The in Vitro Actions of Loxapine on Dopaminergic and Serotonergic Receptors. Time to Consider Atypical Classification of This Antipsychotic Drug?

Abstract

Background: The denomination of typical antipsychotic for loxapine has poor relation to current knowledge of the molecule's relevant modes of action. Materials and Methods: Competition binding experiments were performed on expressed human recombinant receptors in CHO cells and HEK-293 cells for D 1 to D 5 , 5-HT 1A , 5-HT 2A , 5-HT 2C , 5-HT 4 , 5-HT 6 , and 5-HT 7 . In vitro autoradiographies using [ 11 C]-Raclopride [ 18 F]-Altanserin [ 18 F]-MPPF [ 11 C]-SB207145, and [ 18 F]-2FNQ1P were measured in brain tissue of a male primate followed by addition of increasing doses of loxapine succinate. Results: In cell cultures, the measured Kb confirmed high affinity of loxapine for the D 2 ; intermediate affinity for the D 1 , D 4 , D 5 , 5-HT 2C receptorsl and a lack of affinity toward D 3 , 5-HT 1A , 5-H T4 , 5-H T6 , and 5-HT 7 receptors. In brain tissue, PET autoradiographies showed a radiopharmaceutical displacement at low concentrations of loxapine on D 2 and 5-HT 2A receptors. Conclusion: This preclinical study reveals that loxapine receptorial spectrum is close to an "atypical" profile (D 2 /5HT 2A ratio, 1.14). Loxapine is rightly classified as a DS-RAn agent in the Neuroscience Based Nomenclature classification.