γ-Hydroxybutyrate (GHB) is used therapeutically and recreationally. The mechanism by
which GHB produces its therapeutic and recreational effects is not entirely clear, although GABAB receptors appear to play an important role. This role could be complex, because there are indications that different GABAB receptor mechanisms mediate the effects of GHB and the prototypical GABAB receptor agonist baclofen. To further explore possible differences in underlying GABAB receptor mechanisms, the present study examined the effects of GHB and baclofen on operant responding, and their antagonism by the GABAB receptor antagonist 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 GBL, and the GABAB receptor agonists baclofen and 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 that to antagonize baclofen and SKF97541
(i.e., 4.5 [4.4-4.7]. This finding is further evidence that the GABAB receptor mechanisms mediating
the effects of GHB and prototypical GABAB 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.