Repeated administration of gamma-hydroxybutyric acid (GHB) to mice: assessment of the sedative and rewarding effects of GHB.

Because of the sedative/hypnotic and euphoric effects of gamma-hydroxybutyric acid (GHB), the recreational use of the drug has increased significantly. In the current study we investigated the sedative and rewarding effects of GHB in Swiss Webster mice. Although the acute administration of GHB (200 mg/kg) caused marked hypolocomotion, repeated administration of the drug for 6 or 14 days produced tolerance to this effect. In addition, the administration of GHB 300 mg/kg to naive mice caused catalepsy, which dissipated in mice pre-exposed to GHB (200 mg/kg). Consequently, after repeated treatment with GHB, tolerance developed to both the hypolocomotion and cataleptic effects of the drug. The administration of GHB or its precursor gamma-butyrolactone for 14 days increased the striatal content of dopamine. The sedative effects of GHB may be due to hypodopaminergic activity from inhibition of dopamine release and a subsequent increase in the intraneuronal dopamine level. The rewarding effect of GHB was assessed in the conditioned place preference paradigm. Mice treated repeatedly with 250 mg/kg for 7 days developed conditioned preference for the GHB-paired compartment of the cage, suggesting that the GHB cue is rewarding. The development of tolerance to the sedative effects of GHB coupled with the rewarding properties of the drug support the abuse potential of GHB. Further studies are necessary to determine the mechanism underlying the development of tolerance to GHB and the rewarding effect of the drug.