Cammalleri Maurizio, Brancucci Alfredo, Berton Fulvia, Loche Antonella, Gessa Gian Luigi, Francesconi Walter
Department of Physiology and Biochemistry G. Moruzzi, University of, Pisa, Italy.
Neuropsychopharmacology. 2002 Dec;27(6):960-9. doi: 10.1016/S0893-133X(02)00378-0.
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.
γ-羟基丁酸（GHB）是一种精神活性药物，也是一种假定的神经递质，由γ-氨基丁酸（GABA）衍生而来。在微摩尔浓度下，GHB与大脑离散区域中存在的特定高亲和力和低亲和力结合位点结合，而在毫摩尔浓度下，GHB也与GABA(B)受体结合。先前的研究表明，GHB抑制海马CA1锥体神经元中NMDA和AMPA受体介导的兴奋性突触后电位。GHB的这种作用在存在GABA(B)阻断的情况下发生，并被特异性GHB受体拮抗剂NCS-382拮抗，这表明它是由GHB受体介导的。在本研究中，我们研究了GHB对通过刺激海马CA1锥体神经元的Schaffer侧支-连合纤维所引发的GABA(A)介导的抑制性突触后电位（GABA(A)-IPSP）的影响。我们观察到，在300 - 600微摩尔浓度下，GHB将GABA(A)-IPSPs抑制了约40%。GHB的抑制作用被NCS-382（500微摩尔）阻断，而NCS-382本身未能改变GABA(A)-IPSPs。此外，在存在河豚毒素（TTX）的情况下，GHB未能改变短暂压力施加GABA所诱导的细胞膜去极化，这表明GHB不抑制突触后GABA反应。然而，GHB降低了成对脉冲刺激在锥体神经元中引发的GABA(A)-IPSPs的幅度，并相对于对照条件增强了成对脉冲易化，这表明GHB减少了神经末梢的GABA释放。最后，在存在BaCl(2)的情况下，GHB未能降低GABA(A)-IPSPs的幅度，这表明GHB的作用是由于GHB受体介导的对Ca(2)+内流的突触前抑制。
