BMY-14802 antagonizes harmaline- and D-serine-induced increases in mouse cerebellar cyclic GMP: Neurochemical evidence for a σ receptor-mediated functional modulation of responses mediated by the N-methyl-D-aspartate receptor complex in vivo

BMY-14802 [α-(4-fluorophenyl)-4-(5-fluoro-pyramidinyl)-1-piperazine butanol], a potent σ ligand with poor affinity for dopamine and phencyclidine receptors in vitro, attenuated parenteral harmaline- and direct intracerebellar D-serine-induced increases in mouse cerebellar cGMP. Intracerebroventricularly injected BMY-14802 also antagonized the effects of intracerebellar D-serine, indicating a central mechanism. However, direct co-injection of BMY-14802 into the cerebellum failed to antagonize the D-serine-induced increases in cGMP, indicating a locus of action outside the cerebellum. In contrast, quisqualate-induced cGMP increases were not attenuated by BMY-14802. These results indicate a functional modulation of the N-methyl-D-aspartate/glycine/phencyclidine/ion channel complex-mediated events by BMY-14802, possibly through a transsynaptic mechanism, thus representing the first in vivo demonstration of a σ ligand modulation of a response mediated through the N-methyl-D-aspartate receptor complex.