gamma-Hydroxybutyrate ligands possess antidopaminergic and neuroleptic-like activities

The action of agonists or antagonists at the gamma-hydroxybutyrate (GHB) receptor represents a possibility to modulate dopaminergic activities in brain. In the present study, GHB and six structural analogs were tested for their ability to displace [3H] GHB binding from striatal membranes. All the analogs tested exhibited higher affinity for GHB as compared with GHB itself. Parallel experiments were carried out on striatal slices in order to determine IC50 values for inhibition of dopamine release in the presence of these compounds. All substances inhibited dopamine release with higher potency as compared with GHB itself. These antidopaminergic activities were confirmed in several neuropharmacological tests, usually used to predict neuroleptic activities in vivo. There appears to be a relationship between the affinity for the GHB striatal low-affinity receptor and the inhibition of dopamine release on one hand, and the antidopaminergic activity (as revealed by the in vivo tests) on the other hand. Thus, it is suggested that GHB agonists possessing antidopaminergic activities, may represent potential drugs endowed with neuroleptic properties.