Clozapine acts as an antagonist of human dopamine D1 receptors in the atrium

Clozapine is one of the oldest antipsychotic drugs, the first atypical neuroleptic drug, and can be found in the World Health Organization’s list of essential drugs. The precise mechanism of action of clozapine as an antipsychotic is not known. However, clozapine binds to many proteins in vitro. The objective of this study was to investigate the role of the dopamine D 1 receptor as a possible explanation for the cardiac side effects of clozapine. To this end, the hypothesis was tested that clozapine reduces the positive inotropic or positive chronotropic effects mediated by human cardiac dopamine D 1 receptors using a novel transgenic mouse model with cardiac myocyte-specific expression of the human dopamine D 1 receptor (D 1 -TG). The force of contraction in the left (LA) and right (RA) atria of adult D 1 -TG mice and, as a control, wild-type (WT) mice was measured and compared to human right atrial preparations (HAP), which were obtained from adult patients with coronary heart disease during cardiac surgery. In the presence of propranolol, which was used to block endogenous β-adrenoceptors, dopamine increased the force of contraction in LA and elevated the beating rate in RA from D 1 -TG. The effects in RA, but not in LA, were antagonized by clozapine. The effects were more pronounced in the presence of haloperidol, a typical antipsychotic drug. This drug was studied for comparison in mouse atrial preparations and was found to antagonize the effects of dopamine in both LA and RA. Furthermore, clozapine decreased dopamine receptor–stimulated contractile force in HAP. These findings suggest that the D 1 receptor antagonism may contribute to cardiac side effects associated with clozapine in patients.