The dopamine D4 receptor is widely distributed in the CNS, particularly in limbic structures such as the prefrontal cortex and hippocampus. As a D2-like dopamine receptor, the D4 subtype is classified a Gi/Go protein coupled receptor and therefore considered as an inhibitor of neuronal firing. We previously reported that the selective D4 agonist PD168077 induces expression of the immediate early gene (IEG) c-Fos and phosphorylation of MAP kinase ERK1/2 in the hypothalamic paraventricular nucleus (PVN) (Otte et al., 2003, SFN Abstracts), a region associated with sexual behavior mediated by D4 receptor transmission. In the present studies, we immunohistochemically examined the ability of a novel, selective D4 antagonist A-381393 (presented at this meeting) to block c-Fos induction and ERK1/2 phosphorylation produced by the D4 agonist PD168077 in the rat PVN. Pretreatment with A-381393 (10 ìmol/kg s.c.) prevented the induction of c-Fos seen with PD168077 (1ìmol/kg s.c.) treatment alone and significantly reduc...