Glutamatergic regulation of haloperidol-induced c-fos expression in the rat striatum and nucleus accumbens.

Acute administration of haloperidol induces the expression of the immediate-early gene c-fos in the striatum and nucleus accumbens via dopamine D(2) receptor antagonism. Dopaminergic transmission in the striatum and nucleus accumbens is modulated by glutamate via N-methyl-D-aspartate (NMDA) receptors. Indeed, haloperidol-induced c-fos expression is dependent on NMDA receptor activation in the dorsolateral part of the striatum. However, the role that NMDA receptors play in haloperidol-induced c-fos expression in other functionally distinct areas of the striatum and nucleus accumbens has not yet been established. Therefore, in the present study the entire rostrocaudal extent of the rat striatum and nucleus accumbens was examined to determine the role that NMDA receptors play in haloperidol-induced c-fos expression. Pretreatment with MK-801, a non-competitive antagonist of NMDA receptors, significantly reduced the number of neurons showing c-fos immunoreactivity in the rostral aspect of the dorsolateral striatum and the entire rostrocaudal extent of the ventrolateral striatum following an acute injection of haloperidol. However, the same treatment did not modify the pattern of haloperidol-mediated c-fos expression in the medial or central parts of the striatum. Similarly, MK-801 pretreatment significantly suppressed the number of neurons expressing c-fos immunoreactivity following haloperidol injection in the entire rostrocaudal extent of the shell region of nucleus accumbens, but not in the core region. The results indicate that haloperidol-induced c-fos expression is dependent on NMDA receptors only in the rostral aspect of the dorsolateral striatum and the rostrocaudal extent of the ventrolateral striatum, the areas involved in motor function. The differential role that NMDA receptors play in modulating haloperidol-mediated dopamine D(2) receptor antagonism between motor and associative areas of the striatum may contribute to the development of extrapyramidal symptoms following chronic haloperidol treatment. Furthermore, the attenuation of the haloperidol-induced c-fos expression by MK-801 was restricted to the nucleus accumbens shell, an area often implicated in the therapeutic effect of haloperidol. Therefore, the NMDA-dopamine D(2) receptor interaction may also play a role in mediating the therapeutic effects of haloperidol.