Disruption of dopamine D1/D2 receptor complex is involved in the function of haloperidol in cardiac H9c2 cells

Haloperidol is an antipsychotic agent and acts as dopamine D2 receptor (D2R) antagonist, as a prototypical ligand of sigma1 receptors (Sig1R) and it increases expression of type 1 IP₃ receptors (IP₃R1). However, precise mechanism of haloperidol action on cardiomyocytes through dopaminergic signaling was not described yet. This study investigated a role of dopamine receptors in haloperidol-induced increase in IP₃R1 and Sig1R, and compared physiological effect of melperone and haloperidol on basic heart parameters in rats.

We used differentiated NG-108 cells and H9c2 cells. Gene expression, Western blot and immunofluorescence were used to evaluate haloperidol-induced differences; proximity ligation assay (PLA) and immunoprecipitation to determine interactions of D1/D2 receptors. To evaluate cardiac parameters, Wistar albino male rats were used.

We have shown that antagonism of D2R with either haloperidol or melperone results in upregulation of both, IP₃R1 and Sig1R, which is associated with increased D2R, but reduced D1R expression. Immunofluorescence, immunoprecipitation and PLA support formation of heteromeric D1/D2 complexes in H9c2 cells. Treatment with haloperidol (but not melperone) caused decrease in systolic and diastolic blood pressure and significant increase in heart rate.

Because D1R/D2R complexes can engage Gq-like signaling in other experimental systems, these results are consistent with the possibility that disruption of D1R/D2R complex in H9c2 cells might cause a decrease in IP₃R1 activity, which in turn may account for the increase expression of IP₃R and Sig1R. D2R is probably not responsible for changes in cardiac parameters, since melperone did not have any effect.