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Time-dependent and sequential modulation of signaling, CREB activation and BDNF expression induced by antidepressants
No full textAlthough cellular processes involved in depression and antidepressants mechanisms are still not well characterized, recent studies showed that intracellular pathways modulating gene transcription are involved in the pathophysiology of depression and in antidepressant mechanisms [1]. The effects of antidepressant on cAMPresponsive element binding protein (CREB) function, a transcription factor regulating expression of several genes involved in neuroplasticity, cell survival, and cognition, has been extensively studied. CREB is activated by several physiological stimuli; in neurons activitydependent phosphorylation of CREB at Ser133 is induced by activation of the calcium/calmodulin-dependent kinase (CaMK) and the mitogen-activated kinase (ERK1/2) cascades [2]. These pathways are involved in both activity-dependent regulation of gene expression and antidepressant mechanisms. Although there is general
agreement that chronic antidepressants stimulate CREB function, conflicting results suggest that different effects may depend on drug type, way of administration and different time window of measurement. In this study we analyzed the time-course of the treatment with the antidepressants fluoxetine (SSRI) and reboxetine (NaRI), by measuring the temporal effects of antidepressants on CaMKIV, CaMKII, ERK1/2 activation in nuclear fraction from hippocampus (HC) and prefrontal/frontal cortex (P/FC). Furthermore, we measured the timecourse of nuclear CREB activation in the same areas and the expression of brain-derived neurotrophic factor (BDNF), a CREB-regulated gene, implicated in both pathophysiology and pharmacology of mood disorders. Male rats were treated with fluoxetine (10 mg/kg) or reboxetine (10 mg/kg) administered in drinking water. Rats were divided in 5 groups following this schedule: control, one-week treatment, two-week treatment, three-week treatment and three-week treatment plus one-week drug wash-out. Nuclei from HC and P/FC were prepared by differential centrifugation. Phosphorylation and expression levels of proteins were measured by SDS-PAGE, Western Blot and immunostaining P/FC, while both drugs persistently activated ERK2 in HC. Finaly, BDNF (14kDa) expression showed a profile similar to CREB activation, with an increase of expressionat 2 weeks followed by a reduction. Our results suggest a transient profile of CREB activation by antidepressants, with a peak of phosphorylation in the first 1-2 weeks and subsequent return to basal levels. This profile is consistent with t. Pharmacological treatments did not alter CREB expression, but fluoxetine for 1 and 2 weeks increased CREB phosphorylation in nuclear fraction from HC, while one-week treatment with reboxetine induced CREB activation in nuclei from P/FC. With both drugs CREB phosphorylation returned to basal levels during three-week treatment and the wash out week. CaMKIV activation followed a temporal profile similar to CREB time-course in HC, while in P/FC phosphorylation was sustained up to the wash-out week. CaMKII activation showed a down-regulation in HC from rats treated with fluoxetine. Regarding ERK1/2 activation, three-week treatment reduced ERK1/2 phosphorylation in he activation of CaMKIV in HC and P/FC and ERK2 in P/FC. Furthermore, BDNF expression shows a similar biphasic profile, with the increase following one week after the peak of CREB activation. These results suggest that time-dependent activation of signalling and CREB by antidepressants is a rather early event, followed by sequential activation of the CREB-dependent gene BDNF.
Reference(s)
[1] Tardito D, Perez J, Tiraboschi E, et al., 2006, Signaling pathways regulating gene expression, neuroplasticity, and neurotrophic mechanisms in the action of antidepressants: a critical overview. Pharmacol Rev 58(1): 115-34.
[2] Kasahara J, Fukunaga K, Miyamoto E, 2001, Activation of calcium/calmodulin-dependent protein kinase IV in long term potentiation in the rat hippocampal CA1 region. J Biol Chem 276(26): 24044-50
Proteomic analysis of a behavioral animal model of depression after antidepressant treatment
No full textAntidepressant treatments and function of glutamate ionotropic receptors mediating amine release in hippocampus
No full textPrevious evidences showed that, besides noradrenaline (NA) and 5-hydroxytryptamine (5-HT), glutamate transmission is involved in the mechanism of action of antidepressants (ADs), although the relations between aminergic and glutamatergic systems are poorly understood.
The aims of this investigation were to evaluate changes in the function of glutamate AMPA and NMDA receptors produced by acute and chronic
administration of the two ADs reboxetine and fluoxetine, selective inhibitors of NA and 5-HT uptake, respectively. Rats were treated acutely
(intraperitoneal injection) or chronically (osmotic minipump infusion) with reboxetine or fluoxetine. Isolated hippocampal nerve endings (synaptosomes) prepared following acute/chronic treatments were labelled with [3H]NA or [3H]5-HT and [3H]amine release was monitored during
exposure in superfusion to NMDA/glycine, AMPA or Kþ-depolarization. Acute and chronic reboxetine reduced the release of [3H]NA evoked by
NMDA/glycine or by AMPA. The NMDA/glycine-evoked release of [3H]NAwas also down-regulated by chronic fluoxetine. Only acute, but not
chronic, fluoxetine inhibited the AMPA-evoked release of [3H]5-HT. The release of [3H]NA and [3H]5-HT elicited by Kþ-depolarization
was almost abolished by acute reboxetine or fluoxetine, respectively, but recovered during chronic ADs administration. ADs reduced NMDA
receptor-mediated releasing effects in noradrenergic terminals after acute and chronic administration, although by different mechanisms.
Chronic treatments markedly reduced the expression level of NR1 subunit in synaptic membranes. The noradrenergic and serotonergic release
systems seem to be partly functionally interconnected and interact with glutamatergic transmission to down-regulate its function. The results obtained support the view that glutamate plays a major role in AD activit
Lo stress acuto aumenta il rilascio di glutammato dai sinaptosomi di corteccia frontale/prefrontale e gli antidepressivi proteggono dallo stress
No full textEffects of stress and antidepressant drugs on presynaptic molecular mechanisms regulating glutamatergic neurotransmission
No full textGENDEP – Proteomica funzionale di modelli animali di depressione con interazione gene-ambiente
No full textModulation of presynaptic glutamate release: Implications for mood disorders and therapy
No full textChronic antidepressants block the increase in depolarization-evoked release of glutamate induced by acute stress
No full textGENDEP – Proteomica funzionale sinaptica in un modello animale di depressione con interazione gene-ambiente
No full textSynaptoproteomic analysis of a rat model of depression with gene-environment interaction
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