Haloperidol is an antipsychotic agent that primarily acts as an antagonist of D2 dopamine receptors. Besides other receptor systems, it targets sigma 1 receptors (sigma 1Rs) and inositol 1,4,5-trisphosphate receptors (IP(3)Rs). Aim of this work was to investigate possible changes in IP(3)Rs and sigma 1Rs resulting from haloperidol treatment and to propose physiological consequences in differentiated NG-108 cells, i.e., effect on cellular plasticity. Haloperidol treatment resulted in up-regulation of both type 1 IP(3)Rs (IP(3)R1s) and sigma 1Rs at mRNA and protein levels. Haloperidol treatment did not alter expression of other types of IP(3)Rs. Calcium release from endoplasmic reticulum (ER) mediated by increased amount of IP(3)R1s elevated cytosolic calcium and generated ER stress. IP(3)R1s were bound to sigma 1Rs, and translocation of this complex from ER to nucleus occurred in the group of cells treated with haloperidol, which was followed by increased nuclear calcium levels. Haloperidol-induced changes in cytosolic, reticular, and nuclear calcium levels were similar when specific sigma 1 blocker -BD 1047- was used. Changes in calcium levels in nucleus, ER, and cytoplasm might be responsible for alterations in cellular plasticity, because length of neurites increased and number of neurites decreased in haloperidol-treated differentiated NG-108 cells.