Sigma receptors are saturable, high affinity binding sites for several important classes of psychotropic drugs, including typical antipsychotic, antidepressant, anticonvulsant, and psychotomimetic compounds. They are likely to contribute to the beneficial and/or side-effect profile of these compounds. Sigma sites are present not only in the central nervous system but also occur in several peripheral tissues, and are expressed in high density in a number of tumor cell lines. They may thus play an important role in cell function. Previous studies had shown that sigma receptor ligands induce morphological changes and ultimately, cell death. Studies were aimed at determining the subtype of sigma receptor mediating these effects and the mode of cell death (ie. whether by necrosis or apoptosis). The sigma subtype mediating both of these cellular effects was determined to be sigma-2, since subtype selective sigma-2 ligands (CB-64D and ibogaine) and subtype non-selective ligands (such as reduced haloperidol) induced morphological changes and cell death, whereas sigma-1 selective ligands (e.g. (+)-pentazocine) were without effect. The mode of cell death was investigated using human SK-N-SH neuroblastoma cells and rat cerebellar granule cells. Apoptotic cell death was indicated by three independent methods: 1) TUNEL, 2) Annexin-V staining, and 3) Hoechst nuclear staining. Annexin-V binding, which measures inversion of phosphatidyl serine as an early event during apoptosis, showed staining first over cell processes and subsequently over cell bodies. Studies are currently underway to determine the intracellular signals involved, with particular emphasis on the role of intracellular calcium release and caspases. The ability of sigma receptors to induce apoptotic cell death suggest a role in the regulation of cell proliferation.