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Alterations in Neuronal Transport but not Blood-Brain Barrier Transport are Observed during Gamma-Hydroxybutyrate (GHB) Sedative/Hypnotic Tolerance

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Abstract

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.

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Abbreviations

AUC:

area under curve

AUMC:

area under first moment curve

BBB:

blood brain barrier

C :

perfusion fluid concentration of tracer

CL/F :

systemic clearance

CLin :

influx clearance

C max :

maximum concentration

CNS:

central nervous system

DPH:

1,6-diphenyl-1,3,5-hexatriene

GABA:

γ-aminobutyric acid

GBL:

γ-butyrolactone

GHB:

γ-hydroxybutyrate

LRR:

loss in righting reflex

MCT:

monocarboxylate acid transporter

MRT:

mean residence time

P :

fluorescence polarization

Q :

mass of radiotracer in the brain region normalized for wet brain tissue weight

r :

anisotropy

RRR:

return in righting reflex

S 2 :

lipid order

T :

time of perfusion

T 1/2 :

half life

T max :

time to maximum concentration

V/F:

volume of distribution

V vasc :

regional volume of the cerebrovascular capillary bed

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Acknowledgments

The authors would like to thank Mr. David Soda for his assistance with the jugular vein cannulations and Dr. S. Balasubramanian and his group for insightful discussions and suggestions for the membrane fluidity fluorescence studies. This work was supported in part by National Institutes of Health grant DA 14988 and a Merck predoctoral fellowship.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, H517 Cooke-Hochstetter, Buffalo, NY, 14260, USA

    Indranil Bhattacharya, Joseph J. Raybon & Kathleen M. K. Boje

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  1. Indranil Bhattacharya
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  2. Joseph J. Raybon
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  3. Kathleen M. K. Boje
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Correspondence to Kathleen M. K. Boje.

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Indranil Bhattacharya and Joseph J. Raybon have contributed equally to this work.

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Bhattacharya, I., Raybon, J.J. & Boje, K.M.K. Alterations in Neuronal Transport but not Blood-Brain Barrier Transport are Observed during Gamma-Hydroxybutyrate (GHB) Sedative/Hypnotic Tolerance. Pharm Res 23, 2067–2077 (2006). https://doi.org/10.1007/s11095-006-9066-6

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