Presynaptic Modulation of Spontaneous Inhibitory Postsynaptic Currents by Gamma-hydroxybutyrate in the Substantia Nigra Pars Compacta

Abstract

The regulation of GABA release from the inhibitory input to dopamine cells in the substantia nigra pars compacta (SNc) plays a key role in different reward-related behaviors. Gamma-hydroxybutyrate (GHB) has therapeutical properties in various psychiatric disorders, especially in alcohol abuse. GHB is also used as a drug of abuse, which induces sedation and euphoria. Using whole-cell patch-clamp recordings, we studied the effects of GHB on GABA release in the SNc by recording spontaneous inhibitory postsynaptic currents (sIPSCs) in brain slices of 21-to 25-day-old rats. We found that GHB depressed the frequency and amplitude of sIPSCs, while the frequency and the amplitude of miniature inhibitory postsynaptic currents (mIPSCs), recorded in the presence of TTX, were not affected. However, in the presence of high extracellular potassium (15 mM), which increases the contribution of voltage-dependent calcium channels, GHB induced a reduction in the frequency of the mIPSCs without any effect on their amplitude. All of these effects were GABA B -independent and they were blocked by the GHB receptor antagonist NCS-382. The present results indicate that GHB inhibits spontaneous inhibitory synaptic transmission recorded from dopaminergic neurons in the SNc likely by reducing voltage-dependent calcium influx involved in presynaptic GABA release.

Novel Cyclic γ-Hydroxybutyrate (GHB) Analogs with High Affinity and Stereoselectivity of Binding to GHB Sites in Rat Brain

“…In this context, it will be necessary to determine the intrinsic activity of the compounds. Although isolated reports of functional assays have been described in the literature (Castelli et al, 2003;Kemmel et al, 2003;Brancucci et al, 2004), these remain to be validated by other laboratories. The compounds are also ideal lead structures, presenting ample opportunity for further substitution and structural elaboration, again with the advantage of low molecular weight and high binding efficiency of the scaffolds, bearing in mind that the synthesis of a radioligand with high specific activity could greatly aid in the molecular cloning of the GHB receptor or lay the way for tomography studies.…”

“…GHB has been shown to be a low-affinity (Mathivet et al, 1997) weak partial agonist at GABA B receptors (Lingenhoehl et al, 1999) and may also be converted into GABA in vivo and thus affect GABA receptors indirectly (Hechler et al, 1997). However, based on recent data, it would also seem that specific GHB receptor-mediated effects exist (Castelli et al, 2003;Kemmel et al, 2003;Brancucci et al, 2004). This, in combination with the presence of high-affinity [ 3 H]GHB binding sites in the brain (Benavides et al, 1982), suggests the existence of a distinct GHB receptor.…”

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

“…The effect of 10 mM GHB was unaffected by 1 to 4 mM NCS-382 but prevented by 1 M CGP 55845 or 200 M barium. Howard, 1996;Maitre, 1997), and GHB can alter synaptic activity with GABA B receptors blocked, an effect prevented by the putative GHB receptor antagonist NCS-382 (Berton et al, 1999;Cammalleri et al, 2002;Brancucci et al, 2004). This latter action occurs at low concentrations of GHB, whereas the modulation of postsynaptic conductances requires high (millimolar) concentrations.…”

A single acute pharmacological dose of γ-hydroxybutyrate modifies multiple gene expression patterns in rat hippocampus and frontal cortex

“…The majority of GABA A receptors contain a ␥2 subunit, expressed throughout the brain except in the thalamus. It is well known that GHB administration in rats modifies GABA release in brain (9,10,28), leading to a pharmacological profile (sleep, anesthesia, anxiolysis) similar to those described for other GABA A agonists.…”