 | CELLULAR AND MOLECULAR MECHANISMS OF DRUGS OF ABUSE II: COCAINE, SUBSTITUTED AMPHETAMINES, GHB, AND OPIATES
Copyright © 2002 by the New York Academy of Sciences
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Annals of the New York Academy of Sciences 965:461-472 (2002)
© 2002 New York Academy of Sciences
Enzyme and Receptor Antagonists for Preventing Toxicity from the Gamma-Hydroxybutyric Acid Precursor 1,4-Butanediol in CD-1 Mice
LAWRENCE S. QUANGa,b,c,
MALHAR C. DESAIc,
JAMES C. KRANERd,
MICHAEL W. SHANNONa,b,c,
ALAN D. WOOLFb,c AND
TIMOTHY J. MAHERc
aDivision of Emergency Medicine, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA
bProgram in Clinical Pharmacology/Toxicology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA
cDepartment of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, Boston, Massachusetts 02115, USA
dAmerican Institute of Toxicology (AIT) Laboratories, Indianapolis, Indiana 46241, USA
Address for correspondence: Lawrence S. Quang, M.D., Division of Emergency Medicine, Children's Hospital Boston, 300 Longwood Ave., Boston, MA 02115. Voice: 617-355-5189; fax: 617-738-0032.
lawrence.quang{at}tch.harvard.edu
Ann. N.Y. Acad. Sci. 965: 461-472 (2002).
1,4-Butanediol (1,4-BD), the diol alcohol precursor of gamma-hydroxybutyric acid (GHB), undergoes in vivo enzymatic biotransformation to GHB by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase. The subsequent metabolite, GHB, is pharmacologically active at GABA B and GHB receptors. GHB can be metabolized in vivo to gamma-aminobutyric acid (GABA) and trans-4-hydroxycrotonic acid (T-HCA), which are also pharmacologically active at GABA B receptors and GHB receptors, respectively. Therefore, we speculate that 1,4-BD overdose toxicity can be prevented or attenuated with the ADH enzyme inhibitor 4-methylpyrazole (4-MP) as well as with CGP-35348 and NCS-382, novel high-affinity receptor antagonists of GABA B receptors and GHB receptors, respectively. In our murine model of acute 1,4-BD overdose, pretreatment of CD-1 mice with 4-MP significantly attenuated increases in blood GHB concentrations and prevented loss of the righting reflex and failure of the rotarod test. Also, pretreatment with CGP-35348 and its combination with NCS-382 significantly decreased the duration of failure for the rotarod test and the percentage of animals failing the rotarod test, respectively. However, pretreatment of CD-1 mice with NCS-382 alone produced prolonged failure of the rotarod test, an unexpected synergistic effect with 1,4-BD and presumably GHB, which has not previously been demonstrated.
Key Words: 1,4-butanediol • gamma-hydroxybutyric acid • 4-methylpyrazole • NCS-382 • CGP-35348 • gamma-aminobutyric acid • trans-4-hydroxycrotonic acid • GABAB receptor • GHB receptor • alcohol dehydrogenase
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