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

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-HT(4), 5-HT(6), 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 (D2/5HT(2A) ratio, 1.14). Loxapine is rightly classified as a DS-RAn agent in the Neuroscience Based Nomenclature classification.