Membrane Partition and Structural Reorganization Induced by Antipsychotics with Distinct Clinical Profiles

Antipsychotics (APs) are used in the treatment of severe mental disorders. Their mechanism of action involves interaction with multiple brain targets, notably the dopamine D2 receptor (D2R), where they compete with dopamine. Due to their lipophilic nature, APs also partition and accumulate in lipid membranes, particularly around the D2R and in synaptic vesicles. When intercalated into brain membranes, APs slowly accumulate and act as reservoirs, allowing their rapid release on demand to modulate neurotransmitter signaling. They also modify the physicochemical and mechanical properties of the lipid bilayer. These modifications can subsequently affect the conformational changes of embedded membrane proteins like the D2R. This study investigated two major APs with different pharmacological and clinical profiles: chlorpromazine, which exerts its clinical activity mainly through a strong antagonistic action at the D2R, and clozapine, the weakest D2R antagonist of all APs. Surprisingly, although D2R antagonism is usually associated with AP potency, clozapine has repeatedly demonstrated clinically superior efficacy to all APs and is therefore recommended for treatment-resistant schizophrenia. The current work aims to extend the classical AP receptor-mediated paradigmatic mode of action to their potential and unique membrane remodeling properties by thoroughly comparing their partitioning and impact on the physicochemical properties of the lipid membrane. Lipid model membranes mimicking synaptic vesicles have been investigated by using a combination of several biophysical methods. The study aims to determine how the partitioning of the two APs modifies membrane order, phase transition, thickness, elasticity, phase separation, membrane integrity, and charge. Differences have been demonstrated between these two compounds, which may further differ both over time as they accumulate, as well as depending on their pre- or postsynaptic location.