Modèles de sensibilisation comportementale et troubles psychiques : aspects actuels

Abstract

Behavioral sensitization is a preclinical model which can be defined as an augmentation in the behavioral effect of a psychostimulant upon re-administration. It has two phases, induction and expression. Induction refers to the transient sequence of events precipitated by psychostimulant administration that leads to the enduring changes in neural functions responsible for behavioral augmentation. Expression corresponds to the enduring neural alterations arising from the induction process that directly mediate the augmented behavorial response. These two processes are not only temporally but also anatomically and biochemically distinct. Induction seems to require the stimulation of dopamine D1 receptors in the ventral tegmental area (VTA) either directly by dopamine (DA) agonists, or indirectly via GABAergic inhibition; the stimulation of excitatory amino acid (EEA) receptor in the VTA, the amygdala and the hippocampus may also have a central role in the induction process. Contrary to its induction the expression of sensitization depends on the stimulation of the DA terminal fields and appears to be D2 mediated, whereas GABA and EEA do not seem to play a role. These processes result in an enhanced DA efflux induced by repeated exposure to stimulants. At least three different subcellular cascades have been involved in the molecular mechanisms of sensitization. Activation of these cascades induce changes in expression of neuritogenesis and synaptogenesis genes and remodelling of neural networks. First used to conceptualize various aspects of the course of affective disorders, behavioral sensitization models have been recently applied to the pathophysiology of schizophrenia, as a consequence of a better understanding of their neurobiologic underpinnings. Other psychiatric syndroms such as anxious disorders and drug addiction have been concerned too. Behavioral sensitization helps understand syndrome progression manifested by either increasing frequency, severity or spontaneity of psychiatric episodes, as well as the deteriorative course of some psychotic illnesses since sensitization, if sustained can lead to potential neurotoxic effects producing structural alterations. This model has found many applications in the psychopharmacological domain. Repeated application of stimulants either parenterally or directly into the brain may also produce a progressive increase in neural excitability, eventually producing major motor seizures in response to a previously subthreshold dose of drug. This could explain why anticonvulsants may be effective in psychiatric disorders in which behavioral sensitization is deemed to be involved. Recent data show that drugs like valproate are not only useful for treating affective illness but are also efficient in schizophrenia and anxious disorders. Contrary to lithium, valproate appears to prevent not only the induction but also the expression of behavioral sensitization in rodents. Drugs like olanzapine have, in addition to their D2 blockade effect, the capacity to block D1 receptors which may be linked to their antimanic and mood stabilising properties, considering the role of D1 receptors in the induction of sensitization phenomena. It is also possible that 5HT2 blockade play a role in this respect, as these receptors have been involved too in the development of behavioral sensitization. Finally the model allows specific predictions about the course of some psychiatric illnesses and particularly regarding the fact that treatment intervention that limit duration and number of psychiatric episodes may prevent progression of brain pathology. However such hypotheses have still to be tested through futures studies.