Fibroblast growth factor-2 (FGF-2) is a member of a large family of trophic factors whose expression is regulated under several conditions in different areas of the brain. The goal of our experiments was to determine whether the administration of 4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-[4-(1,2,4-triazol-1-il)butyl] pyridine citrate (E-5842), a sigma-1 receptor ligand and putative atypical antipsychotic, could regulate the expression of FGF-2. After chronic treatment with E-5842 (21 days, and the animals killed 24 h after the last administration), an up-regulation was observed of the expression of FGF-2 mRNA in the prefrontal cortex and the striatum, and a down-regulation of the expression of FGF-2 mRNA in the hypothalamus of the rat brain. Acute treatment with E-5842 (one single administration and animals killed 6 h later) up-regulated FGF-2 expression in the prefrontal cortex, the striatum, the hypothalamus and the hippocampus in a dose-dependent manner. The acute up-regulation was transient and disappeared 24 h after E-5842 administration. The induction of FGF-2 in the striatum after repeated administration has been described for clozapine, but our data concerning regulation in the prefrontal cortex suggest that this effect is unique to E-5852 among other antipsychotics. Given the neuroprotective activity of FGF-2, the data presented here might be relevant to the deficit in cognition and other symptoms that appear in schizophrenia.