Abstract
Haloperidol is an antipsychotic agent that primarily acts as an antagonist of D2 dopamine receptors. Besides other receptor systems, it targets sigma 1 receptors (σ1Rs) and inositol 1,4,5-trisphosphate receptors (IP3Rs). Aim of this work was to investigate possible changes in IP3Rs and σ1Rs 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 IP3Rs (IP3R1s) and σ1Rs at mRNA and protein levels. Haloperidol treatment did not alter expression of other types of IP3Rs. Calcium release from endoplasmic reticulum (ER) mediated by increased amount of IP3R1s elevated cytosolic calcium and generated ER stress. IP3R1s were bound to σ1Rs, 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 σ1 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.
Highlights
Haloperidol is a typical antipsychotic agent used in the treatment of psychiatric disorders, including various psychoses such as schizophrenia and severe agitated delirium.Cell Mol Neurobiol (2018) 38:181–194Several adverse effects of haloperidol treatment are reported among them extrapyramidal side effects such as dystonia and muscle rigidity, palpitations, and changes of arterial blood pressure are common; QT interval prolongation eventually followed by cardiac arrhythmias such as Torsade de Pointe, are reported (Remijnse et al 2002).Haloperidol exhibits high-affinity dopamine D2 receptor (D2R) antagonism
In differentiated NG-108 cells, we observed a concentration-dependent increase in IP3R1 mRNA (Fig. 1a; black columns) and in r1R (Fig. 1b; black columns), while in non-differentiated cells, no changes in the corresponding mRNA (Fig. 1a, b; striped columns) or protein (Fig. 1c, d) were visible
We have clearly shown that in differentiated NG-108 cells haloperidol modulates plasticity of these cells, i.e., decreases number of neurites and increases the length of neurites
Summary
Haloperidol is a typical antipsychotic agent used in the treatment of psychiatric disorders, including various psychoses such as schizophrenia and severe agitated delirium.Cell Mol Neurobiol (2018) 38:181–194Several adverse effects of haloperidol treatment are reported among them extrapyramidal side effects such as dystonia and muscle rigidity, palpitations, and changes of arterial blood pressure are common; QT interval prolongation eventually followed by cardiac arrhythmias such as Torsade de Pointe, are reported (Remijnse et al 2002).Haloperidol exhibits high-affinity dopamine D2 receptor (D2R) antagonism. D2Rs play an important role in pathophysiology of brain signaling. These receptors exist as monomeric units, but they can form oligomers. Putative D1/D2 receptor heterodimers have been suggested to regulate diacylglycerol and IP3 signaling by activating Gq (Rashid et al 2007). It appears that D1 and D2 receptors are both necessary for this pathway; the application of dopamine or a combination of two selective D1 and D2 receptor agonists is able to increase intracellular calcium, whereas treatment with either D1 or D2 receptor antagonist can abolish this effect (Hasbi et al 2009)
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