Morfología de desgaste

During the past decade several important studies have implicated NMDA receptors in the aetiology o f depression. This was initially supported by findings that functional antagonists of the NMDA receptor mimic the effects o f clinically effective antidepressant drugs in a preclinical animal model predictive o f antidepressant activity (Trullas and Skolnick, 1990). Subsequently it was shown that chronic treatment with NMDA antagonists induces antidepressant activity in putative animal models of depression (Papp and Moryl, 1994). Additional evidence supporting a role for NMDA receptors in the mechanism of antidepressant action follows from the observation that

there is an important interaction between the glutamatergic and the monoaminergic systems in the brain (Pallotta et ah, 1998; 1999). The therapeutic relevance o f this interaction is underscored by the finding that chronic treatment with NMDA antagonists produces a down-regulation of cortical p-adrenoreceptors comparable to that produced by chronic treatment with the TCA imipramine (Paul et ah, 1992). The role o f NMDA receptors in the aetiology of depression is also supported by post-mortem data, showing a glutamatergic dysfunction in the frontal cortex of untreated depressed suicide victims (Nowak et al, 1995). Finally, Nowak et ah, (1993) have shown that chronic treatment with imipramine alters ligand binding to the NMDA receptor. The altered ligand binding would be expected to dampen NMDA functioning and is manifest as; (i) a reduced potency o f glycine to inhibit [^H] 5,7-dichlorokynurenic acid (DCKA) to strychnine-insensitive glycine receptors; (ii) a diminution in the number o f glycine displaceable [^H]CGP 39653 binding sites and (iii) a reduction in basal [^H]MK-801 binding that was reversed by the addition o f positive modulators such as glycine and glutamate.

The former observations support the role o f NMDA receptors in the mechanism of action of antidepressants. These studies have led to the hypothesis that conventional antidepressant drug therapies aimed at altering the efficacy o f monoaminergic systems ultimately exert their therapeutic effect by altering the efficacy o f the glutamatergic system. Further evidence in support of this hypothesis came when Paul and co-workers (1994) showed that chronic (14 days) but not acute (1 day) treatment with 17 out of 18 clinically active antidepressants were able to reduce DCKA binding. It is still difficult to determine whether these effects form the basis o f antidepressant action or are merely a secondary side effect of antidepressant drugs. However, it is clear that these neurochemical effects have a superior indicative value of antidepressant activity compared to p-adrenoreceptor down-regulation.

1.14.1 Molecular evidence for NMDAR involvement in depression

Based on recombinant DNA studies it has become clear that subunit composition plays a crucial role in determining the pharmacological and physiological properties o f ligand gated ion channels, such as the NMDA receptor (Monaghan et al, 1989). Recently, in situ hybridization studies have revealed that chronic treatment with the antidepressants imipramine and citalopram produces region-specific and treatment-specific changes in

mRNA levels encoding NMDA receptor protein subunits (Boyer et al., 1998). These observations form the basis for alternative hypothesis for mechanisms underlying the adaptive changes in NMDA receptor functioning.

Although it is clear that chronic antidepressant treatment with compounds from each major class of antidepressants causes an adaptation of NMDA functioning, it is still unclear what the functional consequences o f these adaptive changes are and how these changes are connected to the monoaminergic systems and depression.

1.14.2 NMDA, monoamines and intracellular second messengers

The exact mechanisms by which antidepressants cause an adaptive change in the functioning of the NMDA receptor are as yet unclear. However, since conventional antidepressants modulate monoaminergic transmission, it has been hypothesised that the adaptations in NMDA functioning are secondary to antidepressant actions at monoaminergic terminals (Skolnick, 1999). Direct evidence for this theory comes from experiments showing that lesions in the noradrenergic system block the adaptive changes caused by chronic desipramine treatment (Harkin et al., 2000). Additionally, there is considerable evidence suggesting that the monoaminergic and the glutamatergic systems are strongly synaptically linked to one another (Pallotta et al, 1999).

Most currently used antidepressants, when administered chronically, increase synaptic levels o f monoamines with concomitant stimulation o f adenylyl cyclase via G-protein coupled receptors (e.g. j8-adrenergic, 5-HT4,6,?) (for review see Duman et al, 1997). The resulting increased formation o f cAMP leads to activation o f cAMP dependent protein kinase (PKA), with subsequent phosphorylation of substrate proteins. A possible substrate for PKA is the cAMP response element binding protein (CREE), which is capable o f regulating gene expression (Duman et al, 1997). Phosphorylation o f CREE dramatically increases its ability to regulate gene expression. CREE is capable o f up- regulating the expression of specific genes containing the cAMP response element, one o f which is the brain-derived neurotrophic factor (EDNF) (Nibuya et al., 1995). It is demonstrated that the expression of EDNF is increased after chronic but not acute treatment with antidepressants from several different classes (Nibuya et al., 1995, 1996). This effect is believed to be mediated by CREE, since there is also an elevation of CREE mRNA and protein after chronic treatment with antidepressants (Nibuya et al,

1995). Further evidence that the cAMP system mediates the induction of BDNF is provided by the observation that inhibitors of phosphodiesterase (PDF) IV, a key enzyme responsible for the breakdown of c AMP, increase the expression of both CREB and BDNF in rat hippocampus (Fujimaki et ah, 2000).

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