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Conselho Nacional de Desenvolvimento Científico e Tecnológico / Arcaine is a competitive antagonist of the polyamine binding site at the NMDA receptor which induces state-dependent recall. However, no study has addressed the involvement of other neurotransmitter/neuromodulators in arcaine-induced state dependency. The current study investigates whether the opioid system is involved in arcaine-induced state-dependent memory retrieval of the inhibitory avoidance task (IA) in rats. The systemic administration of arcaine (30 mg/kg, i.p.) or morphine (5 mg/kg, i.p.) zero, 3, 6 or 9 hours posttraining, reduced step-down latencies at testing. Arcaine (30 mg/kg, i.p.) or morphine (5 mg/kg, i.p.) injection 30 min before testing reversed the performance deficit induced by administration of arcaine or morphine zero, 3 or 6, but not 9 hours post-training. The reversal of arcaine-induced impairment of IA performance was completely transferred to morphine, and vice-versa. The association of low and ineffective doses of morphine and arcaine (10 and 1.5 mg/kg, respectively) were additive and caused state-dependency. Naloxone (2 mg/kg, 3 min post-training, or 1 mg/kg, 1 hour pre-test, i.p.), reversed the amnesia and the state dependency induced by morphine and arcaine. These results suggest that state dependency induced by arcaine involves the opioid system. / A arcaína é um antagonista do sítio de ligação das poliaminas no receptor NMDA, a qual induz dependência de estado. No entanto, nenhum estudo abordou o envolvimento de outros neurotransmissores/neuromoduladores na dependência de estado induzida pela arcaína. No presente estudo, investigamos se o sistema opióide está envolvido na dependência de estado induzida pela arcaína na tarefa de esquiva inibitória (IA) em ratos. A administração sistêmica de arcaína (30 mg/kg, i.p) ou morfina (5 mg/kg, i.p) zero, 3, 6 ou 9 horas pós-treino, reduziu a latência de descida da plataforma no dia do teste. A injeção de arcaína (30 mg/kg, i.p) ou morfina (5 mg/kg, i.p) 30 minutos antes do teste, reverteu o déficit de desempenho induzido pela administração de arcaína ou morfina zero, 3 ou 6, mas não 9 horas pós-treino. A reversão da piora da memória induzida pela arcaína foi totalmente transferida para a morfina, e vice-versa. A associação de baixas doses de arcaína e morfina (10 e 1,5 mg/kg, respectivamente), que individualmente não pioraram a memória, induziram dependência de estado. A naloxona (2 mg/kg, 3 min pós-treino, ou 1 mg/kg uma hora pré-teste, i.p), reverteu a amnésia e a dependência de estado induzida pela arcaína e morfina. Esses resultados sugerem que a dependência de estado induzida pela arcaína envolve o sistema opióide.

Le but de cette thèse était la recherche de biomarqueurs des troubles de l'humeur (dépression unipolaire et troubles bipolaires). Compte tenu de l'étiologie de ces troubles (hypométabolisme du cortex préfrontal dorso-latéral et déficit de la neurotransmission GABA/glutamatergique), nous avons choisi d'étudier deux biomarqueurs : la performance saccadique et l'excitabilité corticale. Nos résultats montrent que les performances saccadiques (antisaccades) permettent (i) de discriminer les patients présentant des troubles de l'humeur de sujets sains, (ii) d'objectiver l'amélioration thymique des patients suite à un traitement, et (iii) d'évaluer l'effet neuromodulateur à court-terme d'une séance de stimulation magnétique transcrânienne répétée. Concernant les mesures d'excitabilité corticale, aucune différence liée à l'amélioration thymique des patients, ni de différences entre patients et contrôles ne ressortent significativement. Nous avons suggéré que le non-contrôle du « State-Dependency » (i.e., de l'« état neurocognitif » des sujets pendant les stimulations) puisse être l'une des causes de l'absence de résultats, et validé cette hypothèse en manipulant les registres cognitifs et émotionnels des sujets.Le second aspect de notre travail de thèse avait trait à l'étude de l'efficacité de la stimulation magnétique transcrânienne répétée (rTMS) comme alternative thérapeutique non médicamenteuse des troubles de l'humeur. Si la littérature s'accorde sur une efficacité significative mais modérée de la rTMS comme traitement, nos données n'ont pas mis en évidence de supériorité du traitement actif par rapport au traitement placebo dans le cas de la neurostimulation iTBS. Une des raisons de ce manque d'efficacité du traitement actif pourrait être liée à des questions d'ordre méthodologique, comme le choix des paramètres de stimulation. Plus généralement, cette absence de résultats incite à questionner le postulat théorique basant l'étude de la réactivité du CPFDL ou sa neuromodulation sur les propriétés du cortex moteur. Notre expérience, étudiant la réactivité de différentes zones corticales par couplage TMS-EEG, va dans ce sens en montrant que la réactivité du cortex moteur diffère de celle des autres cortex. Le couplage TMS-EEG devrait permettre de mieux comprendre l'impact de la neuromodulation rTMS sur la cible corticale visée, et donc d'adapter les paramètres de stimulations aux aires cérébrales stimulées, permettant à terme de traiter plus efficacement les troubles de l'humeur. / The aim of this doctoral thesis was to develop biomarkers for mood disorders (unipolar major depression and bipolar disorders). Considering mood disorders' etiology (Dorso lateral prefrontal cortex hypometabolism and GABA/glutamate neurotransmission deficits), we decided to study two biomarkers: saccadic performance and cortical excitability. Our results showed that saccadic performance (notably Antisaccades) allows (i) discriminating bipolar patients from healthy subjects, (ii) ascertaining patients' mood improvement, and (iii) evaluating the short-term neuromodulation induced by repetitive transcranial magnetic stimulation.Regarding cortical excitability measurements, our results did not reveal any differences neither between patients and healthy subjects, nor between Responders and non Responders to a treatment (Ketamine injection or rTMS). We suggested that the null results could be explained by the lack of control of State-Dependency. This assumption was tested and validated through the manipulation of the subjects' cognitive and emotional states.A second aim of this doctoral thesis was to study the efficacy of rTMS, a non pharmacological therapeutic alternative, as a treatment for mood disorders. Meta-analyses showed that anti depressant effect of rTMS seems to be significant but still moderate. In our experiment, mood improvement did not differ between active and sham rTMS. Basic methodological reasons such as stimulation parameters could explain this lack of efficacy. Overall, one could wonder about the validity of the theoretical postulate of rTMS, drawn upon motor cortex reactivity. This postulate inferred that both cortical reactivity of motor cortex and DLPFC are similar. Using TMS-EEG coupling, we studied the reactivity of these cortices, to TMS pulses, which revealed that motor cortex and DLPFC reactivities should not be assimilated. This result calls into question the relevance of the rTMS theoretical postulate. Coupling TMS and EEG should allow a better understanding of the impact of rTMS neuromodulatory effect over the targeted area, and thus to a better adaption of the stimulation parameters, which could lead to an improvement of rTMS efficacy as a treatment for mood disorders.

No / To investigate the underlying nature of the effects of transcranial magnetic stimulation (TMS) on speed perception, we applied repetitive TMS (rTMS) to human V5/MT+ following adaptation to either fast- (20 deg/s) or slow (4 deg/s)-moving grating stimuli. The adapting stimuli induced changes in the perceived speed of a standard reference stimulus moving at 10 deg/s. In the absence of rTMS, adaptation to the slower stimulus led to an increase in perceived speed of the reference, whilst adaptation to the faster stimulus produced a reduction in perceived speed. These induced changes in speed perception can be modelled by a ratio-taking operation of the outputs of two temporally tuned mechanisms that decay exponentially over time. When rTMS was applied to V5/MT+ following adaptation, the perceived speed of the reference stimulus was reduced, irrespective of whether adaptation had been to the faster- or slower-moving stimulus. The fact that rTMS after adaptation always reduces perceived speed, independent of which temporal mechanism has undergone adaptation, suggests that rTMS does not selectively facilitate activity of adapted neurons but instead leads to suppression of neural function. The results highlight the fact that potentially different effects are generated by TMS on adapted neuronal populations depending upon whether or not they are responding to visual stimuli. / BBSRC