Cataleptic effects of γ-hydroxybutyrate (GHB), its precursor γ-butyrolactone (GBL), and GABAB receptor agonists in mice: differential antagonism by the GABAB receptor antagonist CGP35348

Abstract

The finding that CGP35348 was about threefold less potent to antagonize GHB and GBL than baclofen and SKF97541 is further evidence that the mechanisms mediating the effects of GHB and GABA(B) agonists are not identical. Differential involvement of GABA(B) receptor subtypes, or differential interactions with GABA(B) receptors, may possibly explain why GHB is effective for treating narcolepsy and is abused whereas baclofen is not.

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

“…The latter finding is consistent with evidence that PCP and GHB enhance each other's discriminative stimulus effects, but PCP and baclofen do not (Koek et al 2007a). Taken together, these findings are further evidence that the GABA B receptor mechanisms mediating the effects of GHB and baclofen are not identical (e.g., Koek et al 2007b), and suggest that these GABA B receptor mechanisms are differentially modulated by glutamatergic systems.…”

“…The GABA B receptor antagonist CGP35348 antagonizes the discriminative stimulus effects of GHB and baclofen, consistent with the involvement of GABA B receptors, but is less potent to antagonize these effects of GHB than those of baclofen Carter et al 2006). Recently, we reported that CGP35348 was also less potent to antagonize the cataleptic effects of GHB and its precursor GBL than those of the GABA B receptor agonists baclofen and SKF97541 (Koek et al 2007b). Together, these findings suggest a possible role for different GABA B receptor subtypes or different interactions with the same GABA B receptor in the behavioral effects of GHB and baclofen.…”

“…in Swiss-Webster mice (Itzhak and Ali 2002), and 320 mg/kg GHB i.p. in C57BL/6J mice (Carter et al 2005;Koek et al 2007b), the same strain as used in the present study. The lowest dose of GHB and baclofen that produced near-maximal catalepsy in the cumulative dosing procedure used here (i.e., 320 and 10 mg/kg i.p., respectively) was the same as in the single dosing procedure used previously (Carter et al 2005;Koek et al 2007b), suggesting that, under the conditions of these experiments, the potency of GHB and baclofen to produce catalepsy in C57BL/6J mice is not markedly affected by the use of single or cumulative dosing.…”

“…in C57BL/6J mice (Carter et al 2005;Koek et al 2007b), the same strain as used in the present study. The lowest dose of GHB and baclofen that produced near-maximal catalepsy in the cumulative dosing procedure used here (i.e., 320 and 10 mg/kg i.p., respectively) was the same as in the single dosing procedure used previously (Carter et al 2005;Koek et al 2007b), suggesting that, under the conditions of these experiments, the potency of GHB and baclofen to produce catalepsy in C57BL/6J mice is not markedly affected by the use of single or cumulative dosing. The observation that GHB, which has agonist activity at GABA B receptors (Lingenhoehl et al 1999), has cataleptic effects in common with a wellcharacterized GABA B receptor agonist and the finding that these effects can be blocked by the GABA B receptor antagonist CGP35348 (e.g., Koek et al 2007b) are further evidence that GABA B receptors are involved in GHB-induced catalepsy.…”

“…As described elsewhere (Carter et al 2005;Koek et al 2007b), catalepsy was examined using a horizontal cylindrical metal bar (diameter, 1 cm) supported 4 cm above the floor by two 8×8-cm square pieces of Plexiglas (Instrumentation Services, University of Texas Health Science Center). Mice were tested for catalepsy by placing their forepaws on the bar while the hind paws remain on the floor and then recording the time that both forepaws remained on the bar up to a maximum of 30 s. Each animal received an i.p.…”