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

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.

Fig. 1

Cataleptic effects of cumulative doses of GHB and the GABA_B receptor agonist baclofen after administration of saline or different doses of the NMDA antagonists ketamine, phencyclidine (PCP), or dizocilpine (MK-801) in C57BL/6J mice (n=8–13 per dose, all injections i.p.). a Effects of the NMDA antagonists before the administration of GHB. b and c Effects of the NMDA antagonists on the dose–response curves of GHB and baclofen, respectively. d Effects of the NMDA antagonists on the area under the dose–response curves of GHB (filled symbols) and baclofen (open circles) shown in b and c, respectively. Symbols represent mean ± SEM; if not shown, SEM values are contained by the symbol. Asterisks P<0.05 (Dunnett’s test vs control)

Fig. 2

Relation between the potencies of the NMDA antagonists ketamine, phencyclidine (PCP), and dizocilpine (MK-801) to enhance GHB-induced catalepsy in mice and their potencies to a antagonize NMDA-induced convulsions in mice (Koek and Colpaert 1990), b inhibit in vivo labeling of the NMDA receptor-associated ion channel with the phencyclidine derivative [³H]TCP in mouse brain, which correlates strongly (r=0.93) with in vitro [³H]TCP binding in rat brain (Maurice and Vignon 1990), c inhibit [³H]dopamine uptake into rat striatal synaptosomes (Johnson and Snell 1985; Snell et al. 1988), and d inhibit [³H]MPP⁺ uptake by rat organic cation transporter 1 (OCT1) in transfected HEK293 cells (Amphoux et al. 2006). MSD minimum significant dose, r Pearson’s correlation coefficient