Comparative effects of dopamine D(1) and D(2) receptor antagonists on nerve growth factor protein induction.

We previously reported that following acute administration of haloperidol or (-)-sulpiride, both dopamine D(2)-receptor antagonists, to mice induced nerve growth factor (NGF) gene expression, mediated by the interaction of c-fos with the AP-1 binding site present in the first intron on the NGF gene. In contrast, the D(1)-receptor antagonist R-(-)-8-chloro-2,3,4, 5-tetrahydro-3,1-methyl-5-phenyl-11-3-benzyoepine-7-ol (SCH23390) did not induce NGF mRNA expression. We report here immunohistochemical and Western blot analyses showing that following injection of these drugs for 14 consecutive days, the amount of NGF protein increased gradually and was induced significantly in the hippocampus, piriform cortex, amygdala, dorsal striatum, and nucleus accumbens neurons. NGF enhances the release of acetylcholine from these regions. Cholinergic innervation in the striatum and nucleus accumbens neurons is believed to be related to late-onset extrapyramidal symptoms, while in the hippocampus and piriform cortex it is involved in enhancing cognition. Thus, our data suggest that haloperidol- and (-)-sulpiride-induced NGF expression may be associated with both beneficial and adverse effects.