Enhancement of N-methyl-D-aspartate (NMDA) immunoreactivity in residual dendritic spines in the caudate-putamen nucleus after chronic haloperidol administration

Glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype in the caudate-putamen nucleus (CPN) have been implicated in the adverse motor effects produced by chronic administration of the typical antipsychotic drug haloperidol. To determine the functionally relevant sites, we examined the electron microscopic immunocytochemical localization of the R1 receptor subunit (NMDAR1) in the dorsolateral CPN of rats receiving 4 months of biweekly depot intramuscular injections of either haloperidol or vehicle. In all animals, NMDAR1 immunoreactivity was seen mainly in dendritic spines, but was also present in a few somata and dendrites of spiny neurons, axon terminals, and glia. In comparison with controls, the disector stereological analysis showed a significant reduction in the numerical density of total NMDAR1-labeled and unlabeled dendritic spines in the dorsolateral CPN after haloperidol administration. When labeled spines were identified separately based exclusively on the presence of immunoreactivity within a single plane of section, there was, however, a significant increase in the numerical density of NMDAR1-containing spines in haloperidol vs control animals. This increase was not seen using a classic disector, suggesting that the enhancement was mainly attributed to more frequent detection of spines having higher levels of NMDA immunoreactivity. Our results are the first to identify dendritic spines in the dorsolateral CPN as preferential sites for the regulated expression of NMDA receptors following chronic administration of haloperidol.