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 neuro protective properties. However, we have previously demonstrated that gacycl idine enantiomers [(-) and (+)GK11] interact with other ('non-NMDA') bindin g sites which may play a role in the lower self-neurotoxicity of this compo und relative to the other NMDA receptor antagonists. Evidence for these bin ding sites has been obtained from autoradiographic and membrane binding exp eriments. They were found to be expressed at high levels in the molecular l ayer of the cerebellum, although they can also been seen in the granular la yer and in telencephalic regions. The present study was designed to further characterize these gacyclidine 'non-NMDA' binding sites. The pharmacologic al profiles obtained on cerebellar and telencephalic membrane homogenates s howed that they could not be linked directly to the main receptors or uptak e complexes of the central nervous system (CNS), However, the comparison of (-) and (+)[H-3]GK11 binding distribution in different mutant animals bear ing specific cellular deficits in the cerebellum has demonstrated that the gacyclidine 'non-NMDA' binding sites are associated with the dendritic tree s of Purkinje cells. Interestingly, our study also shows that the radioliga nd binding to both cerebellar and telencephalic structures could be modulat ed by endogeneous factors which can be removed by a stringent prewashing pr ocedure.