Objective: Current antidepressant medications have variable efficacy on neurovegetative symptoms of depression. Besides elevation of mood, antidepressants also differ in efficacy to alleviate additional symptoms, such as relieving cognitive impairments commonly recognized in depressed patients . Brain-derived neurotrophic factor (BDNF) modulates synaptic plasticity in response to environmental stimuli in brain circuits regulating emotionality and cognition. However, detailed knowledge is limited on BDNF signaling in different brain regions . Glutamatergic transmission regulates BDNF signaling and particularly alterations of the NMDA receptor have recently been implicated in depression . This study aimed to compare baseline conditions and responses to two principal antidepressant regiments, the tricyclic agent (TCA) nortriptyline and the selective reuptake inhibitor (SSRI) escitalopram, on differential aspects of BDNF signaling by assessment of glutamatergic receptors and distinct phosphorylation sites of the TrkB receptor in the Flinder Sensitive Line (FSL) of rats . FSL rats are used as a potentially translational model for validation of pharmacological targets with resemblance for behavioral and neurochemical features of depression . Methods: Escitalopram (340 mg/kg pellets for 3 weeks followed by 410 mg/kg), nortriptyline (330 mg/kg) or vehicle was administered in food pellets to adult FSL and control FRL rats. Behavioral antidepressant-like actions were verified after 6 weeks and the rats were sacrificed with brain regions analyzed using immunoprecipitation, immunoblotting and in situ hybridization. Results: Immunoblotting revealed more than 50% reductions of the core NR1 subunit in the medial prefrontal cortex (p<0.001), hippocampus (p<0.01) and entorhinal cortex (p<0.01), compared to protein levels of FRL controls. NR2A and NR2B subunits were reduced in the medial prefrontal cortex (p<0.001; p<0.001) and hippocampal region (p<0.001; p<0.01). In contrast, no changes were found of NMDA receptor subunits in additional brain regions investigated or alterations of other glutamatergic receptors examined. Basal protein levels and phosphorylation state of TrkA, TrkB, BDNF mRNA or mature BDNF did not differ, while proBDNF was decreased in the hippocampus and increased in the entorhinal cortex of FSL rats (p<0.05; p<0.05). Consistent with several previous reports , both antidepressants increased mRNA expression of BDNF specifically in the dentate gyrus (p<0.05) of the hippocampus, with no detectable change of protein levels. Notably, nortriptyline increased phosphorylation of TrkB at Tyr816 and Tyr705 (p<0.01; p<0.01) in the hippocampus, while escitalopram induced phosphorylation at Tyr816 (p<0.05), but none of the antidepressants altered phosphorylation levels at the Tyr515 site of the TrkB receptor. Conclusions: FSL rats displayed glutamatergic deficits which appear to be specific for NMDA receptors in corticolimbic brain regions. These results in the multigenetic rat model of depression resemble findings reported in clinically depressed patients . Both nortriptyline and escitalopram increased BDNF mRNA but induced phosphorylation-site specific regulation of TrkB, indicating distinct activation of downstream signaling cascades. These data on differential regulation of BDNF/TrkB signaling by the TCA and SSRI antidepressants have implications for the understanding of molecular pathways of antidepressants beyond monoaminergic mechanisms and glutamatergic modulation.
|Titolo:||Glutamatergic deficits and differential antidepressant regulation in rat model of depression|
|Data di pubblicazione:||2011|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Citazione:||Glutamatergic deficits and differential antidepressant regulation in rat model of depression / T.M. Eriksson, P. Delagrange, M. Spedding, M. Popoli, A.A. Mathe, S.O. Ogren, P. Svenningsson. ((Intervento presentato al 24. convegno ECNP Congress tenutosi a Paris nel 2011.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|