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 (...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2019 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/171725 |
| Acceso en línea: | https://hdl.handle.net/2445/171725 http://hdl.handle.net/10803/669917 |
| Access Level: | acceso abierto |
| Palabra clave: | Neurofarmacologia Esquizofrènia Depressió psíquica Ciències de la salut Neuropharmacology Schizophrenia Mental depression Medical sciences |
| Sumario: | [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. |
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