Pharmacokinetics and pharmacodynamics of γ-hydroxybutyric acid during tolerance in rats: Effects on extracellular dopamine

γ-Hydroxybutyrate (GHB) is a potent sedative/hypnotic and drug of abuse. Tolerance develops to GHB's sedative/hypnotic effects. It is hypothesized that GHB tolerance may be mediated by alterations in central nervous system pharmacokinetics or neurotransmitter response. Rats were dosed daily with GHB (548 mg/kg s.c. q.d. for 5 days), and sleep time was measured as an index of behavioral tolerance. Plasma and brain GHB pharmacokinetics on days 1 and 5 were monitored using blood and microdialysis sampling. Extracellular (ECF) striatal dopamine levels were measured by microdialysis as a pharmacodynamic endpoint of tolerance. Pharmacokinetic (PK)/pharmacodynamic (PD) modeling was performed to describe the plasma and brain disposition using an indirect response model with inhibition of dopamine synthesis rate to describe the pharmacodynamic response. GHB plasma and brain ECF concentration versus time profiles following acute or chronic exposure were not significantly different. GHB sedative/hypnotic tolerance was observed by day 5. Acute GHB administration resulted in a decrease in striatal ECF dopamine (DA) levels compared with baseline levels. GHB tolerance was reflected by a 60% decrease in dopamine area under the curve (effect and baseline): acute, 10.1 ± 15.3% basal DA/min/10^-3 versus chronic, 4.73 ± 1.49% basal DA/min/10^-3 (p < 0.05, n = 5; unpaired Student's t test). The PK/PD model revealed an increase in the IC50 following chronic exposure indicating decreased dopaminergic sensitivity toward the inhibitory effects of GHB. Our findings indicate that GHB pharmacokinetics do not contribute to behavioral tolerance; however, changes in neurotransmitter responsiveness may suggest specific neurochemical pathways involved in the development and expression of tolerance.