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)

γ-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 γ-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 pA₂ value of CGP35348 to antagonize GHB and GBL [i.e., 3.9 (3.7- 4.2)] that was different (P = 0.0011) from the pA₂ 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.