Jean-Jacques Bourguignon

Extracellular Events Induced by γ‐Hydroxybutyrate in Striatum: A Microdialysis Study

Abstract: The modification of dopamine release and accumulation induced by γ‐hydroxybutyrate (GHB) was studied using both striatal slices and in vivo microdialysis of caudate‐putamen. GHB inhibited dopamine release for ∼5–10 min in vitro, and this was associated with an accumulation of dopamine in the tissue. Subsequently, there was an increase in dopamine release. In the microdialysis experiments, low doses of GHB inhibited dopamine release, whereas higher doses strongly increased release; the initial decrease seen in slices could not be detected in vivo. Thus, GHB had a biphasic effect on the release of dopamine: An initial decrease in the release of transmitter was followed by an increase. A time‐dependent biphasic effect was observed when GHB was added to brain slices, and a dose‐dependent biphasic effect was seen in dialysate after systemic administration of GHB. Naloxone blocked GHB‐induced dopamine accumulation and release both in vitro and in vivo. GHB also increased the release of opioid‐like substances in the striatum. A specific antagonist of GHB receptors completely blocked both the dopamine response and the release of opioid‐like substances. These data suggest that GHB increases dopamine release via specific receptors that may modulate the activity of opioid interneurons.

The active analog approach applied to the pharmacophore identification of benzodiazepine receptor ligands

SummaryApplied to seven potent benzodiazepine-receptor ligands belonging to chemically different classes, the active analog approach allowed the stepwise identification of the pharmacophoric pattern associated with the recognition by the benzodiazepine receptor.A unique pharmacophore model was derived which involves six critical zones: (a) a π-electron rich aromatic (PAR) zone; (b) two electron-rich zones δ1 and δ2 placed at 5.0 and 4.5 Å respectively from the reference centroid in the PAR zone; (c) a freely rotating aromatic ring (FRA) region; (d) an out-of-plane region (OPR), strongly associated with agonist properties; and (e) an additional hydrophobic region (AHR).The model accommodates all presently known ligands of the benzodiazepine receptor, identifies sensitivity to steric hindrance close to the δ1 zone, accounts forR andS differential affinities and distinguishes requirements for agonist versus non-agonist activity profiles.

Trans-γ-hydroxycrotonic acid binding sites in brain: evidence for a subpopulation of γ-hydroxybutyrate

Abstract Trans -γ-hydroxycrotonate (THCA), a compound naturally present in rat brain, possesses high-affinity binding sites with a heterogeneous distribution which are superimposable with those for γ-hydroxybutyrate (GHB). Binding studies of THCA on rat brain membranes revealed two binding components, one of high affinity ( K d 1 , 7 nM, B max 1 42 fmol/mg protein) and the other of low affinity ( K d 2 , 2 μM, B max 2 13 pmol/mg protein). Displacement curves of [ 3 H]THCA by THCA and GHB or of [ 3 H]GHB by THCA are in favour of the existence of a specific high affinity site for THCA. Quantitative autoradiography with image analysis of [ 3 H]THCA binding in rat brain slices indicated that [ 3 H]THCA high affinity binding was displaced at a lower potency by GHB. THCA showed also some selectivity in displacing [ 3 H]GHB from its high affinity binding site ( K d = 95 nM). This mutual overlap favours a subpopulation of GHB receptors, which have THCA as a natural ligand, showing partial agonistic properties compared to GHB. The functional significance of this result remains unknown.