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

Abstract

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 dissector 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 dissector, 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.

?-opioid and NMDA-type glutamate receptors are often colocalized in spiny neurons within patches of the caudate-putamen nucleus

“…The number of labeled profiles per unit area (area density) in the present study reflects the content of immunoreactivity and the size and prevalence of similar unlabeled structures within the neuropil, as has been shown for NR1 in the dorsolateral CPN (Rodríguez and Pickel, 1999). Thus, the area density is useful mainly for comparative purpose with respect to MOR and NR1 within the same sections.…”

Striatal plasticity and medium spiny neuron dendritic remodeling in parkinsonism

“…First, it is clear that dopamine depletion is the initiating event: MSN spine loss is seen in postmortem studies of PD, and in animals treated with 6-hydroxydopamine or reserpine to deplete striatal dopamine stores, as well as in animals in which dopamine signaling has been disrupted by chronic treatment with the D 2 receptor antagonist haloperidol [3,[6][7][8]10]. The latter finding, and the observation that MSNs of mice genetically lacking the D 2 dopamine receptor suffer from a loss of dendritic spines (unpublished observation), suggests that spine loss might be confined to MSNs that normally express the D 2 receptor.…”

N-Methyl-d-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives

“…Interesting differences have emerged between clozapine and haloperidol. These agents preferentially enhance glutamate levels and activity at NMDA receptors in cortex vs striatum, respectively (Yamamoto et al 1994;Arvanov et al 1997;Hayashi et al 1999;Rodriguez and Pickel 1999).…”