Selective γ‐hydroxybutyric acid receptor ligands increase extracellular glutamate in the hippocampus, but fail to activate G protein and to produce the sedative/hypnotic effect of γ‐hydroxybutyric acid

  title={Selective $\gamma$‐hydroxybutyric acid receptor ligands increase extracellular glutamate in the hippocampus, but fail to activate G protein and to produce the sedative/hypnotic effect of $\gamma$‐hydroxybutyric acid},
  author={Maria Paola Castelli and Luca Ferraro and Ignazia Mocci and Francesca Carta and Mauro A. M. Carai and Tiziana Antonelli and Sergio Tanganelli and Giorgio Cignarella and Gian Luigi Gessa},
  journal={Journal of Neurochemistry},
Two γ‐hydroxybutyric acid (GHB) analogues, trans‐γ‐hydroxycrotonic acid (t‐HCA) and γ‐(p‐methoxybenzyl)‐γ‐hydroxybutyric acid (NCS‐435) displaced [3H]GHB from GHB receptors with the same affinity as GHB but, unlike GHB, failed to displace [3H]baclofen from GABAB receptors. The effect of the GHB analogues, GHB and baclofen, on G protein activity and hippocampal extracellular glutamate levels was compared. While GHB and baclofen stimulated 5′‐O‐(3‐[35S]thiotriphospate) [35S]GTPγS binding both in… 

Metabolic GHB precursor succinate binds to γ‐hydroxybutyrate receptors: Characterization of human basal ganglia areas nucleus accumbens and globus pallidus

It is suggested that succinate (and possibly drugs available as succinate salt derivatives) can mimic some of the actions of GHB.

Phenylacetic acids and the structurally related non‐steroidal anti‐inflammatory drug diclofenac bind to specific γ‐hydroxybutyric acid sites in rat brain

Measuring the affinities of structurally related NSAIDs for the [3H]NCS‐382 site identified diclofenac, a clinically relevant NSAID of the phenylacetic acid (PAA) type, as a GHB ligand (Ki value of 5.1 μm), and other non‐NSAID PAAs also exhibited affinity similar to GHB.

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

Three conformationally restricted GHB analogs are synthesized and assayed for binding against the GHB-specific ligand [3H]NCS-382 in rat brain homogenate and show excellent potential as lead structures and novel tools for studying specific GHB receptor-mediated pharmacology.

GET73 increases rat extracellular hippocampal CA1 GABA levels through a possible involvement of local mGlu5 receptor

The present data suggest that the GET73‐induced increase in hippocampal CA1 GABA levels operates independently of local GABA reuptake and/or GABAA or GABAB receptors, which may be relevant to the ability of GET73 to reduce alcohol intake in an alcohol‐preferring rat strain.



Evidence for a G Protein‐Coupled γ‐Hydroxybutyric Acid Receptor

The hypothesis that GHB induces a Gprotein‐mediated decrease in adenylyl cyclase via a GHB‐specific G protein‐coupled presynaptic receptor that is different from the GABABR is supported.

γ‐Hydroxybutyrate modulation of glutamate levels in the hippocampus: an in vivo and in vitro study

Findings indicate that γ‐hydroxybutyric acid exerts a concentration‐dependent regulation of hippocampal glutamate transmission via two opposing mechanisms, whereby a direct γ-hydroxy butyricacid receptor mediated facilitation is observed at nanomolar γ•hydroxyButyric Acid concentrations, and an indirect GABAB receptor mediated inhibition predominates at millimolar concentrations.

Presynaptic gamma-hydroxybutyric acid (GHB) and gamma-aminobutyric acidB (GABAB) receptor-mediated release of GABA and glutamate (GLU) in rat thalamic ventrobasal nucleus (VB): a possible mechanism for the generation of absence-like seizures induced by GHB.

By selectively modulating the basal and K(+)-evoked release of GABA and GLU, GHB induces, in the thalamic ventrobasal relay nucleus, an optimal "excitatory" environment conducive to the generation of absence seizures, raising the possibility that a presynaptic GHB/GABAB receptor complex occurs in VB.

Gamma-hydroxybutyrate is a GABAB receptor agonist that increases a potassium conductance in rat ventral tegmental dopamine neurons.

Electrophysiological recordings suggest that GHB is an agonist at gamma-aminobutyric acid receptors and would be expected to inhibit DA release by causing K+-dependent membrane hyperpolarization.


A specific gamma-hydroxybutyrate receptor ligand possesses both antagonistic and anticonvulsant properties.

The results suggest that NCS-382 may represent a harbinger for a new class of anticonvulsant drugs that most probably act by modifying the endogenous GHB system.