Administration of gamma-hydroxybutyrate (GHB) to animals induces electroencephalographic and behavioral changes that resemble petit-mal seizures. Furthermore, these GHB-induced electroencephalogram-behavioral changes can be blocked by anticonvulsant drugs, which are specific in their action against petit-mal seizures. These effects of GHB on electroencephalogram and behavior may well be due to an effect of exogenously administrated GHB on GHB-mediated systems in the brain. GHB has many properties of a neuromodulator including the existence of receptors with a specific affinity for this compound. A synthetic structural analog of GHB, NCS-382, possessed anticonvulsant activity against several animal models of seizure and, in particular, against that induced by GHB administration. NCS-382 was also shown to be an antagonist at GHB receptor sites and blocked the neuropharmacologic effects induced in the striatum and hippocampus by GHB administration. In particular, NCS-382 inhibited the increase in cGMP levels and in inositol phosphate turnover induced by GHB in hippocampus. Furthermore, in vivo dialysis demonstrated that NCS-382 blocked the increased release of dopamine in striatum after GHB administration in vivo. Thus, this ligand appears to be the first described antagonist substance for GHB receptor(s). These 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.