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NEUROPHARMACOLOGY

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

The Scripps Research Institute, Department of Neuropharmacology, La Jolla, California

-Hydroxybutyrate (GHB) is used for the treatment of alcoholism and to induce absence seizures in animals, but it has also recently emerged as a drug of abuse. In hippocampal neurons, GHB may activate its own putative receptor as well as GABA_B receptors to affect synaptic transmission. We used voltage-clamp recordings of rat CA1 pyramidal neurons to characterize the postsynaptic conductances affected by GHB and to 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 (I_h). Like GHB, the selective GABA_B-receptor agonist baclofen (20 µM) increased a potassium current and decreased I_h. In the presence of 10 mM GHB, the baclofen effects were largely occluded. The selective GABA_B receptor antagonist CGP 55845 [3-N[1-(S)-(3,4-dichlorophenyl)ethyl]amino-2-(S)-hydroxypropyl-p-benzyl-phosphinic acid] blocked the effects of both GHB and baclofen, whereas the putative GHB receptor antagonist NCS-382 [(2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene ethanoic acid] 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 I_h by GHB and baclofen was also prevented by barium, suggesting that the diminution of I_h is secondary to GIRK augmentation. Our results indicate that high GHB levels, which can be reached during abuse or intoxication, activate only GABA_B receptors and not GHB receptors at the postsynaptic level to augment an inwardly rectifying K⁺ current and decrease I_h.

Address correspondence to: Dr. P. Schweitzer, CVN-12, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037. E-mail: pschweitzer{at}scripps.edu.

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