Mostafa El Mansari

University of Ottawa, Ottawa, Ontario, Canada

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Publications (42)212.93 Total impact

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    ABSTRACT: The rapid antidepressant action of a subanesthetic dose of ketamine in treatment-resistant patients represents the most striking recent breakthrough in the understanding of the antidepressant response. Evidence demonstrates tight interactions between the glutamatergic and monoaminergic systems. It is thus hypothesized that monoamine systems may play a role in the immediate/rapid effects of ketamine. In vivo electrophysiological recordings were carried in male rats following ketamine administration (10 and 25 mg/kg, i.p.) to first assess its effects on monoaminergic neuron firing. In a second series of experiments, the effects of ketamine administration on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)- and N-methyl-D-aspartate receptor (NMDA)-evoked responses in hippocampus CA3 pyramidal neurons were also investigated using micro-iontophoretic applications. Although acute (~2 hours) ketamine administration did not affect the mean firing activity of dorsal raphe serotonin and ventral tegmental area dopamine neurons, it did increase that of locus coeruleus norepinephrine neurons. In the latter brain region, while ketamine also enhanced bursting activity, it did increase population activity of dopamine neurons in the ventral tegmental area. These effects of ketamine were prevented by the prior administration of the AMPA receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide. An increase in AMPA-evoked response of CA3 pyramidal neurons was also observed 30 minutes following acute ketamine administration. The present findings suggest that acute ketamine administration produces a rapid enhancement of catecholaminergic neurons firing activity through an amplification of AMPA transmission. These effects may play a crucial role in the antidepressant effects of ketamine observed shortly following its infusion in depressed patients. © The Author(s) 2015.
    Journal of Psychopharmacology 03/2015; 29(7). DOI:10.1177/0269881115573809 · 2.81 Impact Factor
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    Mostafa El Mansari · Maurice Lecours · Pierre Blier
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    ABSTRACT: Vortioxetine is a novel multimodal antidepressant that is a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist, an inhibitor of the serotonin (5-HT) transporter, and a 5-HT1D, 5-HT3, and 5-HT7 receptor antagonist in vitro. In vivo studies have shown that vortioxetine enhances levels of 5-HT and desensitizes 5-HT1A autoreceptors. The aim of the present study was to investigate the effects of acute and long-term administration of vortioxetine on the terminal 5-HT1B receptor and the tonic activation of 5-HT1A receptor in the rat hippocampus. These receptors were assessed following vortioxetine administration acutely or subcutaneously using minipumps for 14 days. These studies were carried out using in vivo electrophysiological recording, microiontophoresis, and stimulation of the ascending 5-HT fibers. Vortioxetine enhanced the inhibitory effect of the stimulation of the 5-HT bundle at a high, but not low frequency and reversed the inhibitory effect of the 5-HT1B receptor agonist CP 94253. These results indicate that this compound acted as a 5-HT1B receptor partial agonist. Vortioxetine inhibited 5-HT reuptake but did not dampen the sensitivity of postsynaptic 5-HT1A receptors on pyramidal neurons. Long-term administration of vortioxetine and escitalopram (both at 5 mg/kg/day) induced an increase of tonic activation of the 5-HT1A receptors in CA3 pyramidal neurons, resulting in an increase in 5-HT transmission. In addition, vortioxetine decreased the function of terminal 5-HT1B autoreceptor following its sustained administration. Desensitization of 5-HT1B autoreceptor and an increase of tonic activation of 5-HT1A receptors in the hippocampus may contribute to the antidepressant effect of vortioxetine.
    Psychopharmacology 02/2015; 232(13). DOI:10.1007/s00213-015-3870-9 · 3.99 Impact Factor
  • Chris A. Oosterhof · Mostafa El Mansari · Pierre Blier
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    ABSTRACT: Asenapine is a tetracyclic atypical antipsychotic used for treatment of schizophrenia and mania. Previous in vivo electrophysiological studies demonstrated antagonistic action of asenapine at dopamine D2, serotonin (5-HT)2A, and α2-adrenergic receptors. Here, we assessed monoamine system activities after two-day and 21-day asenapine administration at a dosage (0.1 mg/kg/day) resulting in clinically relevant plasma levels. In the ventral tegmental area (VTA), asenapine increased the number of spontaneously active dopamine neurons, while firing parameters remained unchanged. Asenapine partially prevented the D2 autoreceptor-mediated inhibitory response to apomorphine after two days of administration. This effect was lost after 21 days of administration, suggesting adaptive changes leading to D2 receptor sensitization. Asenapine increased the firing activity of noradrenergic neurons in the locus coeruleus (LC) after 21, but not two days of administration. Furthermore, it potently blocked 5-HT2A receptors while α2-adrenergic receptors were unaffected by this drug regimen. Both acute and long-term asenapine administration partially blocked α2-adrenergic receptors in the CA3 region of the hippocampus, and noradrenergic tone on α1- and α2-adrenoceptors remained unchanged. In the dorsal raphe nucleus, asenapine increased the firing rate of 5-HT neurons after two, but not 21 days of administration. In addition, responsiveness of 5-HT1A autoreceptors was unaltered by asenapine. In the hippocampus, 21-day asenapine administration increased serotonergic tone by partial agonistic action on postsynaptic 5-HT1A and terminal 5-HT1B receptors. Taken together, asenapine had profound effects on both catecholamine systems, potently blocked 5-HT2A receptors, and enhanced 5-HT tone, effects that could be important in treatment of mood disorders and schizophrenia.
    European Neuropsychopharmacology 01/2015; 25(4). DOI:10.1016/j.euroneuro.2015.01.006 · 5.40 Impact Factor
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    ABSTRACT: Olfactory bulbectomized (OBX) rats generally manifest many of the neurochemical, physiological, and behavioural 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 (5-HT) reuptake inhibitors (SSRIs). The purpose of the present study was first to characterize the firing activity of dorsal raphe 5-HT neurons in OBX rats and then examine the effects of two antidepressants, namely bupropion and paroxetine. 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. Following ablation of olfactory bulbs, the firing rate of 5-HT neurons was decreased by 36%, leaving those of norepinephrine and dopamine neurons unchanged. In OBX rats, bupropion (30 mg/kg/day) restored the firing rate of 5-HT neurons to the control level following 2- and 14-day administration and also induced an increase in the tonic activation of 5-HT1A receptors; paroxetine (10 mg/kg/day) did not result in a return to normal of the attenuated firing of 5-HT neurons in OBX rats. In the hippocampus, although at higher dose of WAY 100635 than that required in bupropion-treated animals, paroxetine administration also resulted in an increase in the tonic activation of 5-HT1A receptors. The present results indicate that unlike paroxetine, bupropion administration normalized 5-HT neuronal activity and increased tonic activation of the 5-HT1A receptors in hippocampus. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 10/2014; 18(4). DOI:10.1093/ijnp/pyu050 · 5.26 Impact Factor
  • Chris A Oosterhof · Mostafa El Mansari · Pierre Blier
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    ABSTRACT: Brexpiprazole, a compound sharing structural molecular characteristics with aripiprazole, is currently under investigation for the treatment of schizophrenia and depression. Using electrophysiological techniques, the present study assessed the in vivo action of brexpiprazole on serotonin (5-HT)1A, 5-HT1B, 5-HT2A receptor subtypes, dopamine (DA) D2 autoreceptors, and α1- and α2-adrenergic receptors. In addition, the effects on 5-HT1A autoreceptors in the dorsal raphe nucleus (DRN) and D2 autoreceptors in the ventral tegmental area (VTA) were compared to those of aripiprazole, an agent in wide clinical use. In the DRN, brexpiprazole completely inhibited the firing of 5-HT neurons via 5-HT1A agonism, and was more potent than aripiprazole (ED50=230 and 700 μg/kg, respectively). In the locus coeruleus, brexpiprazole reversed the inhibitory effect of the preferential 5-HT2A receptor agonist DOI on norepinephrine neuronal firing (ED50=110 μg/kg), demonstrating 5-HT2A antagonistic action. Brexpiprazole reversed the inhibitory effect of the DA agonist apomorphine on VTA DA neurons (ED50=61 μg/kg), whereas it was ineffective when administered alone, indicating partial agonistic action on D2 receptors. Compared to aripiprazole, which significantly inhibited the firing activity of VTA DA neurons, brexpiprazole displayed less efficacy at D2 receptors. In the hippocampus, brexpiprazole acted as a full agonist at 5-HT1A receptors on pyramidal neurons. Furthermore, it increased 5-HT release by terminal α2-adrenergic heteroceptor but not 5-HT1B autoreceptor antagonism. In the lateral geniculate nucleus, brexpiprazole displayed α1B-adrenoceptor antagonistic action. Taken together, these results provide insight in the in vivo action of brexpiprazole on monoamine targets relevant in the treatment of depression and schizophrenia.
    Journal of Pharmacology and Experimental Therapeutics 09/2014; 351(3). DOI:10.1124/jpet.114.218578 · 3.86 Impact Factor
  • Franck Chenu · Stacey Shim · Mostafa El Mansari · Pierre Blier
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    ABSTRACT: 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-HT2B) and serotonin 2C (5-HT2C) 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-HT2C receptor antagonist SB 242084 (0.5 mg/kg/day), the selective 5-HT2B 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-HT2C receptor blockade resulted in a disinhibition of DA neurons. When 5-HT2B receptors were also blocked, the firing and the bursting activity of DA neurons were both enhanced, thus reproducing the effect of agomelatine.
    Journal of Psychopharmacology 11/2013; 28(2). DOI:10.1177/0269881113510071 · 2.81 Impact Factor
  • Peter Tsen · Mostafa El Mansari · Pierre Blier
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    ABSTRACT: Electroconvulsive therapy (ECT) treats depression by repeated administration of seizure-inducing electrical stimuli. To assess the effects of repeated electroconvulsive shocks (ECS), an animal model of ECT on monoamine transmission, Sprague-Dawley rats were administered 6 ECS over 2 weeks and in vivo single unit extracellular electrophysiological recordings were obtained 48 hours after the final ECS. Overall firing activity of dopamine (DA) neurons in the ventral tegmental area was unchanged following repeated administration of ECS. In the LC, the burst activity of norepinephrine (NE) neurons was increased while population activity was decreased after ECS. In the substantia nigra pars compacta (SNc), there were more spontaneously active neurons, suggesting greater DA tone in the nigrostriatal motor pathway, which may contribute to an alleviation of motor retardation. In the facial motor nucleus (FMN), facilitation of electrophysiological activity by serotonin (5-HT) and NE was determined to be through the 5-HT2C receptor and α1 -adrenoceptor, respectively. Locally administered NE, but not 5-HT, facilitated glutamate-induced firing following repeated ECS, which may contribute to improved motor function. These results showed that repeated ECS enhances DA activity in the SNc and NE transmission in the FMN, which could be a part of the mechanism behind the alleviation of depressive symptoms, including motor retardation, by ECT. Synapse, 2013. © 2013 Wiley Periodicals, Inc.
    Synapse 10/2013; 67(10). DOI:10.1002/syn.21685 · 2.43 Impact Factor
  • Stacey Shim · Mostafa El Mansari · Pierre Blier
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    ABSTRACT: Carisbamate and lamotrigine are anticonvulsants which act on neuronal voltage-gated sodium channels. Carisbamate has been shown to have antidepressant-like effects in animal models of depression, and lamotrigine is a mood stabilizer with a therapeutic effect in depressive episodes of patients with bipolar disorder. This study examined the effects of carisbamate and lamotrigine on monoaminergic transmission in rodents which could contribute to their antidepressant action. In vivo electrophysiological recordings were carried out in rats, after 2 and 14 days administration of vehicle, carisbamate (60 mg/kg/day) or lamotrigine (25 mg/kg/day). Overall firing activity of the dorsal raphe nucleus (DRN) serotonin (5-HT), locus coeruleus (LC) norepinephrine (NE) and ventral tegmental area (VTA) dopamine (DA) neurons were decreased with carisbamate. Lamotrigine also decreased 5-HT neuronal firing and this effect was dampened by lesion of the prefrontal cortex. Despite these decreases in firing activity after their prolonged administration, both anticonvulsants exhibited significant increase in tonic activation of hippocampus 5-HT1A receptors as shown by a disinhibition of the firing activity of pyramidal neurons in response to the selective antagonist WAY-100635. This reveals an increase in 5-HT level that may be attributed to a desensitization of the terminal 5-HT1B autoreceptors. This study demonstrates that sustained carisbamate and lamotrigine administration decreases 5-HT firing in the DRN but nevertheless enhances 5-HT transmission in the forebrain. This serotonergic effect may be associated with an antiglutamatergic action, and may contribute to the antidepressant-like effect of carisbamate in the forced swim test (FST) and the antidepressant properties of lamotrigine.
    Journal of Pharmacology and Experimental Therapeutics 08/2013; 347(2). DOI:10.1124/jpet.113.203315 · 3.86 Impact Factor
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    Pierre Blier · Mostafa El Mansari
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    ABSTRACT: The serotonin (5-HT, 5-hydroxytryptamine) system has been implicated in the pathogenesis of major depressive disorder (MDD). The case for its contribution to the therapeutic efficacy of a wide variety of antidepressant treatments is, however, much stronger. All antidepressant strategies have been shown to enhance 5-HT transmission in the brain of laboratory animals. Catecholamines, norepinephrine (NE) and dopamine (DA) can also play a pivotal role in the mechanism of action of certain antidepressant strategies. The enhancement of 5-HT transmission by selective serotonin reuptake inhibitors, which leads to a dampening of the activity of NE and DA neurons, may account in part for the low remission rate achieved with these medications and/or the residuals symptoms after remission is achieved. The functional connectivity between the 5-HT, NE and DA systems can be used to understand the mechanism of action of a wide variety of augmentation strategies in treatment-resistant MDD. Proof-of-concept studies have shown that antidepressant medications with complementary mechanisms of action on monoaminergic systems can double the remission rate achieved in a trial of standard duration. Novel approaches are also being used to treat MDD, which also appear to involve the monoaminergic system(s) to a varying extent.
    Philosophical Transactions of The Royal Society B Biological Sciences 01/2013; 368(1615):20120536. DOI:10.1098/rstb.2012.0536 · 6.31 Impact Factor
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    Franck Chenu · Mostafa El Mansari · Pierre Blier
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    ABSTRACT: 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.Neuropsychopharmacology advance online publication, 8 August 2012; doi:10.1038/npp.2012.140.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 08/2012; 38(2). DOI:10.1038/npp.2012.140 · 7.83 Impact Factor
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    Stella Manta · Mostafa El Mansari · Guy Debonnel · Pierre Blier
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    ABSTRACT: Vagus nerve stimulation (VNS) is an adjunctive treatment for resistant epilepsy and depression. Electrophysiological recordings in the rat brain have already shown that chronic VNS increases norepinephrine (NE) neuronal firing activity and, subsequently, that of serotonin (5-HT) neurons through an activation of their excitatory α1-adrenoceptors. Long-term VNS was shown to increase the tonic activation of post-synaptic 5-HT1A receptors in the hippocampus. This study was aimed at examining the effect of VNS on extracellular 5-HT, NE and dopamine (DA) levels in different brain areas using in vivo microdialysis, on NE transmission in the hippocampus, and DA neuronal firing activity using electrophysiology. Rats were implanted with a VNS device and stimulated for 14 d with standard parameters used in treatment-resistant depression (0.25 mA, 20 Hz, 500 μs, 30 s on-5 min off). The results of the present study revealed that 2-wk VNS significantly increased extracellular NE levels in the prefrontal cortex and the hippocampus and enhanced the tonic activation of post-synaptic α2-adrenoceptors on pyramidal neurons. The electrophysiological experiments revealed a significant decrease in ventral tegmental area DA neuronal firing rate after long-term VNS; extracellular DA levels were nevertheless increased in the prefrontal cortex and nucleus accumbens. Chronic VNS significantly increased extracellular 5-HT levels in the dorsal raphe but not in the hippocampus and prefrontal cortex. In conclusion, the effect of VNS in increasing the transmission of monoaminergic systems targeted in the treatment of resistant depression should be involved, at least in part, in its antidepressant properties observed in patients not responding to many antidepressant strategies.
    The International Journal of Neuropsychopharmacology 04/2012; 16(2):1-12. DOI:10.1017/S1461145712000387 · 5.26 Impact Factor
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    Olga Chernoloz · Mostafa El Mansari · Pierre Blier
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    ABSTRACT: Long-term administration of the dopamine (DA) D2-like (D3/2) receptor agonist pramipexole (PPX) has been previously found to desensitize D2 autoreceptors, thereby allowing a normalization of the firing of DA neurons and serotonin (5-HT)1A autoreceptors, permitting an enhancement of the spontaneous firing of 5-HT neurons. We hypothesized that PPX would increase overall DA and 5-HT neurotransmission in the forebrain as a result of these changes at the presynaptic level. Osmotic minipumps were implanted subcutaneously in male Sprague-Dawley rats, delivering PPX at a dose of 1 mg/kg/d for 14 days. The in vivo electrophysiologic microiontophoretic experiments were carried out in anesthetized rats. The sensitivity of postsynaptic D2 receptors in the prefrontal cortex (PFC) remained unaltered following PPX administration, as indicated by the unchanged responsiveness to the microiontophoretic application of DA. Their tonic activation was, however, significantly increased by 104% compared with the control level. The sensitivity of postsynaptic 5-HT1A receptors was not altered, as indicated by the unchanged responsiveness to the microiontophoretic application of 5-HT. Similar to other antidepressant treatments, long-term PPX administration enhanced the tonic activation of 5-HT1A receptors on CA3 pyramidal neurons by 142% compared with the control level. Limitations: The assessment of DA and 5-HT neuronal tone was restricted to the PFC and the hippocampus, respectively. Chronic PPX administration led to a net enhancement in DA and 5-HT neurotransmission, as indicated by the increased tonic activation of postsynaptic D2 and 5-HT1A receptors in forebrain structures.
    Journal of psychiatry & neuroscience: JPN 03/2012; 37(2):113-21. DOI:10.1503/jpn.110038 · 7.49 Impact Factor
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    Olga Chernoloz · Mostafa El Mansari · Pierre Blier
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    ABSTRACT: Quetiapine is now used in the treatment of unipolar and bipolar disorders, both alone and in combination with other medications. In the current study, the sustained administration of quetiapine and N-Desalkyl quetiapine (NQuet) in rats in a 3 : 1 mixture (hQuetiapine (hQuet)) was used to mimic quetiapine exposure in patients because rats do not produce the latter important metabolite of quetiapine. Sustained administration of hQuet for 2 and 14 days, respectively, significantly enhanced the firing rate of norepinephrine (NE) neurons by blocking the cell body α₂-adrenergic autoreceptors on NE neurons, whether it was given alone or with a serotonin (5-HT) reuptake inhibitor. The 14-day regimen of hQuet enhanced the tonic activation of postsynaptic α₂- but not α₁-adrenergic receptors in the hippocampus. This increase in NE transmission was attributable to increased firing of NE neurons, the inhibition of NE reuptake by NQuet, and the attenuated function of terminal α₂-adrenergic receptors on NE terminals. Sustained administration of hQuet for 2 and 14 days, respectively, significantly inhibited the firing rate of 5-HT, whether it was given alone or with a 5-HT reuptake inhibitor, because of the blockade of excitatory α₁-adrenergic receptors on 5-HT neurons. Nevertheless, the 14-day regimen of hQuet enhanced the tonic activation of postsynaptic 5-HT(1A) receptors in the hippocampus. This increase in 5-HT transmission was attributable to the attenuated inhibitory function of the α₂-adrenergic receptors on 5-HT terminals and possibly to direct 5-HT(1A) receptor agonism by NQuet. The enhancement of NE and 5-HT transmission by hQuet may contribute to its antidepressant action in mood disorders.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 02/2012; 37(7):1717-28. DOI:10.1038/npp.2012.18 · 7.83 Impact Factor
  • Ramez Ghanbari · Mostafa El Mansari · Pierre Blier
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    ABSTRACT: Previous study has documented the long-term effects of the antidepressant trazodone on the serotonin (5-HT) system. The present work examined the impact of sustained trazodone on ventral tegmental area (VTA) dopamine (DA) and locus ceruleus (LC) norepinephrine (NE) neurons firing activity, and characterized its effects at 5-HT(2C), 5-HT(2A) receptors and α₁- and α₂-adrenoceptors. Electrophysiological recordings were carried out in anesthetized rats. Subcutaneously implanted minipumps delivered vehicle or trazodone (10 mg/kg/day) for 2 or 14 days. Administration of trazodone for 2 and 14 days did not alter the firing activity of DA neurons. Systemic injection of trazodone, however, reversed the inhibitory effect of the 5-HT(2C) receptor agonist Ro 60,0175 on the DA neuronal firing, suggesting an antagonistic action of trazodone at this receptor. Administration of trazodone for 2 days significantly enhanced the NE neurons firing. Despite a return of the NE neurons firing rate to the baseline following 14-day trazodone, the percentage of neurons discharging in burst was increased by this regimen. Administration of trazodone for 14 days enhanced the tonic activation of postsynaptic α₂-adrenoceptors, as indicated by the disinhibitory effect of the α₂-adrenoceptor antagonist idazoxan on hippocampus pyramidal neurons firing. The inhibitory effect of acute trazodone on dorsal raphe (DR) 5-HT neurons firing was shown to be through the 5-HT(1A) receptor. Systemic injection of trazodone reversed the inhibitory action of 5-HT(2A) agonist DOI on the NE neurons firing rate, indicating its antagonistic action at 5-HT(2A) receptors. The enhancement in α₂-adrenergic transmission by trazodone, and its 5-HT(2A) and 5-HT(2C) receptor antagonism may contribute to its therapeutic action in major depression.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 12/2011; 22(7):518-26. DOI:10.1016/j.euroneuro.2011.11.005 · 5.40 Impact Factor
  • Franck Chenu · Ramez Ghanbari · Mostafa El Mansari · Pierre Blier
    The International Journal of Neuropsychopharmacology 09/2011; 15(4):551-3; author reply 555-7. DOI:10.1017/S1461145711001362 · 5.26 Impact Factor
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    Stella Manta · Mostafa El Mansari · Pierre Blier
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    ABSTRACT: Vagus nerve stimulation (VNS) is indicated for treatment-resistant epilepsy and depression. Electrophysiologic recordings in the rat brain have shown that VNS promptly increases the firing rate of NE neurons and subsequently that of 5-HT neurons. Thus far, it appears that the standard stimulation parameters currently used in depressed patients produce an optimal activation of 5-HT neurons. This study was therefore aimed at investigating additional alterations of stimulation parameters to optimize VNS efficacy to further increase 5-HT neuronal activity. Rats were implanted with a VNS device and stimulated for 14 days using standard (0.25 mA/20 Hz/500 microseconds/30 seconds ON-5 minutes OFF, continuously) or various stimulation parameters: extension of the OFF period (30 seconds ON every 10 to 30 minutes), the OFF and ON periods, discontinuous stimulation (12 hours per day using standard parameters), and burst stimulation modes. Rat dorsal raphe 5-HT neurons were recorded under chloral hydrate anesthesia. Both 12-hour stimulation periods for 14 days, and the 30-second stimulation every 10 or 15 minutes significantly increased the firing activity of 5-HT neurons to the same extent as standard parameters while the 30-minute intervals were ineffective. Stimulations in a burst mode and the pseudo-one-pulse stimulations also significantly increased 5-HT neuronal activity. These results indicate that less stimulation is sufficient to achieve the same VNS efficacy on 5-HT neuronal firing. These data may be relevant for patients using VNS because these new parameters could minimize or prevent side effects and increase battery life of the stimulator.
    Brain Stimulation 05/2011; 5(3):422-9. DOI:10.1016/j.brs.2011.04.005 · 5.43 Impact Factor
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    Bruno P Guiard · ME Mostafa El Mansari · Dennis L Murphy · Pierre Blier
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    ABSTRACT: A serotonin (5-HT) transporter (5-HTT; SERT) polymorphism has been associated with depressive states and poor responses to selective serotonin reuptake inhibitors (SSRIs). Given the similar attenuation of SERT activity in SERT+/- mice and in humans with short allele(s) of SERT in its promoter region, it is conceivable that SERT+/- mice offer an adequate model to mimic the human subpopulation with respect to their altered response to SSRIs. This study investigated the effects of the most selective SSRI escitalopram, in heterozygous SERT+/- mice using a combined electrophysiological and neurochemical approach. Results indicated that administration of escitalopram for 2 d resulted in a 72% and 63% decrease in dorsal raphe 5-HT neuronal firing rate in SERT+/+ and SERT+/- mice, respectively. In contrast, administration of escitalopram for 21 d produced a gradual recovery of 5-HT neuronal firing rate to basal level in SERT+/+, but not in SERT+/- mice. In the hippocampus, microdialysis revealed that sustained administration of escitalopram produced a greater increase in extracellular 5-HT ([5-HT]ext) outflow in SERT+/- than in the wild-types with or without a washout of the SSRI. Nevertheless, the ability of microiontophoretically applied 5-HT to inhibit the firing rate of CA3 pyramidal neurons was not different between SERT+/+ and SERT+/- mice given escitalopram for 21 d. The data indicate that the poor response to SSRIs of depressive patients with short allele(s) of SERT is not attributable to a lesser increase in 5-HT transmission in the hippocampus.
    The International Journal of Neuropsychopharmacology 03/2011; 15(3):1-13. DOI:10.1017/S1461145711000484 · 5.26 Impact Factor
  • Ramez Ghanbari · Mostafa El Mansari · Pierre Blier
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    ABSTRACT: Previous studies reported that bupropion, an effective antidepressant, exerts modulatory actions on serotonin (5-HT) and norepinephrine (NE) neurons. This study examined effects of bupropion administration on 5-HT and NE neurotransmission in hippocampus. Electrophysiological recordings were obtained from anesthetized Sprague-Dawley rats. Subcutaneously implanted minipumps delivered saline or bupropion (30 mg/kg/day) for 2 and 14 days. Although sustained bupropion administration did not alter the sensitivity of 5-HT(1A) and α₂-adrenergic receptors, the tonic activation of postsynaptic 5-HT(1A) receptors by endogenous 5-HT was enhanced in 14-day bupropion-treated rats to a greater extent than in the 2-day and control rats, as revealed by the greater disinhibitory action of the 5-HT(1A) antagonist WAY-100635 on hippocampus pyramidal neurons. The function of terminal 5-HT(1B) autoreceptors was not changed as determined by the unaltered effectiveness of different frequencies of stimulation of the ascending 5-HT fibers. The function of α₂-adrenergic receptors on 5-HT terminals was, however, diminished, as indicated by the lesser effect of the α₂-adrenoceptor agonist clonidine. Tonic activation of postsynaptic α₂- and α₁-adrenoceptors by endogenous NE was also increased in 14-day bupropion-treated rats, as indicated by the greater effect of the α₂- and α₁-adrenoceptor antagonists idazoxan and prazosin, respectively, on pyramidal firing. The function of terminal α₂-adrenergic autoreceptors was attenuated since increasing frequency of stimulation of the ascending NE pathway produced a lesser degree of suppression of pyramidal neurons in rats administered bupropion than the control. Enhancement of 5-HT and NE transmissions in hippocampus by prolonged bupropion may account for its effectiveness in major depression.
    Psychopharmacology 03/2011; 217(1):61-73. DOI:10.1007/s00213-011-2260-1 · 3.99 Impact Factor
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    ABSTRACT: Current antidepressants still display unsatisfactory efficacy and a delayed onset of therapeutic action. Here we show that the pharmacological blockade of serotonin 7 (5-HT(7)) receptors produced a faster antidepressant-like response than the commonly prescribed antidepressant fluoxetine. In the rat, the selective 5-HT(7) receptor antagonist SB-269970 counteracted the anxiogenic-like effect of fluoxetine in the open field and exerted an antidepressant-like effect in the forced swim test. In vivo, 5-HT(7) receptors negatively regulate the firing activity of dorsal raphe 5-HT neurons and become desensitized after long-term administration of fluoxetine. In contrast with fluoxetine, a 1-week treatment with SB-269970 did not alter 5-HT firing activity but desensitized cell body 5-HT autoreceptors, enhanced the hippocampal cell proliferation, and counteracted the depressive-like behavior in olfactory bulbectomized rats. Finally, unlike fluoxetine, early-life administration of SB-269970, did not induce anxious/depressive-like behaviors in adulthood. Together, these findings indicate that the 5-HT(7) receptor antagonists may represent a new class of antidepressants with faster therapeutic action.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 02/2011; 36(6):1275-88. DOI:10.1038/npp.2011.13 · 7.83 Impact Factor
  • Ramez Ghanbari · Mostafa El Mansari · Pierre Blier
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    ABSTRACT: Despite its clinical use for more than two decades, the mechanisms by which trazodone acts as an antidepressant are not clear, because it has affinity for a variety of 5-hydroxytryptamine (5-HT; serotonin) receptors and the 5-HT transporter. This study examined the effects of sustained trazodone administration on 5-HT neurotransmission. Electrophysiological recordings were conducted in anesthetized rats. Subcutaneously implanted minipumps delivered vehicle or trazodone (10 mg/kg/day) for 2 and 14 days. A 2-day trazodone administration suppressed the firing rate of raphe 5-HT neurons, which recovered to baseline after 14 days. This was attributable to 5-HT(1A) autoreceptor desensitization because the suppressant effect of the 5-HT autoreceptor agonist lysergic acid diethylamide was dampened in 14-day trazodone-treated rats. Prolonged trazodone administration did not change the sensitivity of postsynaptic 5-HT(1A) and α(2)-adrenergic receptors in hippocampus, but enhanced synaptic 5-HT levels because the 5-HT(1A) antagonist N-{2-[4 (2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride (WAY-100635) enhanced hippocampal firing in treated rats, but not in controls. Trazodone administration for 14 days increased the 50% recovery time value, an index of 5-HT transporter blockade in vivo, and decreased the inhibitory function of terminal 5-HT(1B) autoreceptors on the electrically evoked release of 5-HT. The agonistic action of trazodone at 5-HT(1A) receptors was characterized as being full because it did not attenuate the inhibitory action of 5-HT when coapplied locally. The enhanced 5-HT neurotransmission by trazodone is caused in part by reuptake blockade and activation of postsynaptic 5-HT(1A) receptors, which may account for its effectiveness in major depression.
    Journal of Pharmacology and Experimental Therapeutics 10/2010; 335(1):197-206. DOI:10.1124/jpet.110.169417 · 3.86 Impact Factor

Publication Stats

1k Citations
212.93 Total Impact Points

Institutions

  • 2005–2015
    • University of Ottawa
      • Institute of Mental Health Research (IMHR)
      Ottawa, Ontario, Canada
  • 2006
    • Claude Bernard University Lyon 1
      • Laboratoire de neuropsychopharmacologie
      Villeurbanne, Rhône-Alpes, France
  • 1996
    • McGill University
      • Department of Psychiatry
      Montréal, Quebec, Canada