Neurobiological mechanisms involved in the antidepressant and psychotomimetic effects of NMDA receptor antagonists: role of the GluN2C subunit
[eng] Sub-anesthetic doses of ketamine evoke rapid and persistent antidepressant effects in treatment-resistant depressed patients through still poorly-known mechanisms. Ketamine also evokes transient psychotomimetic effects, shared by other non-competitive NMDA-R antagonists such as phencyclidine (...
| Autor: | |
|---|---|
| Formato: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2019 |
| País: | España |
| Recursos: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/171725 |
| Acesso em linha: | https://hdl.handle.net/2445/171725 http://hdl.handle.net/10803/669917 |
| Access Level: | acceso abierto |
| Palavra-chave: | Neurofarmacologia Esquizofrènia Depressió psíquica Ciències de la salut Neuropharmacology Schizophrenia Mental depression Medical sciences |
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Neurobiological mechanisms involved in the antidepressant and psychotomimetic effects of NMDA receptor antagonists: role of the GluN2C subunit |
| title |
Neurobiological mechanisms involved in the antidepressant and psychotomimetic effects of NMDA receptor antagonists: role of the GluN2C subunit |
| spellingShingle |
Neurobiological mechanisms involved in the antidepressant and psychotomimetic effects of NMDA receptor antagonists: role of the GluN2C subunit Tarrés Gatius, Mireia Neurofarmacologia Esquizofrènia Depressió psíquica Ciències de la salut Neuropharmacology Schizophrenia Mental depression Medical sciences |
| title_short |
Neurobiological mechanisms involved in the antidepressant and psychotomimetic effects of NMDA receptor antagonists: role of the GluN2C subunit |
| title_full |
Neurobiological mechanisms involved in the antidepressant and psychotomimetic effects of NMDA receptor antagonists: role of the GluN2C subunit |
| title_fullStr |
Neurobiological mechanisms involved in the antidepressant and psychotomimetic effects of NMDA receptor antagonists: role of the GluN2C subunit |
| title_full_unstemmed |
Neurobiological mechanisms involved in the antidepressant and psychotomimetic effects of NMDA receptor antagonists: role of the GluN2C subunit |
| title_sort |
Neurobiological mechanisms involved in the antidepressant and psychotomimetic effects of NMDA receptor antagonists: role of the GluN2C subunit |
| dc.creator.none.fl_str_mv |
Tarrés Gatius, Mireia |
| author |
Tarrés Gatius, Mireia |
| author_facet |
Tarrés Gatius, Mireia |
| author_role |
author |
| dc.contributor.none.fl_str_mv |
Castañé, Anna Artigas Pérez, Francesc Universitat de Barcelona. Facultat de Medicina i Ciències de la Salut |
| dc.subject.none.fl_str_mv |
Neurofarmacologia Esquizofrènia Depressió psíquica Ciències de la salut Neuropharmacology Schizophrenia Mental depression Medical sciences |
| topic |
Neurofarmacologia Esquizofrènia Depressió psíquica Ciències de la salut Neuropharmacology Schizophrenia Mental depression Medical sciences |
| description |
[eng] Sub-anesthetic doses of ketamine evoke rapid and persistent antidepressant effects in treatment-resistant depressed patients through still poorly-known mechanisms. Ketamine also evokes transient psychotomimetic effects, shared by other non-competitive NMDA-R antagonists such as phencyclidine (PCP) and dizocilpine (MK-801), which are used as pharmacological models of schizophrenia. Previous studies indicate that PCP activates thalamo- cortical circuits after the blockade of NMDA-R in GABAergic neurons of the reticular nucleus (RtN). Given that one of the sites of action of non-competitive NMDA-R antagonists is the RtN and that the GluN2C subunit is expressed in this nucleus, our working hypothesis was that the psychotomimetic and the antidepressant-like effects induced by non-competitive NMDA-R antagonists would be partly attenuated in absence of the GluN2C subunit. All three NMDA-R antagonists induced psychotomimetic effects in both genotypes. While locomotor activity was increased in GluN2CKO mice, stereotyped behaviors like circling and ataxia signs (falls, hindlimb abduction) were dramatically attenuated, suggesting a better motor coordination in absence of the GluN2C subunit. In agreement, GluN2CKO mice spent more time on the rotarod compared to WT mice after PCP or MK-801 administration. However, there were no genotype differences in the PPI test, showing that the GluN2C subunit is not involved in sensory gating. Moreover, PCP and MK-801 evoked a general pattern of c-fos activation, except in cerebellum, where significant reductions and genotype differences were noted. Ketamine reduced the immobility time in male and female WT and GluN2CKO mice in tests used for the screening of antidepressants, showing that the GluN2C subunit does not contribute to the antidepressant-like effects induced by ketamine in both sexes. This acute antidepressant-like effect might be mediated by a transient increase of serotonin, but not glutamate, in the medial prefrontal cortex. Moreover, ketamine increased c-fos expression in the thalamus of female but not male mice, while reductions were only present in the cerebellum of male mice, suggesting sex-differentiated effects of ketamine. Regarding NMDA-R subunits distribution, deletion of the GluN2C subunit led to minor changes in the expression of GluN2A, GluN2B or GluN2D subunits, suggesting that it was not systematically replaced by any other GluN2 subunits. However, it produced remarkable changes in the expression of the GluN1 subunit in cerebellar and thalamic areas, which may contribute to the behavioral and molecular differences between both genotypes. In conclusion, the GluN2C subunit appears to be strongly involved in motor components of the behavioral syndrome induced by non-competitive NMDA-R antagonists, while the antidepressant-like effects of ketamine are preserved. Its genetic deletion results in an improved motor coordination after NMDA-R blockade. This supports the presence of GluN2C‐containing NMDA‐R in cerebellar circuits controlling motor activity and equilibrium, which are sensitive to the action of ketamine, PCP, and MK-801. Overall, the present study supports the involvement of cerebellar GluN2C subunits as a key element in the psychotomimetic actions of non- competitive NMDA-R antagonists. The differential role of the GluN2C subunit in mediating the psychotomimetic and antidepressant effects of ketamine identifies this subunit as a potential target for preventing the emergence of pro-psychotic effects while keeping a full antidepressant action. |
| publishDate |
2019 |
| dc.date.none.fl_str_mv |
2019 |
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info:eu-repo/semantics/doctoralThesis info:eu-repo/semantics/publishedVersion |
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doctoralThesis |
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publishedVersion |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/2445/171725 http://hdl.handle.net/10803/669917 |
| url |
https://hdl.handle.net/2445/171725 http://hdl.handle.net/10803/669917 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.rights.none.fl_str_mv |
cc-by-nc-nd, (c) Tarrés, 2019 http://creativecommons.org/licenses/by-nc-nd/3.0/ info:eu-repo/semantics/openAccess |
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cc-by-nc-nd, (c) Tarrés, 2019 http://creativecommons.org/licenses/by-nc-nd/3.0/ |
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openAccess |
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application/pdf |
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Universitat de Barcelona |
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Universitat de Barcelona |
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Tesis Doctorals - Facultat - Medicina i Ciències de la Salut reponame:Dipòsit Digital de la UB instname:Universidad de Barcelona |
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Universidad de Barcelona |
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Dipòsit Digital de la UB |
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Dipòsit Digital de la UB |
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1869418001266114560 |
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Neurobiological mechanisms involved in the antidepressant and psychotomimetic effects of NMDA receptor antagonists: role of the GluN2C subunitTarrés Gatius, MireiaNeurofarmacologiaEsquizofrèniaDepressió psíquicaCiències de la salutNeuropharmacologySchizophreniaMental depressionMedical sciences[eng] Sub-anesthetic doses of ketamine evoke rapid and persistent antidepressant effects in treatment-resistant depressed patients through still poorly-known mechanisms. Ketamine also evokes transient psychotomimetic effects, shared by other non-competitive NMDA-R antagonists such as phencyclidine (PCP) and dizocilpine (MK-801), which are used as pharmacological models of schizophrenia. Previous studies indicate that PCP activates thalamo- cortical circuits after the blockade of NMDA-R in GABAergic neurons of the reticular nucleus (RtN). Given that one of the sites of action of non-competitive NMDA-R antagonists is the RtN and that the GluN2C subunit is expressed in this nucleus, our working hypothesis was that the psychotomimetic and the antidepressant-like effects induced by non-competitive NMDA-R antagonists would be partly attenuated in absence of the GluN2C subunit. All three NMDA-R antagonists induced psychotomimetic effects in both genotypes. While locomotor activity was increased in GluN2CKO mice, stereotyped behaviors like circling and ataxia signs (falls, hindlimb abduction) were dramatically attenuated, suggesting a better motor coordination in absence of the GluN2C subunit. In agreement, GluN2CKO mice spent more time on the rotarod compared to WT mice after PCP or MK-801 administration. However, there were no genotype differences in the PPI test, showing that the GluN2C subunit is not involved in sensory gating. Moreover, PCP and MK-801 evoked a general pattern of c-fos activation, except in cerebellum, where significant reductions and genotype differences were noted. Ketamine reduced the immobility time in male and female WT and GluN2CKO mice in tests used for the screening of antidepressants, showing that the GluN2C subunit does not contribute to the antidepressant-like effects induced by ketamine in both sexes. This acute antidepressant-like effect might be mediated by a transient increase of serotonin, but not glutamate, in the medial prefrontal cortex. Moreover, ketamine increased c-fos expression in the thalamus of female but not male mice, while reductions were only present in the cerebellum of male mice, suggesting sex-differentiated effects of ketamine. Regarding NMDA-R subunits distribution, deletion of the GluN2C subunit led to minor changes in the expression of GluN2A, GluN2B or GluN2D subunits, suggesting that it was not systematically replaced by any other GluN2 subunits. However, it produced remarkable changes in the expression of the GluN1 subunit in cerebellar and thalamic areas, which may contribute to the behavioral and molecular differences between both genotypes. In conclusion, the GluN2C subunit appears to be strongly involved in motor components of the behavioral syndrome induced by non-competitive NMDA-R antagonists, while the antidepressant-like effects of ketamine are preserved. Its genetic deletion results in an improved motor coordination after NMDA-R blockade. This supports the presence of GluN2C‐containing NMDA‐R in cerebellar circuits controlling motor activity and equilibrium, which are sensitive to the action of ketamine, PCP, and MK-801. Overall, the present study supports the involvement of cerebellar GluN2C subunits as a key element in the psychotomimetic actions of non- competitive NMDA-R antagonists. The differential role of the GluN2C subunit in mediating the psychotomimetic and antidepressant effects of ketamine identifies this subunit as a potential target for preventing the emergence of pro-psychotic effects while keeping a full antidepressant action.[spa] La ketamina, la fenciclidina (PCP) y la dizocilpina (MK-801) son antagonistas no competitivos del receptor NMDA y se utilizan como modelos farmacológicos de esquizofrenia ya que su administración evoca unos síntomas parecidos a los de un estado psicótico. Además, la ketamina también ejerce un efecto antidepresivo rápido y sostenido en el tiempo en pacientes depresivos resistentes a los tratamientos convencionales. Estudios previos han demostrado que PCP actuaría preferencialmente sobre neuronas GABAérgicas del núcleo reticular del tálamo, bloqueando su efecto inhibidor y, en consecuencia, activando circuitos tálamo-corticales. Dado que la subunidad GluN2C del NMDA-R se expresa en dicho núcleo talámico, en esta tesis hemos estudiado la posible implicación de la subunidad GluN2C en los efectos psicotomiméticos y antidepresivos inducidos por los antagonistas no competitivos del NMDA-R, bajo la hipótesis de trabajo de que estos efectos serían menores en ausencia de dicha subunidad. El tratamiento agudo con MK-801, PCP y ketamina indujo efectos psicotomiméticos en ratones WT y GluN2CKO. No obstante, la intensidad de las rotaciones (movimiento estereotipado), el número de caídas y el arrastrado de patas traseras (signos de ataxia) fueron significativamente menores en los ratones GluN2CKO, sugiriendo una mejor coordinación motora en ausencia de la subunidad GluN2C. De acuerdo con estos resultados, en los ratones GluN2CKO observamos un mayor tiempo de permanencia en el rotarod en comparación con los ratones WT tras la administración aguda de MK-801 o PCP. Sin embargo, no encontramos diferencias de genotipo en el test de la inhibición pre-pulso, sugiriendo que la subunidad GluN2C no estaría relacionada con la regulación sensoriomotora. La administración de MK-801 y PCP provocó un aumento generalizado de la expresión del gen c-fos en el cerebro de los ratones WT y GluN2CKO, excepto en el cerebelo, dónde se observaron reducciones y diferencias de genotipo en su expresión. Respecto a los efectos antidepresivos, ketamina redujo el tiempo de inmovilidad en machos y hembras WT y GluN2CKO, sugiriendo que la subunidad GluN2C no está involucrada en la acción antidepresiva de ketamina. Además, ketamina aumentó la liberación de serotonina en la corteza prefrontal en ambos géneros, sugiriendo que el efecto antidepresivo podría estar relacionado con este neurotransmisor. En comparación con MK-801 y PCP, el patrón de expresión de c-fos después de la administración de ketamina no fue tan intenso y se observaron diferencias de género. En conclusión, este trabajo demuestra que existe una disociación en cuanto a la participación de la subunidad GluN2C en los efectos motores y el efecto antidepresivo inducidos por antagonistas no competitivos del NMDA-R. Debido a que la subunidad GluN2C se encuentra altamente expresada en el cerebelo y que ésta es un área involucrada en coordinación motora, los NMDA-R de cerebelo podrían jugar un papel importante en el mecanismo de acción de MK-801, PCP y ketamina.Universitat de BarcelonaCastañé, AnnaArtigas Pérez, FrancescUniversitat de Barcelona. Facultat de Medicina i Ciències de la Salut2019info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/171725http://hdl.handle.net/10803/669917Tesis Doctorals - Facultat - Medicina i Ciències de la Salutreponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaIngléscc-by-nc-nd, (c) Tarrés, 2019http://creativecommons.org/licenses/by-nc-nd/3.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1717252026-05-27T06:46:51Z |
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15.301603 |