Data di Pubblicazione:
2011
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.
Abstract:
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 [1]. 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 [2]. Glutamatergic
transmission regulates BDNF signaling and particularly alterations
of the NMDA receptor have recently been implicated in depression
[1]. 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 [3]. FSL rats are used as a potentially translational
model for validation of pharmacological targets with resemblance
for behavioral and neurochemical features of depression [3].
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 [2], 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 [1].
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.
Tipologia IRIS:
14 - Intervento a convegno non pubblicato
Elenco autori:
T.M. Eriksson, P. Delagrange, M. Spedding, M. Popoli, A.A. Mathe, S.O. Ogren, P. Svenningsson
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