Membrane Stabilization by Antipsychotics

With the introduction of chlorpromazine to psychotic patients in state and provincial hospitals in North America in the late 1950s and early 1960s, the number of patients hospitalized with schizophrenia became markedly reduced. The basic science premise gradually emerged - if the target sites for antipsychotics could be found, then perhaps these sites were overactive in psychosis or schizophrenia. In the 1960s, however, no one agreed on what schizophrenia was. Inclusion criteria varied so much that it was impossible to decide which patients to study, let alone what to study. But everyone agreed that chlorpromazine and the many other new antipsychotic drugs, most of which were phenothiazines, alleviated the symptoms of schizophrenia, however defined.

But where in the nervous system does one start to look for an antipsychotic target? Moreover, were there many types of antipsychotic targets to identify?

With the advent of the electron microscope, the 1960s was an active decade of discovery of subcellular particles and cell membranes. In those days, therefore, it seemed reasonable to start by examining the actions of antipsychotics on cell membranes. In particular, did antipsychotics readily locate to cell surfaces and cell membranes and thereby alter membrane structure and function? Did antipsychotics target mitochondria, the structure of which was being rapidly revealed by electron microscopy?

In my own research in 1963, it was important to determine whether antipsy-chotics permeated cell membranes and whether the drugs were membrane active. I started with an artificial lipid film floating on water, and measured the film pressure with a 1 cm square of sand-blasted aluminum hanging into the bath (Wilhelmy method; [6]). Upon the addition of an antipsychotic to the water below the film, the aluminum plate immediately rose, showing that the film pressure had been altered by the antipsychotic. This indicated that the antipsychotic molecules had entered into the single layer of lipid molecules floating on the water surface, expanding the intermolecular spaces between the lipid molecules. Therefore, could it be that cell membrane lipids were targets for antipsychotics?

To my surprise, however, when I omitted the lipid molecules, the addition of the antipsychotic still altered the surface pressure of the water surface. In other words, I had accidentally discovered that antipsychotics were surface active [7].

These surface-active potencies showed an excellent correlation with clinical antipsychotic potencies. However, I later realized that the antipsychotic concentrations were all in the micromolar range, a concentration subsequently found to be far in excess of that which was clinically effective in the plasma water or spinal fluid in patients taking antipsychotic medications.

Although all the antipsychotics were surface active and readily acted on artificial lipid films, it was essential to determine whether antipsychotics had similar membrane actions on human red blood cell membranes. In fact, this did occur, and it was found that low concentrations of antipsychotics readily expanded red blood cell membranes by ~0.1-1% and, in doing so, exerted an anti-hemolytic action by allowing the cells to become slightly larger and stabilized before hemolysis occurred [8-11].

This membrane stabilization by antipsychotics was also associated with electrical stabilization of the membrane. That is, it soon became clear that the antipsychotics were potent anesthetics, blocking nerve impulses at antipsychotic concentrations of between 20 nM and 1,000 nM (Fig. 1.1, top correlation line) [10, 12]. However, here too, these membrane-stabilizing concentrations were still in excess of those found clinically in the spinal fluid of treated patients (see following section). The driving criterion throughout this research was to find a target that was sensitive to the antipsychotic concentrations found in the spinal fluid of psychotic patients on maintenance doses of antipsychotic medications.

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