Cataleptic effects of γ-hydroxybutyrate (GHB) and baclofen in mice: mediation by GABAB 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-asparate (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.

Effects of the GABAB Receptor-Positive Modulators CGP7930 and rac-BHFF in Baclofen- and γ-Hydroxybutyrate-Discriminating Pigeons

“…However, there is growing evidence that the GABA B receptor mechanisms underlying the effects of baclofen and GHB are not identical. First, differential enhancement of behavioral effects (discriminative stimulus effects, catalepsy) of baclofen and GHB by N-methyl-D-aspartate antagonists suggests that the GABA B receptors involved in these effects of baclofen and GHB are not identical (Koek et al, 2007a;Koek and France, 2008). Second, differential antagonism of behavioral effects of baclofen and GHB by CGP35348, reported previously (Koek et al, , 2007bCarter et al, 2006) and also observed in the present study, is further evidence that different GABA B receptor populations mediate these effects of baclofen and GHB.…”

“…First, the GABA B receptor antagonist 3-aminopropyl(diethoxymethyl) phosphinic acid (CGP35348) antagonizes the behavioral effects of GHB (discriminative stimulus effects, suppression of operant responding, catalepsy) less potently than those of baclofen (Koek et al, , 2007bCarter et al, 2006). Second, N-methyl-D-aspartate antagonists enhance the behavioral effects of GHB (discriminative stimulus effects, catalepsy), but not those of baclofen (Koek et al, 2007a;Koek and France, 2008). Preferential activity of GHB at GABA B heteroreceptors on glutamatergic neurons and baclofen at GABA B autoreceptors on GABAergic neurons could conceivably account for some of these differences (Carter et al, 2009).…”

Behavioral Effects of γ-Hydroxybutyrate, Its Precursor γ-Butyrolactone, and GABAB Receptor Agonists: Time Course and Differential Antagonism by the GABAB Receptor Antagonist 3-Aminopropyl(diethoxymethyl)phosphinic Acid (CGP35348)

“…The cataleptic effects of GHB are enhanced not only by MK-801 but also by other drugs with NMDA antagonist activity, such as phencyclidine (PCP) and ketamine. However, these NMDA antagonists do not affect the cataleptic effects of baclofen (Koek and France, 2008). Similar interactions have been observed in drug discrimination studies; PCP enhances the discriminative stimulus effects of GHB but not of baclofen (Koek et al, 2007a).…”

“…The NMDA antagonist PCP and GHB enhance each other's discriminative stimulus effects, but PCP and baclofen do not, suggesting that the mechanisms underlying these effects of GHB and baclofen are differentially modulated by the glutamatergic system with which PCP interacts (Koek et al, 2007a). The recent finding that PCP and other antagonists at the NMDA subtype of glutamate receptors enhance the cataleptic effects of GHB but not those of baclofen (Koek and France, 2008) provides further evidence that the GABA B receptor systems mediating the effects of GHB and baclofen are differentially modulated by glutamate.…”

“…One line of evidence is from studies that examined the interactions of GHB and baclofen with antagonists at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. The NMDA antagonist dizocilpine (MK-801) enhances GHB-induced catalepsy in rodents (Sevak et al, 2004(Sevak et al, , 2005Koek and France, 2008). The cataleptic effects of GHB are enhanced not only by MK-801 but also by other drugs with NMDA antagonist activity, such as phencyclidine (PCP) and ketamine.…”