Pre-clinical Pharmacology of Atypical Antipsychotic Drugs: A Selective Review

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Abstract
The primary basis for the action of neuroleptic drugs has been suggested to be a blockade of D2receptors in the mesolimbic system, with subsequent decrease in the firing rate of ventral tegmental (A10) dopamine neurons by the process of depolarisation inactivation (Matthyssee, 1974; Bunneyet al, 1991). The main evidence for this hypothesis is that: the affinities for the D2receptor of all effective antipsychotic drugs are positively correlated with their average clinical dose (Seeman & Lee, 1975; Creeseet al, 1976); and chronic administration of antipsychotic drugs produces nearly complete inhibition of the firing of ventral tegmental (A10) dopamine neurons that project to the limbic forebrain (Chiodo & Bunney, 1983). Clozapine, the prototypical atypical antipsychotic drug, also satisfies both criteria (Seeman & Lee, 1975; Chiodo & Bunney, 1985). However, the demonstration that clozapine is more effective than other neuroleptics for the treatment of both schizophrenic patients who are responsive to typical neuroleptics (Meltzer, 1992) as well as those who are resistant (Kaneet al, 1988) suggests that this simple dopamine hypothesis of neuroleptic drug action is insufficient. Indeed, there is evidence that clozapine at clinically effective doses produceslessD2receptor occupancy and, hence, less antagonism of D2receptors in the striatum, and probably also in the limbic system, than typical neuroleptic drugs (Fardeet al, 1992); this further challenges the adequacy of the dopamine hypothesis to explain the greater efficacy of clozapine. This leaves the need to consider what else besides a D2receptor blockade may explain the action of clozapine and, indeed, whether limited blockade is superior to a more complete one.