Les adaptations receptorielles observees au cours du traitement de la depression ne predisent pas l'ensemble des ajustements biologiques operes par la therapeutique. L'objectif de ce travail est d'apporter les informations les plus recentes dans le domaine qui soient propices a une meilleure comprehension biologique de cette pathologie et de ses therapeutiques. On sait depuis peu que les antidepresseurs modulent l'expression et l'activation de certains facteurs de transcription comme le CREB (AMPc response element binding protein) et de facteurs neurotrophiques comme le BDNF (brain derived neurotrophic factor) dans le cerveau. L'observation que certaines manifestations depressives peuvent etre induites (ou a l'inverse supprimees) par la reduction (ou a l'inverse l'augmentation) de ces proteines nucleaires suggere ainsi l'existence de veritables << memoires biologiques >> du processus depressif par epuisement de ces facteurs et ouvre des perspectives nouvelles dans la therapeutique de la depression.
Mood disorders remain a puzzling clinical entity in psychiatry, not only at the symptomatic level (maniac versus depressive episodes, unipolar versus bipolar forms...) but also at the therapeutic level. Indeed, despite medications, the treatment responsiveness is rarely above 70%, occurs within the following weeks after initiation and is often not maintained on a half- to 1 year follow-up. The pioneering works of Axelrod's and Brodie's groups in the early 60s enlightening the ability of antidepressants to acutely increase central monoaminergic (serotoninergic or 5-HT, and noradrenergic or NAdr) activities have introduced the notion that these therapeutics affect the neuronal physiology. Since then, the affective disorders have been conceptualized as a biochemical disease corresponding to the mirror image of this antidepressant drug effectiveness. However, such understanding of the pathology minimizes or even denies the importance of some pharmacologically-induced events, e.g. the hypersensitization of postsynaptic 5-HT 1 A receptors combined with the desensitization of 5-HT autoreceptors (in particular of the 5-HT 1 A subtype) which both occur once symptoms alleviate. This has likely weakened the dogma that treatments affect solely membrane-bound monoaminergic receptors. In addition, the use of drug combinations for fastening the clinical response (association with β-adrenergic drugs, anticonvulsants or thymo-regulators) have pointed out to speculate that the clinical drug effectiveness might be underlined by a sustained suractivation of the intracellular cascades triggered by the central monoaminergic systems (i.e. adenylate cyclase by cyclic adenosine monophosphate [cAMP] for the β-adrenergic, 5-HT 1 A and 5-HT 1 B / D receptor subtypes and calcium-dependent phospholipase and protein kinases by inositol triphosphate [IP 3 ] for the 5-HT 1 C and 5-HT 2 receptor subtypes via heterotrimeric G protein-coupled receptors; Fig. 1). Accordingly, in the last decade, a new pathophysiological concept of affective disorders has thus emerged which integrates preferentially the molecular and cellular changes that supervene in response to an over-stimulation of these cascades. Most groups have focused their attention to the ability of antidepressants to enhance the expression and activation of a few transcription factors exemplified by CREB (AMPc response element binding protein) and neurotrophic factors such as nervous growth factor (NGF) and brain derived neurotrophic factor (BDNF) in the brain. Here, a review of the literature is synthesized on the topic that underlies the structural adaptations observed in the brain of depressed subjects and animals exposed to antidepressants. In fact, the hypothesis for a molecular vulnerability of mood disorders, a kind of neuronal memory for depression, has emerged in the early 90s when expression (identified by the messenger ribonucleic acid; mRNA) of various biological markers associated with depression [corticotrophin releasing hormone (CRH), tyrosine hydroxylase (TH), gluco-, mineralocorticoid and adrenergic receptors] was found to increase in parallel with the clinical response following a chronic antidepressant medication. Indeed, occurring with a different delay to the well-known mobilization of serotoninergic and noradrenergic receptors located at the plasma membrane level (that occur rapidly after initiation), the clinical response to antidepressant drugs has coincided with the long-term recruitment of various nuclear transcription factors, the mostly documented one being today CREB, and of various neurotrophic factors exemplified by BDNF. This recent hypothesis based on enhanced levels of both transcription and subsequent neurotrophic factors is nowadays getting more attractive due to specific documentation by both animal and human reports. However, whether quantifying expression (assessed by the mean of the mRNA levels) or protein activity of these factors is representative of the biological responsiveness to antidepressants still remains controversial since both hypotheses have now found their own defenders and detractors.
