Gamma-hydroxybutyric acid tolerance development: Pharmacokinetic and pharmacodynamic perspectives
Raybon, Joseph Jackson
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Gamma-hydroxybutyric acid (GHB) is a central nervous system depressant and drug of abuse. Chronic exposure results in the development of tolerance to its sedative/hypnotic effects. For centrally-acting substances, the existence of tolerance may be a strong indicator of drug dependence and thus a good predictor of a drug's abuse liability. The goal of this dissertation was to investigate the roles of pharmacokinetics (PK) and pharmacodynamics (PD) in the development and expression of GHB tolerance. Various in vitro and in vivo studies were performed to attain a better understanding of this phenomenon. Following five days of GHB administration in rats (548 mg/kg s.c., once daily), the sedative/hypnotic effect time was significantly decreased as a function of days of exposure. We hypothesized that this behavioral change could be mediated, in part, through alterations in neuronal membrane fluidity. Using fluorescence polarization studies, GHB sedative tolerance was found to be associated with a decrease in the membrane fluidity of neuronal preparations which was not due to a direct drug-membrane interaction. Further explorations in vitro revealed that an increase in the neuronal re-uptake of GABA, a mediator of GHB's inhibitory effects, also accompanies the observed biophysical and behavioral changes. In contrast to biophysical or neurochemical changes, an alternative hypothesis that would explain the observed decrease in GHB's sedative effects might involve changes in the pharmacokinetics. It was shown that, upon multiple dosing (548 mg/kg s.c., once daily for 5 days), the behavioral tolerance towards GHB was not associated with alterations in the either the systemic or CNS pharmacokinetics, as probed by microdialysis. However, pharmacodynamic tolerance did develop towards GHB's inhibition of extracellular dopamine release and, as indicated by PKPD modeling, it is likely the result of decreased sensitivity towards GHB's depressant effects. In conclusion it appears that the development of GHB tolerance is multi-faceted, involving biophysical adaptations, changes in neuronal regulatory processes and neurochemical responsiveness, all of which may or may not be related to one another.