Wouter Koek1, Charles P France. 1. Department of Psychiatry, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA. koek@uthscsa.edu
Abstract
RATIONALE: Gamma-hydroxybutyrate (GHB) is a gamma-aminobutyric acid (GABA) analog that is used to treat narcolepsy but that is also abused. GHB has many actions in common with the GABA(B) receptor agonist baclofen, but their underlying GABA(B) receptor mechanisms may be different. OBJECTIVE: The aim of this study is to further investigate a possible differential role of glutamate in GABA(B) receptor-mediated effects of GHB and baclofen. MATERIALS AND METHODS: The experiments examined the effects of non-competitive antagonists at the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors on GHB-induced catalepsy and compared these effects with those on baclofen-induced catalepsy. RESULTS: In C57BL/6J mice, ketamine, phencyclidine (PCP), and dizocilpine (MK-801) all enhanced GHB-induced catalepsy. They did so with a potency order (i.e., MK-801 > PCP > ketamine) consistent with their relative potencies as NMDA antagonists but not as inhibitors of dopamine or organic cation transporters. Ketamine, PCP, and MK-801 enhanced catalepsy along inverted U-shaped dose-response curves likely because higher doses affected motor coordination, which limited their catalepsy-enhancing effects. Doses that were maximally effective to enhance GHB-induced catalepsy did not affect the cataleptic effects of baclofen. CONCLUSIONS: The finding that NMDA receptor antagonists enhance the cataleptic effects of GHB but not those of baclofen is further evidence that the GABA(B) receptor mechanisms mediating the effects of GHB and GABA(B) agonists are not identical. Differential interactions of glutamate with the GABA(B) receptor mechanisms mediating the effects of GHB and baclofen may explain why GHB is effective for treating narcolepsy and is abused, whereas baclofen is not.
RATIONALE: Gamma-hydroxybutyrate (GHB) is a gamma-aminobutyric acid (GABA) analog that is used to treat narcolepsy but that is also abused. GHB has many actions in common with the GABA(B) receptor agonist baclofen, but their underlying GABA(B) receptor mechanisms may be different. OBJECTIVE: The aim of this study is to further investigate a possible differential role of glutamate in GABA(B) receptor-mediated effects of GHB and baclofen. MATERIALS AND METHODS: The experiments examined the effects of non-competitive antagonists at the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors on GHB-induced catalepsy and compared these effects with those on baclofen-induced catalepsy. RESULTS: In C57BL/6J mice, ketamine, phencyclidine (PCP), and dizocilpine (MK-801) all enhanced GHB-induced catalepsy. They did so with a potency order (i.e., MK-801 > PCP > ketamine) consistent with their relative potencies as NMDA antagonists but not as inhibitors of dopamine or organic cation transporters. Ketamine, PCP, and MK-801 enhanced catalepsy along inverted U-shaped dose-response curves likely because higher doses affected motor coordination, which limited their catalepsy-enhancing effects. Doses that were maximally effective to enhance GHB-induced catalepsy did not affect the cataleptic effects of baclofen. CONCLUSIONS: The finding that NMDA receptor antagonists enhance the cataleptic effects of GHB but not those of baclofen is further evidence that the GABA(B) receptor mechanisms mediating the effects of GHB and GABA(B) agonists are not identical. Differential interactions of glutamate with the GABA(B) receptor mechanisms mediating the effects of GHB and baclofen may explain why GHB is effective for treating narcolepsy and is abused, whereas baclofen is not.
Authors: Klemens Kaupmann; John F Cryan; Petrine Wellendorph; Cedric Mombereau; Gilles Sansig; Klaus Klebs; Markus Schmutz; Wolfgang Froestl; Herman van der Putten; Johannes Mosbacher; Hans Bräuner-Osborne; Peter Waldmeier; Bernhard Bettler Journal: Eur J Neurosci Date: 2003-11 Impact factor: 3.386
Authors: Lawrence P Carter; Huifang Wu; Weibin Chen; Christopher M Cruz; R J Lamb; Wouter Koek; Andy Coop; Charles P France Journal: J Pharmacol Exp Ther Date: 2003-10-20 Impact factor: 4.030
Authors: Wouter Koek; Lauren R Flores; Lawrence P Carter; R J Lamb; Weibin Chen; Huifang Wu; Andrew Coop; Charles P France Journal: J Pharmacol Exp Ther Date: 2004-01-12 Impact factor: 4.030
Authors: Hans G Cruz; Tatiana Ivanova; Marie-Louise Lunn; Markus Stoffel; Paul A Slesinger; Christian Lüscher Journal: Nat Neurosci Date: 2004-01-25 Impact factor: 24.884