Third generation of antipsychotics : critical views on dopamine D2 partial agonism in neuropsychopharmacology
(2011)
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- (en) For the past decades, antipsychotic treatment has always relied on the blockade of dopamine D2 receptors. The ubiquitous blockade of these receptors in the four dopamine pathways leads therefore to adverse secondary effects, so as to the up-regulation and sensitization of the dopamine D2 receptors. The avoidance of such effects by second generation antipsychotics mainly relies on the slight modulation of dopamine D2 blockade and the implication of other pharmacological targets especially from the serotonergic transmission system. Nowadays, despite several issues related to antipsychotic compounds classification, a third generation of antipsychotics, associating a balance of partial agonism at the level of the dopamine D2 and serotonin 5-HT1A receptors has been launched, with aripiprazole as a chief of the file on the market. The benefit of partial agonism should rely on the lack of its receptor target regulation. However, the pharmacodynamic properties of a partial agonist are known to depend on receptor density and sensitivity. Therefore, the clinical response to such compounds can be quite unpredictable, as receptor density and sensitivity vary depending on brain areas and can be remodeled due to the pathological patient status and/or by previous antipsychotic treatment. This latter paradigm was used in order to study the pharmacodynamic and behavioural properties of aripiprazole on rodents that had been previously treated with haloperidol, a first-generation antipsychotic. In parallel, the effects of chronic aripiprazole administration on dopamine D2 and serotonin 5-HT1A receptors density and sensitivity were evaluated. Secondly, the pharmacodynamic properties of aripiprazole were characterized in vitro, in a cell model where the expression of the D2 receptor could be tightly manipulated. Our data indicate that the partial agonist profile of aripiprazole does not only depend on receptor density but mainly on the environment in which the receptors are expressed. Our observations, in accordance with data from the literature, strongly suggest that aripiprazole does not behave as a simple partial agonist but as a “functional selective” partial agonist, activating only a few selected pathways, under certain environmental favorable conditions. Together, this study emphasizes that the pharmacodynamic profile of such compound is quite dependent upon experimental conditions. Despite evidences for the persistent translation gap of in vitro or animal studies to human behavior, our study emphasizes that the clinical response to aripiprazole can be quite unpredictable, especially in a context of therapeutic substitution where receptors have been remodeled by pathology and previous psychotropic treatments. These questions raise up once more the question of an “optimal” classification of antipsychotics, that nowadays still remain a challenge.
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Koener, B. (2011). Third generation of antipsychotics : critical views on dopamine D2 partial agonism in neuropsychopharmacology. https://hdl.handle.net/2078.5/153019