title: Gamma-hydroxybutyrate reduces GABA(A)-mediated inhibitory postsynaptic potentials in the CA1 region of hippocampus.
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 GABA(B) 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 GABA(B) 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 GABA(A) mediated inhibitory postsynaptic potentials (GABA(A)-IPSP) elicited in CA1 hippocampal pyramidal neurons by stimulation of Schaffer collateral-commissural fibers. We observed that GHB inhibited GABA(A)-IPSPs by about 40% at concentrations of 300-600 microM. GHB inhibition was blocked by NCS-382 (500 microM), which per se failed to modify GABA(A)-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 GABA(A)-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 GABA(A)-IPSPs in the presence of BaCl(2), suggesting that the effect of GHB is due to GHB receptor-mediated presynaptic inhibition of Ca(2)+ influx.
authors.affiliation: Department of Physiology and Biochemistry G. Moruzzi, University of, Pisa, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cammalleri
authors.forename: Alfredo
authors.initials: A
authors.lastname: Brancucci
authors.forename: Fulvia
authors.initials: F
authors.lastname: Berton
authors.forename: Antonella
authors.initials: A
authors.lastname: Loche
authors.forename: Gian Luigi
authors.initials: GL
authors.lastname: Gessa
authors.forename: Walter
authors.initials: W
authors.lastname: Francesconi
mesh_terms: D000818:Animals; D058787:GABA-A Receptor Antagonists; D058788:GABA-B Receptor Antagonists; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000502:physiology*; D018080:Receptors, GABA-B / Q000502:physiology; D012978:Sodium Oxybate / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
chemical_list: D058787:GABA-A Receptor Antagonists; D058788:GABA-B Receptor Antagonists; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D012978:Sodium Oxybate