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Une des difficultés mentionnées par les étudiants dyslexiques est la production de textes (Mazur-Palandre, Abadie et Bedoin, 2016). Chez les sujets neurotypiques, les processus orthographiques s’automatisent progressivement avec l’expérience (Berninger et Swanson, 1994), ce qui permettrait – si on se place dans le cadre de la théorie de la capacité pour la production écrite (McCutchen, 1996) - d'affecter davantage de ressources à des processus de niveau supérieur, tels que la révision. Chez les individus dyslexiques, les processus orthographiques sont peu automatisés, et ce même à l’âge adulte ce qui peut donc impacter la production textuelle (Fayol et Miret, 2005). Cette étude vise à analyser les productions écrites d’étudiants dyslexiques et contrôles afin de voir de quelle manière la révision diffère entre les deux groupes d’étudiants. Les étudiants ont été invités à produire des textes écrits, collectés par le biais d’une tablette graphique et du logiciel Eye and Pen©, permettant d'observer la temporalité de l’activité d’écriture, dont les révisions. Les résultats indiquent que les étudiants dyslexiques et contrôles ne diffèrent guère quant à la quantité et les types de révision, ce qui suggère que les étudiants dyslexiques ont mis en place des stratégies. Néanmoins, des analyses complémentaires nuancent les résultats en montrant des différences entre les deux groupes.

Dans le contexte éducatif, l’écriture fait l’objet d’un apprentissage long et formel et les aptitudes en production écrite sont déterminantes pour la réussite académique et professionnelle. La littéracie linguistique (Ravid et Tolchinsky, 2002) réfère au fait que les individus, avec les années de scolarisation, développent leurs connaissances sur la langue écrite et orale (Berman, 1999, 2006 ; Ravid et Tolchinsky, 2002 ; Tolchinsky, 2006). Être linguistiquement mature suppose la maîtrise d’un répertoire linguistique, qui englobe un large éventail de registres et de genres, ainsi que la capacité de s’adapter aux contextes communicationnels (Berman, 2006 ; Berman et Ravid, 2009 ; Ravid et Tolchinsky, 2002 ; Tolchinsky, 2006). Cette littéracie est liée à la flexibilité et à l’adaptabilité rhétorique : les locuteurs/scripteurs ont besoin de capter et de conserver l’attention des destinataires en utilisant des structures linguistiques adaptées (Ravid et Tolchinsky, 2002). Notre travail se propose d’examiner l’impact de la prise en compte de la situation de communication et en particulier du destinataire du message dans le développement linguistique de l’enfant. En effet, nous observons l’adaptabilité des participants de notre étude aux différents contextes de production (narratif écrit, narratif oral, expositif écrit, expositif oral) imposés par le protocole de collecte de données. Dans le présent travail, nous considérons à la fois des textes narratifs et des textes expositifs produits par des enfants (10-11 ans), des adolescents (12-13 ans) et des adultes (BAC+5). Les groupes d’enfants et d’adolescents sont divisés en deux : la moitié représentant des participants issus de milieux favorisés, l’autre moitié des participants de milieux défavorisés. Nous examinons la connectivité syntaxique et en particulier l’articulation entre les propositions en fonction du type de texte, de la modalité et de l’âge et du milieu. Au vu des analyses antérieures et du modèle de la litéracie linguistique de Ravid et Tolchinsky (2002), nous faisons les hypothèses suivantes : (1) le traitement de la connectivité syntaxique diffère selon l’âge des individus; (2) nos populations s’adaptent aux contextes communicationnels et (3) le milieu n’exerce pas d’influence forte sur les choix syntaxiques et plus précisément sur la connectivité syntaxique mais on pourrait attendre une tendance à un maintien à l’écrit des caractéristiques de l’oral.

Les recherches translinguistiques sur le développement du lexique chez l’enfant dégagent des similitudes dans la trajectoire et la composition du vocabulaire durant la deuxième année de vie de l’enfant. Un des faits observés chez la plupart des enfants est une plus grande utilisation des noms (biais nominal) par rapport aux autres catégories lexicales. Ce phénomène de biais nominal a reçu des explications de nature conceptuelle, linguistique ou contextuelle. Mais, rares sont les travaux à avoir envisagé les explications de manière simultanée sur les mêmes sujets. Par ailleurs, ces études se sont concentrées presque exclusivement sur des langues indo-européennes ou asiatiques limitant par la même la généralisation des résultats. Nos travaux tendent à vérifier les explications linguistiques et contextuelles en examinant les caractéristiques du discours adressé à l’enfant dans deux situations de communication (lecture d’album et jeu avec maison de poupée) et deux langues (français et turc). Dans ce travail, nous cherchons à expliquer la répartition lexicale chez les enfants français et turcs au début du développement. Nous nous intéressons en particulier à la distribution et à la position des verbes et des noms dans l’input maternel. Ces caractéristiques changent-elles ou restent-elles les mêmes en fonction de la situation ? Ces caractéristiques sont-elles les mêmes ou sont-elles différentes d’une langue à l’autre ?

À l’entrée de l’école primaire l’enfant peut être considéré comme un locuteur « natif » c’est-à-dire qu’il est tout à fait capable de produire un très grand éventail de phrases grammaticales dans sa langue maternelle. Cependant, pour devenir un locuteur « performant », il est nécessaire que l’enfant apprenne à adapter l’usage de sa langue à une grande variété de contextes communicatifs. Nous proposons que la langue écrite joue un rôle important dans le passage du locuteur natif au locuteur performant (Berman, 2006). Basé sur les données provenant des deux projets de recherche menée auprès des enfants âgés de 10, 12, 15, 16 ans et des adultes (BAC +5) nous allons présenter trois études. La première concerne des constructions passives et des constructions alternatives, en particulier le pronom on. Ces deux constructions peuvent se trouver en compétition pour remplir la même fonction : destituer l’agent d’une activité. La seconde examine des syntagmes nominaux lexicaux, en particulier les syntagmes nominaux en position de sujet. Nous verrons qu’avec le développement les sujets de phrases deviennent plus « lourds », c’est-à-dire qu’ils contiennent plus d’items lexicaux et de constructions diverses. Finalement la troisième étude présentera une analyse des données chronométriques (des pauses) observées lors de la rédaction des textes par les enfants et les adolescents. Le but est de montrer que les données chronométriques fournissent des indices intéressants pour comprendre comment la planification évolue avec le développement.

The goal of this paper is to observe revision during handwritten text production of French students with and without dyslexia. Subjects with typical language development automate spelling during childhood and adolescence, progressively with experience, this enables them-according to capacity theory applied to written text production (McCutchen, Educational Psychology Review, 8, 1996, 299)-to allocate more cognitive resources to higher-level processes (Bereiter & Scardamalia, The psychology of written composition. Hillsdale: Lawrence Erlbaum, 1987). A lack of automation in spelling could result in poor compositional performance (Fayol & Miret, Psychologie Française, 50, 2005, 391). Moreover, Morken and Helland (Dyslexia, 19, 2013, 131) have shown that young children with dyslexia, engaged in a sentence dictation task, revise their text as much as control children, however their revisions are of lower quality. If students with dyslexia have not totally automated spelling (Mazur-Palandre, Développements (Revue Interdisciplinaire du développement Cognitif Normal et Pathologique), 18, 2016, 177), what is the impact on higher-level processes, such as revision? Our goal is to examine if students with dyslexia and control students proofread their texts in the same way. Results show that they display some similarity but students with dyslexia seem to have a deficit in the error detection mechanism (Horowitz & Breznitz, International Journal of Disability, Development and Education, 58, 2011, 33) and revisions are less efficient. We discuss these results by considering previous studies we conducted on spelling, speech and neuropsychological assessments of our dyslexic participants., (© 2023 The Authors. Dyslexia published by John Wiley & Sons Ltd.)

Background: Olfactory bulbectomized rats generally manifest many of the neurochemical, physiological, and behavioral features of major depressive disorder in humans. Another interesting feature of this model is that it responds to chronic but not acute antidepressant treatments, including selective serotonin reuptake inhibitors. The purpose of the present study was first to characterize the firing activity of dorsal raphe serotonin neurons in olfactory bulbectomized rats and then examine the effects of 2 antidepressants, bupropion and paroxetine., Methods: Olfactory bulbectomy was performed by aspirating olfactory bulbs in anesthetized rats. Vehicle and drugs were delivered for 2 and 14 days via subcutaneously implanted minipumps. In vivo electrophysiological recordings were carried out in male anesthetized Sprague-Dawley rats., Results: Following ablation of olfactory bulbs, the firing rate of serotonin neurons was decreased by 36%, leaving those of norepinephrine and dopamine neurons unchanged. In olfactory bulbectomized rats, bupropion (30 mg/kg/d) restored the firing rate of serotonin neurons to the control level following 2- and 14-day administration and also induced an increase in the tonic activation of serotonin(1A) receptors; paroxetine (10 mg/kg/d) did not result in a return to normal of the attenuated firing of serotonin neurons in olfactory bulbectomized rats. In the hippocampus, although at a higher dose of WAY 100635 than that required in bupropion-treated animals, paroxetine administration also resulted in an increase in the tonic activation of serotonin(1A) receptors., Conclusions: The present results indicate that unlike paroxetine, bupropion administration normalized serotonin neuronal activity and increased tonic activation of the serotonin(1A) receptors in hippocampus., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)

Writing words in real life involves setting objectives, imagining a recipient, translating ideas into linguistic forms, managing grapho-motor gestures, etc. Understanding writing requires observation of the processes as they occur in real time. Analysis of pauses is one of the preferred methods for accessing the dynamics of writing and is based on the idea that pauses are behavioral correlates of cognitive processes. However, there is a need to clarify what we are observing when studying pause phenomena, as we will argue in the first section. This taken into account, the study of pause phenomena can be considered following two approaches. A first approach, driven by temporality, would define a threshold and observe where pauses, e.g., scriptural inactivity occurs. A second approach, linguistically driven, would define structural units and look for scriptural inactivity at the boundaries of these units or within these units. Taking a temporally driven approach, we present two methods which aim at the automatic identification of scriptural inactivity which is most likely not attributable to grapho-motor management in texts written by children and adolescents using digitizing tablets in association with Eye and Pen (©) (Chesnet and Alamargot, 2005). The first method is purely statistical and is based on the idea that the distribution of pauses exhibits different Gaussian components each of them corresponding to a different type of pause. After having reviewed the limits of this statistical method, we present a second method based on writing dynamics which attempts to identify breaking points in the writing dynamics rather than relying only on pause duration. This second method needs to be refined to overcome the fact that calculation is impossible when there is insufficient data which is often the case when working with young scriptors.

Melatonin has been widely used for the management of insomnia, but is devoid of antidepressant effect in the clinic. In contrast, agomelatine which is a potent melatonin receptor agonist is an effective antidepressant. It is, however, a potent serotonin 2B (5-HT(2B)) and serotonin 2C (5-HT(2C)) receptor antagonist as well. The present study was aimed at investigating the in vivo effects of repeated administration of melatonin (40 mg/kg/day), the 5-HT(2C) receptor antagonist SB 242084 (0.5 mg/kg/day), the selective 5-HT(2B) receptor antagonist LY 266097 (0.6 mg/kg/day) and their combination on ventral tegmental area (VTA) dopamine (DA), locus coeruleus (LC) norepinephrine (NE), and dorsal raphe nucleus (DRN) serotonin (5-HT) firing activity. Administration of melatonin twice daily increased the number of spontaneously active DA neurons but left the firing of NE neurons unaltered. Long-term administration of melatonin and SB 242084, by themselves, had no effect on the firing rate and burst parameters of 5-HT and DA neurons. Their combination, however, enhanced only the number of spontaneously active DA neurons, while leaving the firing of 5-HT neurons unchanged. The addition of LY 266097, which by itself is devoid of effect, to the previous regimen increased for DA neurons the number of bursts per minute and the percentage of spikes occurring in bursts. In conclusion, the combination of melatonin receptor activation as well as 5-HT(2C) receptor blockade resulted in a disinhibition of DA neurons. When 5-HT(2B) receptors were also blocked, the firing and the bursting activity of DA neurons were both enhanced, thus reproducing the effect of agomelatine.

Agomelatine is a melatonergic MT1/MT2 agonist and a serotonin (5-HT) 5-HT(2C) antagonist. The effects of 2-day and 14-day administration of agomelatine were investigated on the activity of ventral tegmental area (VTA) dopamine (DA), locus coeruleus (LC) norepinephrine (NE), and dorsal raphe nucleus (DRN) 5-HT neurons using in vivo electrophysiology in rats. The 5-HT(1A) transmission was assessed at hippocampus CA3 pyramidal neurons. After a 2-day regimen of agomelatine (40 mg/kg/day, i.p.), an increase in the number of spontaneously active VTA-DA neurons (p<0.001) and in the firing rate of LC-NE neurons (p<0.001) was observed. After 14 days, the administration of agomelatine induced an increase in: (1) the number of spontaneously active DA neurons (p<0.05), (2) the bursting activity of DA neurons (bursts/min, p<0.01 and percentage of spikes occurring in bursts, p<0.05), (3) the firing rate of DRN-5-HT neurons (p<0.05), and (4) the tonic activation of postsynaptic 5-HT(1A) receptors located in the hippocampus. The increase in 5-HT firing rate was D2 dependent, as it was antagonized by the D2 receptor antagonist paliperidone. The enhancement of NE firing was restored by the 5-HT(2A) receptor antagonist MDL-100,907 after the 14-day regimen. All the effects of agomelatine were antagonized by a single administration of the melatonergic antagonist S22153 (except for the increase in the percentage of spikes occurring in burst for DA neurons). The present results suggest that (1) agomelatine exerts direct (2 days) and indirect (14 days) modulations of monoaminergic neuronal activity and (2) the melatonergic agonistic activity of agomelatine contributes to the enhancement of DA and 5-HT neurotransmission.

Triple reuptake inhibitors represent a potential new class of antidepressant drugs that block norepinephrine (NE), dopamine (DA) and serotonin [5-hydroxytryptamine (5-HT)] transporters. The present in-vivo electrophysiological study was undertaken to determine the effects of the triple reuptake inhibitors SEP-225289 and DOV216303 on the neuronal activities of locus coeruleus (LC) NE, ventral tegmental area (VTA) DA and dorsal raphe (DR) 5-HT neurons. Administered acutely, SEP-225289 and DOV216303 dose-dependently decreased the spontaneous firing rate of LC NE, VTA DA and DR 5-HT neurons through the activation of α₂, D₂ and 5-HT(₁A) autoreceptors, respectively. Both compounds predominantly inhibited the firing rate of LC NE neurons while producing only a partial decrease in VTA DA and DR 5-HT neuronal discharge. SEP-225289 was equipotent at inhibiting 5-HT and NE transporters since it prolonged to the same extent the time required for a 50% recovery (RT₅₀) of the firing activity of dorsal hippocampus CA3 pyramidal neurons from the inhibition induced by microiontophoretic application of 5-HT and NE. Finally, in the presence of WAY100635, a 5-HT(₁A) receptor antagonist, SEP-225289 activated 5-HT neurons at doses that normally did not inhibit them. Taken together, the present results indicate that reciprocal interactions among NE, DA and 5-HT inputs need to be considered to anticipate the net effect of triple reuptake inhibitors on the enhancement of brain monoamine transmission. The results also suggest that the therapeutic action of triple reuptake inhibitors may be potentiated by antagonizing the cell body 5-HT(₁A) autoreceptors.

Unlabelled: Topiramate and phenytoin possess mood stabilizing properties. The mechanism of action of anticonvulsants used in the treatment of bipolar depression is complex and still not completely elucidated. Na(+) channels are present at distinct sites in neurons, where they sub serve different functions and play distinct roles. The fact that most of the anticonvulsants used in the treatment of bipolar disorders are blockers of voltage-gated Na channels has determined our interest in evaluating the role of ion channels in bipolar disorders., Objectives: The scope of this study was to determinate if sodium channels are important for topiramate and phenytoin to exert their antidepressant-like functioning., Methods: The role of Na(+) channels in the mechanism of action of the anticonvulsants was investigated by using veratrine a selective activator of Na channels in a mice model of depression, the forced swimming test. Veratrine 0.125 mg/kg and topiramate or phenytoin (16 and 32 mg/kg) were given IP 45 and 30 min, respectively, before the test., Results: The administration of topiramate and phenytoin induce a decrease in the immobility time on the FST which can be considered as an antidepressant-like activity. The antidepressant-like effect of the anticonvulsants was completely reversed by veratrine suggesting that the antidepressant-like effect of topiramate and phenytoin on the FST might be due to their Na(+) channels blocking properties.

Antidepressant drugs modify in different ways the activity of neurons, by increasing monoamines levels and by modulating ion channels. Sodium channels are molecular targets for antiepileptic drugs, which can also be mood stabilizers (i.e. lamotrigine, topiramate, phenytoin, carbamazepine, valproic acid). After a short overview on the sodium channels and the interaction with antidepressants and mood stabilizers, a comparison of the activity of both antidepressants and mood stabilizers with the addition of veratrine (sodium channel opener) on the forced swimming test (FST) in mice was presented. By comparing the antidepressant-like effect of the antidepressants (paroxetine, imipramine and desipramine) with the one of anticonvulsants (lamotrigine, phenytoin and topiramate) on the FST, it seems that the mechanism of action of anticonvulsants and antidepressants are different, because veratrine limits the activity of anticonvulsants but not of antidepressants. The anticonvulsants topiramate and phenytoin reduce the immobility time in the FST in a range of time similar to those induced by antidepressants, suggesting that the FST could be sensitive to both drugs. The magnitude of antidepressant-like effect of the lamotrigine (acting through an increase in monoaminergic neurotransmission and a blockade of sodium channels) in the FST is greater than what is obtained after administration of the other drugs, suggesting that this dual activity could be used as an augmentation strategy. Authors conclude that the development of new drugs acting on sodium channels could potentially be of interest as antidepressants, but also as augmentation strategies for classical antidepressants.

Rationale: A deficiency in brain monoamine systems (serotonin, dopamine, and/or norepinephrine) have long been hypothesized for the pathogenesis of depression. Drugs enhancing neurotransmission of those monoamines have been proven to have antidepressant effects. We hypothesized that aripiprazole, a partial D(2) agonist, could increase the activity of various antidepressants in the mice forced swimming test (FST), an animal model of depression., Objectives: The scope of this study was to investigate the antidepressant-like effect of aripiprazole, when combined with conventional antidepressants drugs., Materials and Methods: This study assessed the effects of co-administration of aripiprazole with selective serotonin reuptake inhibitors (SSRIs; sertraline, paroxetine, and citalopram), selective serotonin-norepinephrine reuptake inhibitors (SNRIs; venlafaxine and minalcipran), selective norepinephrine reuptake inhibitor (NRI; desipramine), and the dual dopamine and norepinephrine reuptake inhibitor (bupropion), using the FST in mice. Subactive doses of aripiprazole and antidepressants sertraline, paroxetine, citalopram, venlafaxine, minalcipran, bupropion (4 and 8 mg/kg), and desipramine (2 and 4 mg/kg) were given i.p. 30 and 45 min, respectively, before the test., Results: Aripiprazole (0.03 and 0.06 mg/kg) combined with inactive doses of antidepressants, increased the activity of all antidepressants with the exception of bupropion and desipramine., Conclusion: The augmentation effects of aripiprazole, in the present study, are in agreement with clinical evidence suggesting that aripiprazole may enhance the efficacy of therapeutic effect of SSRIs and SNRIs but not of NRI. These results suggest that augmentation effect of aripiprazole only appears when 5-HT system is activated and might implicate complex regulation between dopamine and 5-HT(1A) and 5-HT(2A) receptors.

Background: Generic drugs are lower-cost versions of patent-expired brand-name medications. Bioequivalence is decreed when the 90% confidence intervals for the ratios of the generic to the reference compound for the area under the curve and maximum plasma concentration (C(max)) fall within a 0.80 to 1.25 range. The aim of the present pilot study was to compare the pharmacokinetic profiles of brand-name and generic formulations of citalopram and extended-release venlafaxine., Method: Effexor XR/Novo-venlafaxine XR 75 mg and Celexa/Gen-citalopram 40 mg were studied in a randomized crossover design. Healthy male volunteers took either Effexor XR or Novo-venlafaxine XR for 4 days, a 4-day washout was allowed, and then participants took the other venlafaxine formulation for 4 days. This was followed by a washout of at least 7 days. The participants then took Celexa or Gen-citalopram for 8 days, a 14-day washout was allowed, and then participants took the other citalopram formulation for 8 days. In each of the study phases, the sequence of treatment (brand-name x generic) was randomly assigned. Plasma levels of drugs were measured at fixed intervals after participants took the drugs and at steady state. The study was conducted from November 2007 through July 2008., Results: Twelve participants completed the venlafaxine study. Nine of the participants, plus 3 new participants, were then enrolled in the citalopram study, to maintain a total of 12. The plasma levels of citalopram were similar after ingestion of the brand-name and generic drugs. After ingestion of venlafaxine, the C(max) values were 36 +/- 6 ng/mL and 52 +/- 8 ng/mL in the brand-name and generic groups, respectively. The ratio of the log-transformed values of C(max) was 150% and, therefore, not within the acceptable 80% to 125% range. The concentration of the active metabolite of venlafaxine (O-desmethyl-venlafaxine [ODV]) was also significantly increased in the generic group (+43% higher in the generic group at 3 h; +48% higher at 5 h; p < .05). No differences were seen at steady state for either ODV or venlafaxine. Participants taking Novo-venlafaxine reported 3 times more side effects than those taking Effexor XR. Pill contents were identical in the 2 groups, but extraction of venlafaxine occurred more readily with the generic formulation than with the brand-name formulation, which required an additional sonication., Conclusion: Gen-citalopram appeared to be bioequivalent to Celexa, whereas Novo-venlafaxine XR was not bioequivalent to Effexor XR. Consequently, the Novo-venlafaxine formulation released its active ingredient more rapidly and outside the acceptable norm., Trial Registration: clinicaltrials.gov Identifier: NCT00676039., (©Copyright 2009 Physicians Postgraduate Press, Inc.)

Monoamine oxidase inhibitors (MAOIs) exert their antidepressant action by increasing the function of the serotonin (5-HT), norepinephrine and dopamine (DA) systems. There is, however, limited electrophysiological data on the effects of MAOIs on DA neurons. The effects of 2-d and 21-d administration of three MAOIs were investigated (clorgyline, selective MAOI-A; deprenyl, selective MAOI-B; phenelzine, non-selective MAOI) on the firing activity of DA neurons in the ventral tegmental area using in-vivo electrophysiology in rats. Short-term clorgyline (1 mg/kg) and phenelzine (2.5 mg/kg) was devoid of effect on DA neurons, whereas prolonged administration significantly decreased their firing rate (by 30% and 20%, respectively), number of bursts (by 80% and 45%, respectively), and percentage of spikes occurring in bursts only in clorgyline-treated rats (70%). Deprenyl (0.25 mg/kg) was without effects. DA firing was restored in clorgyline-treated rats by inhibiting 5-HT synthesis using para-chlorophenylalanine (p-CPA; 300 mg/kg. d for three consecutive days). The 5-HT3 antagonist ondansetron (0.5 mg/kg) was devoid of effect in control rats, but completely reversed the alterations of DA neuronal activity in clorgyline-treated rats. An attenuation of DA neuronal activity was thus produced by prolonged blockade of MAOA activity. The absence of effect of MAOA inhibition after subacute administration suggested an indirect mechanism. This was confirmed by the observation that p-CPA antagonized the effects of clorgyline. Since ondansetron completely reversed the effects of clorgyline on DA neuronal activity, the effects of MAOA inhibition appeared to be mediated by 5-HT3 receptors.

Objective: We sought to demonstrate whether the specific activation of serotonin1B (5-HT1B) heteroreceptors by systemic or local administration of the selective 5-HT1B receptor agonist anpirtoline could mediate antidepressant-like effects in mice., Methods: We confirmed the selectivity of action of anpirtoline in the forced swim test (FST) in 5-HT1B knockout mice. We then evaluated the behavioural effects of anpirtoline on 5-HT-lesioned (5,7-dihydroxytryptamine creatinine [5,7-DHT]) and 5-HT-depleted (p-CPA) mice. We estimated the depletion level and selectivity of action of 5,7-DHT and p-CPA by measuring the neurotransmitter levels and [3H]-citalopram binding. We investigated the antidepressant-like effect of anpirtoline when locally perfused in an area of the brain where the response is mainly attributable to presynaptic (cortex and hippocampus) or postsynaptic receptors (substantia nigra and caudate putamen). Furthermore, we evaluated the effect of the 5-HT1B receptor antagonist GR127935 on the activity of various antidepressants in the FST., Results: Anpirtoline was devoid of effects in 5-HT1B receptor knockout mice. It induced a greater effect in p-CPA and 5,7-DHT pretreated mice compared with control subjects, suggesting that the antidepressant-like activity of anpirtoline mainly depends on 5-HT1B heteroreceptor stimulation (autoreceptors being destroyed by 5,7-DHT). This observation was confirmed by the results showing the antidepressant-like effect of anpirtoline when locally perfused in areas of the brain that contain postsynaptic receptors. The blockade of 5-HT1B receptors antagonizes the effect of selective serotonin reuptake inhibitors (SSRIs)., Conclusion: Our results demonstrate that the antidepressant-like effect of SSRIs in the FST requires the activation of 5-HT1B heteroreceptors.

Growing evidence supports the involvement of brain-derived neurotrophic factor (BDNF) in mood disorders and the mechanism of action of antidepressant drugs. However, the relationship between BDNF and serotonergic signalling is poorly understood. Heterozygous mutants BDNF +/- mice were utilized to investigate the influence of BDNF on the serotonin (5-HT) system and the activity of the serotonin transporter (SERT) in the hippocampus. The zero net flux method of quantitative microdialysis revealed that BDNF +/- heterozygous mice have increased basal extracellular 5-HT levels in the hippocampus and decreased 5-HT reuptake capacity. In keeping with these results, the selective serotonin reuptake inhibitor paroxetine failed to increase hippocampal extracellular 5-HT levels in BDNF +/- mice while it produced robust effects in wild-type littermates. Using in-vitro autoradiography and synaptosome techniques, we investigated the causes of attenuated 5-HT reuptake in BDNF +/- mice. A significant decrease in [3H]citalopram-binding-site density in the CA3 subregion of the ventral hippocampus and a significant reduction in [3H]5-HT uptake in hippocampal synaptosomes, revealed mainly a decrease in SERT function. However, 5-HT1A autoreceptors were not desensitized in BDNF +/- mice. These results provide evidence that constitutive reductions in BDNF modulate SERT function reuptake in the hippocampus.

Selective serotonin reuptake inhibitors like paroxetine (Prx) often requires 4-6 weeks to achieve clinical benefits in depressed patients. Pindolol shortens this delay and it has been suggested that this effect is mediated by somatodendritic 5-hydroxytryptamine (5-HT) 1A autoreceptors. However clinical data on the beneficial effects of pindolol are conflicting. To study the effects of (+/-)-pindolol-paroxetine administration, we used genetical and pharmacological approaches in 5-HT1A knockout mice (5-HT1A-/-). Two assays, in vivo intracerebral microdialysis in awake mice and the forced swimming test (FST), were used to assess the antidepressant-like effects of this drug combination. Basal levels of extracellular serotonin, 5-HT ([5-HT]ext) in the frontal cortex (FCX) and the dorsal raphe nucleus (DRN) did not differ between the two strains of mice, suggesting a lack of tonic control of 5-HT1A autoreceptors on nerve terminal 5-HT release. Prx (1 and 4 mg/kg) dose-dependently increased cortical [5-HT]ext in both genotypes, but the effects were greater in mutants. The selective 5-HT1A receptor antagonist, WAY-100635 (0.5 mg/kg), or (+/-)-pindolol (5 and 10 mg/kg) potentiated the effects of Prx (4 mg/kg) on cortical [5-HT]ext in 5-HT1A+/+, but not in 5-HT1A-/- mice. Similar responses were obtained following local intra-raphe perfusion by reverse microdialysis of either WAY-100635 or (+/-)-pindolol (100 microM each). In the FST, Prx administration dose-dependently decreased the immobility time in both strains of mice, but the response was much greater in 5HT1A-/- mice. In contrast, (+/-)-pindolol blocked Prx-induced decreases in the immobility time while WAY-100635 had no effect in both genotypes. These findings using 5-HT1A-/- mice confirm that (+/-)-pindolol behaves as an antagonist of 5-HT1A autoreceptor in mice, but its blockade of paroxetine-induced antidepressant-like effects in the FST may be due to its binding to other neurotransmitter receptors.

In the last decade, many augmentation strategies have been developed to increase the activity of antidepressant drugs or to reduce their long onset of action by acting on different targets. One of the first augmentation strategy used in psychiatric disorders is coadministration of lithium and antidepressant drugs. However, the underlaying mechanism of action involved in the potentiatory effect of lithium is still unclear and many hypotheses have been suggested such as activity on BDNF, ACTH, thyroid hormones and serotonin neurotransmission. All these systems being embedded in each other, we focused on the 5-HT neurotransmission-increase induced by lithium treatment. Based on neurobiochemical and behavioral results we tried to better understand its mechanism of action and we concluded that effect of lithium on 5-HT neurotransmission could be linked to a partial agonist activity on 5-HT1B autoreceptors, or to a modulatory activity on these receptors, located in the cortical area in the case of a short term treatment, or in the hippocampus in the case of a long term treatment. We also suggested that the anti-manic effect of lithium was linked to this activity on 5-HT1B receptors, occurring this time on 5-HT1B postsynaptic (heteroreceptors on dopaminergic pathways) receptors levels.

The aim of this work is to define neurotoxins doses to have efficient and specific depletion of noradrenaline (NA), serotonin (5-HT) neurotransmission in cortex, striatum, hippocampus and hypothalamus of Swiss mice after intraperitoneal administration of, respectively, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4) and para-chlorophenylalanine methyl ester hydrochloride (PCPA). The neurotransmitters concentrations were determined by high performance liquid chromatography with amperometric detection. The minimal single dose necessary to produce a highly significant decrease of NA levels (p<0.01 in comparison with control group) in hypothalamus (-44%), hippocampus (-91%), striatum (-40%) and cortex (-68%) was 50mg/kg but DA and 5-HT levels were modified, respectively, in hypothalamus and striatum. Three doses of PCPA 300 mg/kg over 3 consecutive days involve a profound depletion of 5-HT transmission in all discrete brain areas but NA and DA levels were also significantly reduced. In conclusion, DSP-4 has a different efficacy in discrete brain areas with a noradrenergic specificity which is not absolute, PCPA has a similar efficacy in all brain areas but is unspecific of 5-HT transmission.

Interstrain mice variability in response to antidepressant drugs has been reported in the most commonly utilized behavioural animal models of depression: the tail suspension test (TST) and the forced swimming test (FST). The behaviour of mice was examined in both tests for screening various antidepressants with different biochemical mechanism of action. Previous studies have revealed that drug sensitivity depends on the strain and test used. Swiss mice is the most sensitive strain to detect serotonin and/or noradrenaline antidepressants whereas C57BL/6J was the only strain sensitive to bupropion (dopaminergic agent) using the FST. In the TST, all antidepressants studied decreased the immobility time in Swiss and C57BL/6J strains. Detection of an antidepressant-like activity could be performed using only one test (TST with Swiss mice or FST with Swiss and C57Bl/6 Rj mice), but both tests are necessary to conclude on the mechanism of action.

Rationale: Among all animal models, the forced swimming test (FST) remains one of the most used tools for screening antidepressants., Objective: This paper reviews some of the main aspects of the FST in mice. Most of the sensitivity and variability factors that were assessed on the FST are summarized., Mechanisms: We have summarized data found in the literature of antidepressant effects on the FST in mice. From this data set, we have extrapolated information on baseline levels of strain, and sensitivity against antidepressants., Results: We have shown that many parameters have to be considered in this test to gain good reliability. Moreover, there was a fundamental inter-strain difference of response in the FST., Conclusions: The FST is a good screening tool with good reliability and predictive validity. Strain is one of the most important parameters to consider. Swiss and NMRI mice can be used to discriminate the mechanisms of action of drugs. CD-1 seems to be the most useful strain for screening purposes, but this needs to be confirmed with some spontaneous locomotor activity studies.

Abstract The relationship between depression and dopamine deficiency in the mesolimbic pathway has been hypothesized for many years. The experimental studies with animal models of depression and the human studies implicate the role of the dopamine system in depression. Not only do dopaminergic receptor agonists, but also antagonists such as olanzapine exhibit antidepressant effects associated with standard antidepressants in patients with treatment-resistant depression. This paradoxical result suggests that further investigations are necessary to understand the role played by dopamine in depression.