Gamma-hydroxybutyrate reduces GABAA-mediated inhibitory postsynaptic potentials in the CA1 region of hippocampus

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Abstract

Gamma-hydroxybutyric acid (GHB) is a psychoactive drug and a putative neurotransmitter, derived from gamma-aminobutyric acid (GABA). At micromolar concentrations GHB binds to specific high and low affinity binding sites present in discrete areas of the brain, while at millimolar concentrations GHB also binds to GABAB receptors. Previous studies indicated that GHB inhibits both NMDA and AMPA receptor mediated excitatory postsynaptic potentials in hippocampal CA1 pyramidal neurons. This action of GHB occurs in the presence of GABAB blockade and is antagonized by NCS-382, a specific GHB receptor antagonist, suggesting that it is mediated by GHB receptors. In the present study, we have investigated the effect of GHB on GABAA mediated inhibitory postsynaptic potentials (GABAA-IPSP) elicited in CA1 hippocampal pyramidal neurons by stimulation of Schaffer collateral-commissural fibers. We observed that GHB inhibited GABAA-IPSPs by about 40% at concentrations of 300-600 μM. GHB inhibition was blocked by NCS-382 (500 μM), which per se failed to modify GABAA-IPSPs. Moreover, GHB failed to modify cell membrane depolarization induced by the brief pressure application of GABA in the presence of tetrodotoxin (TTX), indicating that GHB does not inhibit postsynaptic GABA responses. However, GHB reduced the amplitude of GABAA-IPSPs elicited in pyramidal neurons by paired pulse stimulation and enhanced paired pulse facilitation with respect to control condition, suggesting that GHB reduces GABA release from nerve terminals. Finally, GHB failed to reduce the amplitude of GABAA-IPSPs in the presence of BaCl2, suggesting that the effect of GHB is due to GHB receptor-mediated presynaptic inhibition of Ca2+ influx. © 2002 American College of Neuropsychopharmacology. Published by Elsevier Science Inc.

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Cammalleri, M., Brancucci, A., Berton, F., Loche, A., Gessa, G. L., & Francesconi, W. (2002). Gamma-hydroxybutyrate reduces GABAA-mediated inhibitory postsynaptic potentials in the CA1 region of hippocampus. Neuropsychopharmacology, 27(6), 960–969. https://doi.org/10.1016/S0893-133X(02)00378-0

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