Characterization of 'non-N-methyl-D-Aspartate' binding sites for gacyclidine enantiomers in the rat cerebellar and telencephalic structures.
Gacyclidine is a non-competitive NMDA receptor antagonist with potent neuroprotective properties. However, we have previously demonstrated that gacyclidine enantiomers [(-) and (+)GK11] interact with other ('non-NMDA') binding sites which may play a role in the lower self-neurotoxicity of this compound relative to the other NMDA receptor antagonists. Evidence for these binding sites has been obtained from autoradiographic and membrane binding experiments. They were found to be expressed at high levels in the molecular layer of the cerebellum, although they can also been seen in the granular layer and in telencephalic regions. The present study was designed to further characterize these gacyclidine 'non-NMDA' binding sites. The pharmacological profiles obtained on cerebellar and telencephalic membrane homogenates showed that they could not be linked directly to the main receptors or uptake complexes of the central nervous system (CNS). However, the comparison of (-) and (+)[(3)H]GK11 binding distribution in different mutant animals bearing specific cellular deficits in the cerebellum has demonstrated that the gacyclidine 'non-NMDA' binding sites are associated with the dendritic trees of Purkinje cells. Interestingly, our study also shows that the radioligand binding to both cerebellar and telencephalic structures could be modulated by endogenous factors which can be removed by a stringent prewashing procedure.
INSERM U336 DPVSN, Institut de biologie, Montpellier, France.
H
H
Hirbec
J M
JM
Kamenka
A
A
Privat
J
J
Vignon
D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002531:Cerebellum / Q000737:chemistry / Q000166:cytology / Q000378:metabolism* / Q000528:radiation effects; D003510:Cyclohexanes / Q000737:chemistry / Q000378:metabolism*; D053138:Cyclohexenes; D003712:Dendrites / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D018377:Neurotransmitter Agents / Q000494:pharmacology; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism*; D011689:Purkinje Cells / Q000166:cytology / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013687:Telencephalon / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*
D003510:Cyclohexanes; D053138:Cyclohexenes; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018377:Neurotransmitter Agents; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C070707:gacyclidine