Stress and antidepressants differentially regulate neurotrophin 3 mRNA expression in the locus coeruleus.

Abstract

The mechanisms by which stress and antidepressants exert opposite effects on the course of clinical depression are not known. However, potential candidates might include neurotrophic factors that regulate the development, plasticity, and survival of neurons. To explore this hypothesis, we examined the effects of stress and antidepressants on neurotrophin expression in the locus coeruleus (LC), which modulates many of the behavioral and physiological responses to stress and has been implicated in mood disorders. Using in situ hybridization, we demonstrate that neurotrophin 3 (NT-3) is expressed in noradrenergic neurons of the LC. Recurrent, but not acute, immobilization stress increased NT-3 mRNA levels in the LC. In contrast, chronic treatment with antidepressants decreased NT-3 mRNA levels. The effect occurred in response to antidepressants that blocked norepinephrine uptake, whereas serotonin-specific reuptake inhibitors did not alter NT-3 levels. Electroconvulsive seizures also decreased NT-3 expression in the LC as well as the hippocampus. Ntrk3 (neurotrophic tyrosine kinase receptor type 3; formerly TrkC), the receptor for NT-3, is expressed in the LC, but its mRNA levels did not change with stress or antidepressant treatments. Because NT-3 is known to be trophic for LC neurons, our results raise the possibility that some of the effects of stress and antidepressants on LC function and plasticity could be mediated through NT-3. Moreover, the coexpression of NT-3 and its receptor in the LC suggests the potential for autocrine mechanisms of action.The behavioral and physiological responses to stress closely resemble the symptoms of clinical depression (1). Stress can precipitate episodes of depression (2), and chronic, uncontrollable stress has been proposed as a model of depression (3). How stress might exacerbate depression in vulnerable patients is not known. However, the locus coeruleus (LC), which plays a major role in behavioral arousal in response to novel or stressful stimuli (4), has long been a focus of investigation. Stress increases the firing rate of LC noradrenergic neurons as well as levels of norepinephrine (NE) and tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of catecholamines (5-9). As a consequence, chronic stress increases the magnitude of NE release in response to a novel stressor (10). In contrast, tricyclic antidepressants (TCAs) decrease LC firing (11) and TH mRNA and protein in the LC (12, 13). Pretreatment with imipramine for 18 days, but not 1 or 7 days, prevents the induction of TH in the LC by cold stress (14). Generally, both the therapeutic and neurochemical effects of antidepressants require several weeks to develop.The mechanisms underlying LC adaptation in response to stress and antidepressants are not presently known. However, a possible candidate for the regulation of LC plasticity might be a neurotrophic factor such as neurotrophin 3 (NT-3). This hypothesis is supported by a recent study demonstrating that enhances the survival of adult LC n...

Neurotrophin-3 modulates noradrenergic neuron function and opiate withdrawal

“…This is in contrast to previous studies in the rat localizing NT-3 mRNA to A6, 5,32 suggesting that related species may differ in regional patterns of neurotrophin gene expression. Because neurotrophins are subject to retrograde 33 and anterograde transport, 34,35 other NT-3 expressing neuronal populations in adult brain 27,36,37 may supply noradrenergic cells with targetderived NT-3.…”

Allele variants in functional MicroRNA target sites of the neurotrophin-3 receptor gene (NTRK3) as susceptibility factors for anxiety disorders

“…Data from a transgenic mouse model overexpressing the full-length isoform of NTRK3 supports this hypothesis [Dierssen, et al, 2006] as these mice present anxiety-like behaviour and show increased cellularity in the LC and other catecholaminergic nuclei. Neurotrophin-3 has trophic effects on LC neurons and mediates the effect of stress and of some antidepressants on LC function and plasticity [Smith, et al, 1995].…”

Profiling of behavioral changes and hippocampal gene expression in mice chronically treated with the SSRI paroxetine

“…In our experiment, we found a twofold decrease of NT-3 mRNA levels in the hippocampus in animals treated chronically with paroxetine. NT-3 levels have been reported to be increased in the hippocampus and in the locus coeruleus by repeated severe stress and decreased by electroconvulsive seizures (ECS) or by long-term treatment with desipramine or imipramine, but not with fluoxetine or trazodone (Smith et al 1995;Smith 1996). Karege et al (2005) reported a significant decrease of BDNF and NT-3 protein levels in the hippocampus of drug-free suicide victims compared with non-suicide controls.…”