Alterations in neuronal transport but not blood-brain barrier transport are observed during gamma-hydroxybutyrate (GHB) sedative/hypnotic tolerance

Purpose. To investigate if γ-Hydroxybutyrate (GHB) tolerance is mediated by alterations in GHB systemic pharmacokinetics, transport (blood brain barrier (BBB) and neuronal) or membrane fluidity. Materials and Methods. GHB tolerance in rats was attained by repeated GHB administration (5.31 mmol/kg, s.c., QD for 5 days). GHB sedative/hypnotic effects were measured daily. GHB pharmacokinetics were determined on day 5. In separate groups, on day 6, in situ brain perfusion was performed to assess BBB transport alterations; or in vitro studies were performed (fluorescence polarization measurements of neuronal membrane fluidity or [³H]GABA neuronal accumulation). Results. GHB sedative/hypnotic tolerance was observed by day 5. No significant GHB pharmacokinetic or BBB transport differences were observed between treated and control rats. Neuronal membrane preparations from GHB tolerant rats showed a significant decrease in fluorescence polarization (treated - 0.320 ± 0.009, n = 5; control - 0.299 ± 0.009, n = 5; p < 0.05). [³H]GABA neuronal transport V_max was significantly increased in tolerant rats (2,110.66 ± 91.06 pmol/mg protein/min vs control (1,612.68 ± 176.03 pmol/mg protein/min; n = 7 p < 0.05). Conclusions. Short term GHB administration at moderate doses results in the development of tolerance which is not due to altered systemic pharmacokinetics or altered BBB transport, but might be due to enhanced membrane rigidity and increased GABA reuptake.