Role of NR2B-containing N-methyl- d-aspartate receptors in haloperidol-induced c-Fos expression in the striatum and nucleus accumbens

Abstract

Administration of haloperidol in rats leads to a robust induction of immediate-early genes including c-Fos throughout the striatum, which is significantly attenuated by pretreatment with the non-competitive N-methyl- d-aspartate (NMDA) receptor antagonist, MK-801. The striatum expresses mainly NR1/NR2A and NR1/NR2B subtypes of NMDA receptors, each having different functional and pharmacological properties. In this study, rats were pretreated with Ro 25-6981, a selective antagonist for NR2B-containing NMDA receptors, in order to determine the relative contribution of this NMDA receptor subtype in NMDA-dependent haloperidol-induced c-Fos expression. Furthermore, to determine whether NMDA receptor subtype dependence of haloperidol-induced c-Fos expression is unique to the binding profile of haloperidol or whether it is a property of D2 receptor antagonism, the selective D2/D3 dopamine receptor antagonist, raclopride, was also used. Pretreatment with Ro 25-6981 led to a significant reduction in the number of nuclei showing c-Fos immunoreactivity in both the medial and lateral parts of the striatum. In the medial part of the striatum, this attenuation was almost as marked as that seen following pretreatment with MK-801; however, in the lateral part MK-801 pretreatment led to a significantly greater reduction in the number of c-Fos positive nuclei than did Ro 25-6981 pretreatment. This suggests that NR2B-containing NMDA receptors are involved in mediating most of the NMDA-dependent c-Fos expression in the medial striatum, but only responsible for mediating part of this induction in the lateral striatum. Furthermore, the pattern of attenuation of raclopride-induced c-Fos expression following Ro 25-6981 pretreatment was similar to that of haloperidol-induced c-Fos expression, indicating that the NMDA receptor subtype dependence of haloperidol-induced c-Fos expression is a property of D2 antagonism. The results indicate that NR2B-containing NMDA receptors are mainly involved in mediating haloperidol-induced c-Fos expression in the medial or “limbic” striatum, and suggest that NR2A-containing NMDA receptors may preferentially mediate haloperidol induced c-Fos expression in the lateral or “motor” striatum. This may have implications in the treatment of schizophrenia because co-administration of a selective blocker of NR2A-containing NMDA receptors may be able to reduce the severity of extrapyramidal motor symptoms caused by haloperidol treatment without interfering with its therapeutic effect that is presumably mediated via the medial part of the striatum.