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Cataleptic effects of gamma-hydroxybutyrate (GHB) and baclofen in mice: mediation by GABA(B) receptors, but differential enhancement by N-methyl-d-aspartate (NMDA) receptor antagonists.

AbstractRATIONALE:
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.
AuthorsWouter Koek, Charles P France
JournalPsychopharmacology (Psychopharmacology (Berl)) Vol. 199 Issue 2 Pg. 191-8 (Aug 2008) ISSN: 0033-3158 [Print] Germany
PMID18446324 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Anesthetics, Intravenous
  • Excitatory Amino Acid Antagonists
  • Muscle Relaxants, Central
  • Receptors, GABA-B
  • Receptors, N-Methyl-D-Aspartate
  • Ketamine
  • Dizocilpine Maleate
  • Sodium Oxybate
  • Baclofen
  • Phencyclidine
Topics
  • Anesthetics, Intravenous (pharmacology)
  • Animals
  • Area Under Curve
  • Ataxia (chemically induced, psychology)
  • Baclofen (pharmacology)
  • Catalepsy (chemically induced)
  • Data Interpretation, Statistical
  • Dizocilpine Maleate (pharmacology)
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Antagonists (pharmacology)
  • Ketamine (pharmacology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle Relaxants, Central (pharmacology)
  • Phencyclidine (pharmacology)
  • Receptors, GABA-B (drug effects)
  • Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors)
  • Sodium Oxybate (pharmacology)

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