BMY-14802 antagonizes harmaline- and D-serine-induced increases in mouse cerebellar cyclic GMP: neurochemical evidence for a sigma receptor-mediated functional modulation of responses mediated by the N-methyl-D-aspartate receptor complex in vivo.
BMY-14802 [alpha-(4-flurophenyl)-4-(5-fluoro-pyramidinyl)-1-piperazine butanol], a potent sigma 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 sigma ligand modulation of a response mediated through the N-methyl-D-aspartate receptor complex.
Rao
T S
TS
CNS Diseases Research, G. D. Searle & Co., St. Louis, Missouri 63198.
Cler
J A
JA
Emmett
M R
MR
Mick
S
S
Iyengar
S
S
Wood
P L
PL
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006246:Harmaline / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism*; D012694:Serine / Q000494:pharmacology*
D000470:Alkaloids; D011743:Pyrimidines; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; C050408:alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol; D012694:Serine; D006246:Harmaline; D006152:Cyclic GMP