INDUCTION OF C-FOS GENE-EXPRESSION BY THE SELECTIVE SIGMA-RECEPTOR LIGAND EMD-57445 IN RAT-BRAIN

Based on animal studies it has been reasoned that ligands to sigma bin ding sites might be effective in the treatment of schizophrenic disord ers and may also be used to investigate this largely elusive disorder on a molecular level. Expression patterns of c-fos in rat brain were s tudied following treatment with single doses of the sigma ligand EMD 5 7445 (0.3, 1, 3, 30 mg/kg s.c.). Specific c-fos gene expression was de tected at all concentrations tested in various cortical areas. The sig nals observed were dose-dependent with the highest intensities in the piriform cortex. Strong signals were also detected in hippocampal area s CA 1,2,3 and the gyrus dentatus, as well as in the medial habenula n uclei. In the caudate putamen, nucleus accumbens and lateral septal nu cleus signals were detectable after administration of doses greater th an or equal to 1 mg/kg. Furthermore, c-fos hybridization was visible i n the amygdala,in the mammillary bodies, the islands of Calleja and in the olfactory tubercle. In the hypothalamus, c-fos expression was see n in the median eminence area after 30 mg/kg EMD 57445. No hybridizati on signals were obtained in brainstem or cerebellum. Since c-fos expre ssion induced by EMD 57445 resembled the pattern obtained with atypica l neuroleptics and studies on animal behavior point to antipsychotic a ctivity, it is concluded that the drug might be suitable in the treatm ent of schizophrenia.