Localization of N-methyl-D-aspartate receptors in the rat striatum: effects of specific lesions on the [3H]3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid binding.

The binding of [3H]3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid ([3H]CPP), a rigid analogue of 2-amino-7-phosphonoheptanoic acid (AP7) and reported to be a selective N-methyl-D-aspartate (NMDA) antagonist, was studied in rat striatal membranes using a centrifugation procedure to separate bound and free radioligand. [3H]CPP bound with high affinity (KD = 272 nM) in a saturable, reversible, and protein concentration-dependent manner. Specific binding was suggested to involve a single class of noninteracting binding sites. The most potent [3H]CPP binding inhibitors tested were CPP, L-glutamate, 2-amino-5-phosphonovalerate, and AP7. NMDA, L-aspartate, and alpha-aminoadipate were also shown to be efficient in inhibiting the binding, whereas quisqualate, D,L-2-amino-4-phosphonobutyrate, kainate, L-glutamate diethylester, and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid were found to be essentially inactive. These data are therefore consistent with the view that [3H]CPP selectively binds to NMDA receptors in the rat striatum. Lesions of intrastriatal neurons using local injections of kainic acid revealed a marked decrease in [3H]CPP binding, suggesting an almost exclusively postsynaptic location of binding sites in the striatum. Conversely, bilateral lesion of corticostriatal glutamatergic fibers resulted in an increased number of [3H]CPP striatal binding sites, providing evidence for a putative supersensitivity response to this striatal deafferentation. Interestingly, lesion of the nigrostriatal dopaminergic neurons using intranigral 6-hydroxydopamine injections resulted, 2-3 weeks later, in a similar increase in the number of [3H]CPP striatal binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)