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

Rationale: Gamma-hydroxybutyrate (GHB) is used to treat narcolepsy but is also abused. GHB has many actions in common with the GABA_B receptor agonist baclofen. Objective: To further study the role of GABA_B receptors in the effects of GHB. Materials and methods: The experiments examined the ability of the GABA_B receptor antagonist CGP35348 to attenuate GHB-induced catalepsy in comparison with its ability to attenuate the cataleptic effects of GABA_B receptor agonists. Results: In C57BL/6J mice, GHB, the GHB precursor gamma-butyrolactone (GBL), and the GABA_B receptor agonists baclofen and SKF97541 all produced catalepsy but differed in potency (i.e., SKF97541>baclofen>GBL>GHB) and in onset of action. The cataleptic effects of drug combinations were assessed at the time of peak effect of each compound, i.e., 60 min after CGP35348 and 60, 30, 30, and 15 min after baclofen, SKF97541, GHB, and GBL, respectively. At 100 mg/kg, CGP35348 shifted the dose-response curves of baclofen and SKF97541 to the right but not those of GHB and GBL; at 320 mg/kg, CGP35348 shifted the curves of all four compounds to the right. Conclusions: 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.