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

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Abstract
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‐methyld‐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 α‐aminoadipate were also shown to be efficient in inhibiting the binding, whereas quisqualate, d,l‐2‐amino‐4‐phosphonobutyrate, kainate, l‐glutamate diethylester, and α‐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. These data suggest the occurrence of functional receptor‐receptor interregulations at the postsynaptic level between dopaminergic and NMDA receptors in complement with the interactions occurring at the presynaptic level between glutamatergic and dopaminergic nerve terminals.

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