1, Samuel G Madamba 1, George Robert Siggins 1

1 The Scripps Research Institute

* Address correspondence to: E-mail: pschweitzer{at}scripps.edu

Abstract

Gamma-Hydroxybutyrate (GHB) is used for the treatment of alcoholism and to induce absence seizures in animals, but also has recently emerged as a drug of abuse. In hippocampal neurons, GHB may activate its own putative receptor as well as GABAB receptors to affect synaptic transmission. We used voltage-clamp recordings of rat CA1 pyramidal neurons to characterize the postsynaptic conductances affected by GHB and further clarify the site of GHB action. Low concentrations of GHB (0.1-1 mM) did not affect postsynaptic properties, but 10 mM GHB elicited an outward current at resting potential by augmenting an inwardly rectifying potassium current and concomitantly decreased the hyperpolarization-activated h-current (Ih). Like GHB, the selective GABAB-receptor agonist baclofen (20 µM) increased a potassium current and decreased Ih. In the presence of 10 mM GHB, the baclofen effects were largely occluded. The selective GABAB receptor antagonist CGP 55845 blocked the effects of both GHB and baclofen, whereas the putative GHB receptor antagonist NCS-382 was ineffective. The GHB and baclofen effects were prevented in the presence of 200 µM barium indicating that GHB augments a K+ conductance, probably a G-protein coupled inwardly rectifying K+ (GIRK) current. The decrease of Ih by GHB and baclofen also was prevented by barium, suggesting that the diminution of Ih is secondary to GIRK augmentation. Our results indicate that high GHB levels, which can be reached during abuse or intoxication, activate only GABAB receptors and not GHB receptors at the postsynaptic level to augment an inwardly rectifying K+ current and decrease Ih.


Key words: GABA receptor, GHB, Postsynaptic conductance, channel, slice, voltage clamp


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