The GABA B receptor antagonists CGP35348 and CGP52432 inhibit glycine exocytosis: study with GABA B1- and GABA B2-deficient mice.

GABA(B) receptors mediate inhibition of neurotransmitter exocytosis from nerve endings. Unexpectedly, the well known GABA(B) receptor antagonist CGP35348 and, in part, the compound CGP52432, are now found to inhibit on their own the K(+)-evoked exocytosis of glycine when added at low micromolar concentrations to superfused mouse glycinergic nerve endings prelabelled with [(3)H]glycine through GLYT2 transporters. CGP35348 inhibited [(3)H]glycine release both in spinal cord and in hippocampus, but was also able to prevent the inhibitory effect of (-)-baclofen; CGP52432 exhibited intrinsic activity only in the hippocampus; in spinal cord, it behaved exclusively as a silent orthosteric antagonist by blocking the release inhibition brought about by (-)-baclofen. The intrinsic activity of CGP35348 in spinal cord was not prevented by CGP52432, indicating that CGP35348 is not a partial GABA(B) agonist in this experimental system. CGP54626, an extremely potent antagonist, exhibited only a minimal intrinsic activity. SCH50911, a GABA(B) antagonist belonging to a different chemical class, was devoid of significant activity, while phaclofen was effective only at 100-300 microM. In synaptosomes purified from the spinal cord or the hippocampus of mice lacking either the GABA(B1) (GABA(B1-/-) mice) or the GABA(B2) (GABA(B2-/-) mice) subunit, the evoked exocytosis of [(3)H]glycine was no longer inhibited by (-)-baclofen, whereas the intrinsic activity of CGP35348 and CGP52432 was not decreased. Activation of unknown sites on glycinergic terminals is likely to be involved. These unexpected effects should not be ignored when interpreting results obtained with the above GABA(B) receptor antagonists.