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Received for publication April 12, 2004.
Revised May 26, 2004.
Accepted for publication June 1, 2004.
-Hydroxybutyrate (GHB) Carrier Mediated Transport Across the Blood Brain Barrier
-Hydroxybutyrate (sodium oxybate, GHB) is an approved therapeutic agent for cataplexy with narcolepsy. GHB is widely abused as an anabolic agent, euphoriant and date rape drug. Recreational abuse or overdose of GHB (or its precursors: -butyrolactone or 1,4-butanediol) results in dose dependent central nervous system (CNS) effects (respiratory depression, unconsciousness, coma, death) as well as tolerance and withdrawal. An understanding of the CNS transport mechanisms of GHB may provide insight into overdose treatment approaches. The hypothesis that GHB undergoes carrier mediated transport across the BBB was tested using a rat in situ brain perfusion technique. Various pharmacologic agents were used to probe the pharmacological characteristics of the transporter. GHB exhibited carrier mediated transport across the BBB consistent with a high capacity, low affinity transporter; averaged brain region parameters were Vmax = 709 ± 214 nmol/min/g, Km = 11.0 ± 3.56 mM and CLns = 0.019 ± 0.003 cm3/min/g. Short chain monocarboxylic acids (pyruvic, lactic, 
-hydroxybutyric), medium chain fatty acids (hexanoic, valproic) and organic anions (probenecid, benzoic, salicylic, CHC) significantly inhibited GHB influx by 35-90%. Dicarboxylic acids (succinic, glutaric) and -aminobutyric acid did not inhibit GHB BBB transport. Mutual inhibition was observed between GHB and benzoic acid, a well-known substrate of the monocarboxylate transporter (MCT1). These results are suggestive of GHB crossing the BBB via a MCT isoform. These novel findings of GHB BBB transport suggest potential therapeutic approaches in the treatment of GHB overdoses. We are currently conducting "proof-of-concept" studies involving the use of GHB brain transport inhibitors during GHB toxicity.
Key words:
blood brain barrier, central nervous system transport, drugs of abuse, gamma hydroxybutyrate, in situ brain perfusion, monocarboxylate transporter
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