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

Abstract

␥-Hydroxybutyrate (GHB) is used therapeutically and recreationally. The mechanism by which GHB produces its therapeutic and recreational effects is not entirely clear, although GABA B receptors seem to play an important role. This role could be complex, because there are indications that different GABA B receptor mechanisms mediate the effects of GHB and the prototypical GABA B receptor agonist baclofen. To further explore possible differences in underlying GABA B receptor mechanisms, the present study examined the effects of GHB and baclofen on operant responding and their antagonism by the GABA B receptor antagonist 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP35348). Pigeons were trained to peck a key for access to food during response periods that started at different times after the beginning of the session. In these pigeons, GHB, its precursor ␥-butyrolactone (GBL), and the GABA B receptor agonists baclofen and 3-aminopropyl(methyl)phosphinic acid hydrochloride (SKF97541) decreased the rate of responding in a dose-and time-dependent manner. CGP35348 shifted the dose-response curve of each agonist to the right, but the magnitude of the shift differed among the agonists. Schild analysis yielded a pA 2 value of CGP35348 to antagonize GHB and GBL [i.e., 3.9 (3.7-4.2)] that was different (P ϭ 0.0011) from the pA 2 value to antagonize baclofen and SKF97541 [i.e., 4.5 (4.4 -4.7)]. This finding is further evidence that the GABA B receptor mechanisms mediating the effects of GHB and prototypical GABA B receptor agonists are not identical. A better understanding of the similarities and differences between these mechanisms, and their involvement in the therapeutic effects of GHB and baclofen, could lead to more effective medications with fewer adverse effects.

Physical dependence on gamma-hydroxybutrate (GHB) prodrug 1,4-butanediol (1,4-BD): Time course and severity of withdrawal in baboons

“…Similar findings have been reported in other laboratories for the discriminative stimulus effects and cataleptic effects of GBL (Carai et al, 2008; Koek et al, 2007, 2009; Towiwat et al, 2013). One study, however, reported that a GABA-B antagonist failed to block the discriminative stimulus effects of GBL in rats (Baker et al, 2005).…”

Discriminative Stimulus Effects of the GABAB Receptor-Positive Modulator rac-BHFF: Comparison with GABAB Receptor Agonists and Drugs of Abuse

“…However, there is accumulating evidence that the GABA B receptor mechanisms underlying the effects of baclofen and GHB are not identical. Behavioral effects of baclofen and GHB are differentially enhanced by N-methyl-D-aspartate antagonists (Koek et al, 2007a;Koek and France, 2008) and differentially antagonized by CGP35348 (Koek et al, 2004(Koek et al, , 2007b(Koek et al, , 2009Carter et al, 2006). In these studies, CGP35348 completely antagonized baclofen and GHB, but antagonized baclofen more potently than GHB.…”

Anti-hyperalgesic effects of imidazoline I2 receptor ligands in a rat model of inflammatory pain: interactions with oxycodone

“…The slopes and the differences of the experimentally determined composite additive curves and the predicted composite additive curves were compared using the F-test. A non-significant F ratio for slopes and a significant F ratio for intercept show that dose–effect curves are parallel but occupy different positions on the dose axis (Koek et al, 2009). A significant leftward shift of the experimentally determined composite additive curve indicates that the drug combination produces the effect in a manner that is greater than additivity (supra-additivity) (i.e.…”