NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses : Nature : Nature Publishing Group

NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses
Anita E. Autry,1 Megumi Adachi,1 Elena Nosyreva,2 Elisa S. Na,1 Maarten F. Los,1 Peng-fei Cheng,1 Ege T. Kavalali2 & Lisa M. Monteggia1

AffiliationsContributionsCorresponding authors Journal name: Nature
Year published:(2011)
DOI:doi:10.1038/nature10130
Received25 October 2010
Accepted21 April 2011
Published online15 June 2011

Clinical studies consistently demonstrate that a single sub-psychomimetic dose of ketamine, an ionotropic glutamatergic NMDAR (N-methyl-D-aspartate receptor) antagonist, produces fast-acting antidepressant responses in patients suffering from major depressive disorder, although the underlying mechanism is unclear1, 2, 3. Depressed patients report the alleviation of major depressive disorder symptoms within two hours of a single, low-dose intravenous infusion of ketamine, with effects lasting up to two weeks1, 2, 3, unlike traditional antidepressants (serotonin re-uptake inhibitors), which take weeks to reach efficacy. This delay is a major drawback to current therapies for major depressive disorder and faster-acting antidepressants are needed, particularly for suicide-risk patients3. The ability of ketamine to produce rapidly acting, long-lasting antidepressant responses in depressed patients provides a unique opportunity to investigate underlying cellular mechanisms. Here we show that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of brain-derived neurotrophic factor. We find that the ketamine-mediated blockade of NMDAR at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase (also called CaMKIII), resulting in reduced eEF2 phosphorylation and de-suppression of translation of brain-derived neurotrophic factor. Furthermore, we find that inhibitors of eEF2 kinase induce fast-acting behavioural antidepressant-like effects. Our findings indicate that the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast-acting antidepressants.



Figures at a glance

Figure 1: Time course of NMDAR antagonist-mediated antidepressant-like behavioural effects.
Mean immobility ± s.e.m. of C57BL/6 mice in FST after acute treatment with ketamine, CPP or MK-801. Independent groups of mice were used at each time point and for each drug treatment, to avoid behavioural habituation. Analysis of variance (ANOVA) F(3,27) = 30.31, P < 0.0001 for treatment groups; F(3,27) = 19.06, P < 0.0001 for duration of response; F(9,81) = 9.32, P < 0.0001 for treatment-duration interaction. Therefore, we examined treatment effects by time point. a, Ketamine (3.0 mg kg−1) significantly reduced immobility, indicating an antidepressant-like response, at 30 min, 3 h, 24 h and 1 week, compared to vehicle treatment. b, CPP (0.5 mg kg−1) significantly reduced immobility at 30 min, 3 h and 24 h, compared to vehicle treatment. c, MK-801 (0.1 mg kg−1) produced significant decreases in immobility at 30 min and 3 h compared to vehicle treatment. n = 10 mice per group per time point; *, P < 0.05. Here and in all figures, error bars represent s.e.m.

Figure 2: BDNF translation in the antidepressant effects of NMDAR antagonists.
a, Immobility in FST after acute treatment with ketamine (3.0 mg kg−1). At 30 min, ANOVA F(1,35) = 17.13, P = 0.0002 for drug; F(1,35) = 7.57, P = 0.0093 for genotype–drug interaction; multiple comparisons with t-test, *, P < 0.05. At 24 h, in a separate cohort, ANOVA F(1,29) = 3.77, P = 0.0619 for treatment; multiple comparisons with t-test, *, P < 0.05. n = 7–12 mice per group. b, Densitometric analysis of BDNF (normalized to GAPDH) in the hippocampus after treatment with vehicle (control), ketamine (3.0 mg kg−1) or MK-801 (0.1 mg kg−1). At 30 min, ANOVA F(2,12) = 6.77, P = 0.0108 for treatment, Bonferroni post hoc test, *, P < 0.05. At 24 h, no significant differences were seen (n = 5–6 per group). c, Protocol for experiments using the blockers anisomycin and actinomycin D. d, Immobility at 30 min after anisomycin treatment. ANOVA F(1,34) = 11.83, P = 0.0016 for treatment and F(1,34) = 10.91, P = 0.0023 for treatment–inhibitor interaction; multiple comparisons, *, P < 0.05 (n = 8–10 per group). e, Immobility at 24 h after anisomycin treatment. ANOVA F(1,31) = 9.34, P = 0.0046 for treatment; multiple comparisons, *, P < 0.05 (n = 8–10 per group). f, Immobility of wild-type mice given vehicle or NMDA (75 mg kg−1), tested 30 min later in FST. g, Immobility of mice given NBQX (10 mg kg−1) or picrotoxin (1 mg kg−1), tested 30 min later in FST. h, Immobility of mice given vehicle, ketamine (3.0 mg kg−1) or ketamine + NBQX (10 mg kg−1) and tested 30 min later in FST. ANOVA F(2,26) = 8.226, P < 0.0019; Bonferroni post hoc analysis shows that the ketamine effect is reversed by NBQX, *, P < 0.05. i, Densitometric analysis of phosphorylated mTOR (normalized to mTOR) in the hippocampus 30 min after treatment with vehicle or ketamine.

Figure 3: Ketamine blocks NMDAR spontaneous activity, reduces the level of eEF2 phosphorylation and strengthens synaptic responses.

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NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses : Nature : Nature Publishing Group





PSIQUIATRÍA
Actualidad Ultimas noticias - JANOes -
La ketamina se revela eficaz como tratamiento rápido de la depresión
JANO.es · 16 Junio 2011 12:49

.Un estudio llevado a cabo en ratones abre una vía para combatir este trastorno en pacientes con riesgo de suicidio.

Molécula de ketamina. / Ben Mills.


La ketamina y otros anestésicos similares tienen un efecto antidepresivo de acción rápida gracias a la síntesis del factor neurotrófico derivado del cerebro (BDNF, por sus siglas en inglés). Así lo indica un estudio llevado a cabo en ratones y publicado esta semana en la revista Nature que abre una vía para el tratamiento drástico de la depresión severa.

“Los medicamentos tradicionales antidepresivos pueden tardar semanas en producir una mejoría en los pacientes con depresión”, explica Lisa Monteggia, autora principal del estudio e investigadora de la Universidad de Texas (EE UU). Sin embargo, la ketamina, utilizada originalmente por sus propiedades analgésicas y anestésicas, “ejerce una respuesta de acción rápida en pacientes con depresión resistente al tratamiento y con trastorno bipolar”.

Esta rapidez supone una oportunidad única para el tratamiento de personas de alto riesgo, como pacientes con riesgo de suicidio. “Estudios clínicos han mostrado ya que una dosis baja de ketamina intravenosa puede aliviar los síntomas de depresión severa en cuestión de horas, y los efectos pueden durar hasta dos semanas”, subraya Monteggia. Lo que no estaba claro hasta ahora era el mecanismo de esta sustancia en el cerebro.

El trabajo revela que las dosis bajas de ketamina, un bloqueador de los receptores NMDA en el cerebro, aumentan la expresión de un factor de crecimiento específico, el factor neurotrófico derivado del cerebro (BDNF), asociado a efectos antidepresivos.
Los autores demostraron que el vínculo entre el efecto de la ketamina en los receptores NMDA y el aumento de los niveles de BDNF implica cambios en una forma específica de la comunicación (neurotransmisión espontánea) entre las células nerviosas que antes no se habían asociado a ningún tipo de acción de los fármacos.

“El descubrimiento de una nueva vía antidepresiva de acción rápida facilita una manera de desarrollar más velozmente los antidepresivos”, afirma la investigadora. “La identificación de una forma específica de comunicación entre las células nerviosas que participan en el tratamiento antidepresivo supone nuevas pistas sobre lo que ocurre en el cerebro para desencadenar trastornos psiquiátricos como la depresión”, concluye.


Nature (2011); doi:10.1038/nature10130
NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses : Nature : Nature Publishing Group

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