Publications by authors named "Luc Moquin"

20 Publications

  • Page 1 of 1

Efficacy of prophylactic versus therapeutic administration of the NMDA receptor antagonist MK-801 on the acute neurochemical response to a concussion in a rat model combining force and rotation.

J Neurosurg 2021 Oct 15:1-10. Epub 2021 Oct 15.

1Research Center, Hôpital du Sacré-Cœur de Montréal; and.

Objective: Alterations in amino acid concentrations are a major contributor to the persistent neurological and behavioral effects induced by concussions and mild traumatic brain injuries (TBIs). Glutamate, the most abundant excitatory amino acid in the CNS, has a major role in the pathophysiological process of concussion. The indiscriminate liberation of glutamate immediately after a concussion triggers an excitotoxic response that leads to cell death, neuronal damage, and the dysfunction of surviving neurons, largely by overactivation of N-methyl-d-aspartate (NMDA) glutamatergic receptors. The aim of the present study was to investigate the efficacy of prophylactic versus therapeutic administration of MK-801, a promising NMDA receptor antagonist, on the acute changes in amino acid extracellular concentrations involved in excitotoxicity resulting from a concussive trauma.

Methods: The immediate neurochemical response to a concussion cannot be characterized in humans. Therefore, the authors used their previously validated combination of a weight-drop concussion rat model and in vivo cerebral microdialysis. The microdialysis probe was inserted inside the hippocampus and left inserted at impact to allow uninterrupted sampling of amino acids of interest immediately after concussion. The primary outcome included amino acid concentrations and the secondary outcome included righting time. Samples were taken in 10-minute increments for 60 minutes before, during, and 60 minutes after impact, and analyzed for glutamate, gamma-aminobutyric acid, taurine, glycine, glutamine, and serine using high-performance liquid chromatography. Righting time was acquired as a neurological restoration indicator. Physiological saline or 10 mg/kg MK-801 was administrated intraperitoneally 60 minutes before or immediately following induction of sham injury or concussion.

Results: Following induction of concussion, glutamate, taurine, and glycine levels as well as righting times in cases from the MK-801 treatment group were comparable to those of vehicle-treated animals. In contrast, righting times and amino acid concentrations observed within the first 10 minutes after induction of concussion in cases assigned to the MK-801 prophylaxis group were comparable to those of sham-injured animals.

Conclusions: These results suggest that presynaptic actions and peak availability of MK-801 following prophylactic administration significantly inhibit the immediate and indiscriminate release of glutamate, taurine, and glycine in extracellular fluid after a concussion.
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http://dx.doi.org/10.3171/2021.3.JNS204163DOI Listing
October 2021

Lesch-Nyhan disease causes impaired energy metabolism and reduced developmental potential in midbrain dopaminergic cells.

Stem Cell Reports 2021 Jul 1;16(7):1749-1762. Epub 2021 Jul 1.

Psychiatric Genetics Group, McGill University, Montreal, QC, Canada; Department of Psychiatry, McGill University and Douglas Hospital Research Institute, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Montreal, QC H4H 1R3, Canada. Electronic address:

Mutations in HPRT1, a gene encoding a rate-limiting enzyme for purine salvage, cause Lesch-Nyhan disease which is characterized by self-injury and motor impairments. We leveraged stem cell and genetic engineering technologies to model the disease in isogenic and patient-derived forebrain and midbrain cell types. Dopaminergic progenitor cells deficient in HPRT showed decreased intensity of all developmental cell-fate markers measured. Metabolic analyses revealed significant loss of all purine derivatives, except hypoxanthine, and impaired glycolysis and oxidative phosphorylation. real-time glucose tracing demonstrated increased shunting to the pentose phosphate pathway for de novo purine synthesis at the expense of ATP production. Purine depletion in dopaminergic progenitor cells resulted in loss of RHEB, impairing mTORC1 activation. These data demonstrate dopaminergic-specific effects of purine salvage deficiency and unexpectedly reveal that dopaminergic progenitor cells are programmed to a high-energy state prior to higher energy demands of terminally differentiated cells.
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http://dx.doi.org/10.1016/j.stemcr.2021.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282463PMC
July 2021

Mice with dopaminergic neuron-specific deletion of DTNBP-1 gene show blunted nucleus accumbens dopamine release and associated behaviors.

Neuropharmacology 2021 02 16;184:108440. Epub 2020 Dec 16.

Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, Québec, Canada. Electronic address:

Reduced expression of a schizophrenia-associated gene Dystrobrevin Binding Protein 1 (DTNBP1) and its protein product dysbindin-1, has been reported in the brains of schizophrenia patients. DTNBP1-null mutant Sdy (Sandy) mice exhibit several behavioral features relevant to schizophrenia. Changes in dopaminergic as well as glutamatergic and GABAergic neurotransmission in cortico-limbic regions have been reported in Sdy mice. Since dysbindin-1 is expressed in multiple brain regions, it is not known whether dopamine (DA) changes observed in Sdy null mutants are due to dysbindin-1 deficiency in DAergic neurons specifically. Here, using a mouse line with conditional knockout (cKO) of DTNBP1 in DA neurons, we studied the effects of dysbindin-1 deficiency on DA release and DA-dependent behaviors. Spontaneous locomotor activity of cKO mice in novel environment was significantly reduced initially but was comparable at later time points with littermate controls. However, the locomotion-enhancing effect of a low dose of d-amphetamine (d-AMPH; 2.5 mg/kg, ip) was significantly attenuated in the cKO mice suggesting a dampened mesolimbic DA transmission. Similarly, the prepulse inhibition disrupting effect of d-AMPH was found to be significantly reduced in the mutant mice. No significant differences between the cKO and control mice were observed in tests of anxiety, spatial learning and memory and social interaction. In- vivo microdialysis in the nucleus accumbens (NAc) showed a decrease in d-AMPH-induced extracellular DA release in the cKO mice. No significant alterations in protein levels of DA transporter, phosphorylated CaM kinase-II or Akt308 in the NAc were observed in the cKO mice. Taken together, our data suggest an important role of dysbindin-1 in maintaining mesolimbic DA tone and call for further investigations identifying mechanisms linking dysbindin-1, DA and schizophrenia.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108440DOI Listing
February 2021

Cholinergic dysfunction in the dorsal striatum promotes habit formation and maladaptive eating.

J Clin Invest 2020 12;130(12):6616-6630

Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Quebec, Canada.

Dysregulation of habit formation has been recently proposed as pivotal to eating disorders. Here, we report that a subset of patients suffering from restrictive anorexia nervosa have enhanced habit formation compared with healthy controls. Habit formation is modulated by striatal cholinergic interneurons. These interneurons express vesicular transporters for acetylcholine (VAChT) and glutamate (VGLUT3) and use acetylcholine/glutamate cotransmission to regulate striatal functions. Using mice with genetically silenced VAChT (VAChT conditional KO, VAChTcKO) or VGLUT3 (VGLUT3cKO), we investigated the roles that acetylcholine and glutamate released by cholinergic interneurons play in habit formation and maladaptive eating. Silencing glutamate favored goal-directed behaviors and had no impact on eating behavior. In contrast, VAChTcKO mice were more prone to habits and maladaptive eating. Specific deletion of VAChT in the dorsomedial striatum of adult mice was sufficient to phenocopy maladaptive eating behaviors of VAChTcKO mice. Interestingly, VAChTcKO mice had reduced dopamine release in the dorsomedial striatum but not in the dorsolateral striatum. The dysfunctional eating behavior of VAChTcKO mice was alleviated by donepezil and by l-DOPA, confirming an acetylcholine/dopamine deficit. Our study reveals that loss of acetylcholine leads to a dopamine imbalance in striatal compartments, thereby promoting habits and vulnerability to maladaptive eating in mice.
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http://dx.doi.org/10.1172/JCI138532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685731PMC
December 2020

Stimulation of L-type calcium channels increases tyrosine hydroxylase and dopamine in ventral midbrain cells induced from somatic cells.

Stem Cells Transl Med 2020 Jun 10;9(6):697-712. Epub 2020 Mar 10.

Psychiatric Genetics Group, McGill University, Montreal, Quebec, Canada.

Making high-quality dopamine (DA)-producing cells for basic biological or small molecule screening studies is critical for the development of novel therapeutics for disorders of the ventral midbrain. Currently, many ventral midbrain assays have low signal-to-noise ratio due to low levels of cellular DA and the rate-limiting enzyme of DA synthesis, tyrosine hydroxylase (TH), hampering discovery efforts. Using intensively characterized ventral midbrain cells derived from human skin, which demonstrate calcium pacemaking activity and classical electrophysiological properties, we show that an L-type calcium agonist can significantly increase TH protein levels and DA content and release. Live calcium imaging suggests that it is the immediate influx of calcium occurring simultaneously in all cells that drives this effect. Genome-wide expression profiling suggests that L-type calcium channel stimulation has a significant effect on specific genes related to DA synthesis and affects expression of L-type calcium receptor subunits from the CACNA1 and CACNA2D families. Together, our findings provide an advance in the ability to increase DA and TH levels to improve the accuracy of disease modeling and small molecule screening for disorders of the ventral midbrain, including Parkinson's disease.
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http://dx.doi.org/10.1002/sctm.18-0180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214648PMC
June 2020

A Novel and Translational Rat Model of Concussion Combining Force and Rotation with In Vivo Cerebral Microdialysis.

J Vis Exp 2019 07 12(149). Epub 2019 Jul 12.

Research Center, Hôpital du Sacré-Cœur de Montréal.

Persistent cognitive and motor symptoms are known consequences of concussions/mild traumatic brain injury (mTBIs) that can be partly attributable to altered neurotransmission. Indeed, cerebral microdialysis studies in rodents have demonstrated an excessive extracellular glutamate release in the hippocampus within the first 10 min following trauma. Microdialysis offers the clear advantage of in vivo neurotransmitter continuous sampling while not having to sacrifice the animal. In addition to the aforementioned technique, a closed head injury model that exerts rapid acceleration and deceleration of the head and torso is needed, as such a factor is not available in many other animal models. The Wayne State weight-drop model mimics this essential component of human craniocerebral trauma, allowing the induction of an impact on the head of an unrestrained rodent with a falling weight. Our novel and translational rat model combines cerebral microdialysis with the Wayne State weight-drop model to study, in lightly anesthetized and unrestrained adult rats, the acute changes in extracellular neurotransmitter levels following concussion. In this protocol, the microdialysis probe was inserted inside the hippocampus as region of interest, and was left inserted in the brain at impact. There is a high density of terminals and receptors in the hippocampus, making it a relevant region to document altered neurotransmission following concussion. When applied to adult Sprague-Dawley rats, our combined model induced increases in hippocampal extracellular glutamate concentrations within the first 10 min, consistent with the previously reported post-concussion symptomology. This combined weight-drop model provides a reliable tool for researchers to study early therapeutic responses to concussions in addition to repetitive brain injury, since this protocol induces a closed-head mild trauma.
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http://dx.doi.org/10.3791/59585DOI Listing
July 2019

Increased Alcohol Seeking in Mice Lacking Gpr88 Involves Dysfunctional Mesocorticolimbic Networks.

Biol Psychiatry 2018 08 9;84(3):202-212. Epub 2018 Feb 9.

Département de Médecine Translationnelle et Neurogénétique, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U-964, Centre National de la Recherche Scientifique UMR-7104, University of Strasbourg, Illkirch-Graffenstaden, Strasbourg, France; Douglas Mental Health Institute, Department of Psychiatry, McGill University, Montreal, Quebec, Canada. Electronic address:

Backgound: Alcohol use disorder (AUD) is devastating and poorly treated, and innovative targets are actively sought for prevention and treatment. The orphan G protein-coupled receptor GPR88 is enriched in mesocorticolimbic pathways, and Gpr88 knockout mice show hyperactivity and risk-taking behavior, but a potential role for this receptor in drug abuse has not been examined.

Methods: We tested Gpr88 knockout mice for alcohol-drinking and -seeking behaviors. To gain system-level understanding of their alcohol endophenotype, we also analyzed whole-brain functional connectivity in naïve mice using resting-state functional magnetic resonance imaging.

Results: Gpr88 knockout mice showed increased voluntary alcohol drinking at both moderate and excessive levels, with intact alcohol sedation and metabolism. Mutant mice also showed increased operant responding and motivation for alcohol, while food and chocolate operant self-administration were unchanged. Alcohol place conditioning and alcohol-induced dopamine release in the nucleus accumbens were decreased, suggesting reduced alcohol reward in mutant mice that may partly explain enhanced alcohol drinking. Seed-based voxelwise functional connectivity analysis revealed significant remodeling of mesocorticolimbic centers, whose hallmark was predominant weakening of prefrontal cortex, ventral tegmental area, and amygdala connectional patterns. Also, effective connectivity from the ventral tegmental area to the nucleus accumbens and amygdala was reduced.

Conclusions: Gpr88 deletion disrupts executive, reward, and emotional networks in a configuration that reduces alcohol reward and promotes alcohol seeking and drinking. The functional connectivity signature is reminiscent of alterations observed in individuals at risk for AUD. The Gpr88 gene, therefore, may represent a vulnerability/resilience factor for AUD, and a potential drug target for AUD treatment.
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http://dx.doi.org/10.1016/j.biopsych.2018.01.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054571PMC
August 2018

Genetic elimination of dopamine vesicular stocks in the nigrostriatal pathway replicates Parkinson's disease motor symptoms without neuronal degeneration in adult mice.

Sci Rep 2017 09 29;7(1):12432. Epub 2017 Sep 29.

Department of Psychiatry, Douglas Mental Health Research Center, McGill University, Montreal, Quebec, H4H 1R3, Canada.

The type 2 vesicular monoamine transporter (VMAT2), by regulating the storage of monoamines transmitters into synaptic vesicles, has a protective role against their cytoplasmic toxicity. Increasing evidence suggests that impairment of VMAT2 neuroprotection contributes to the pathogenesis of Parkinson's disease (PD). Several transgenic VMAT2 mice models have been developed, however these models lack specificity regarding the monoaminergic system targeting. To circumvent this limitation, we created VMAT2-KO mice specific to the dopamine (DA) nigrostriatal pathway to analyze VMAT2's involvement in DA depletion-induced motor features associated to PD and examine the relevance of DA toxicity in the pathogenesis of neurodegeneration. Adult VMAT2 floxed mice were injected in the substancia nigra (SN) with an adeno-associated virus (AAV) expressing the Cre-recombinase allowing VMAT2 removal in DA neurons of the nigrostriatal pathway solely. VMAT2 deletion in the SN induced both DA depletion exclusively in the dorsal striatum and motor dysfunction. At 16 weeks post-injection, motor symptoms were accompanied with a decreased in food and water consumption and weight loss. However, despite an accelerating death, degeneration of nigrostriatal neurons was not observed in this model during this time frame. This study highlights a non-cytotoxic role of DA in our genetic model of VMAT2 deletion exclusively in nigrostriatal neurons.
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http://dx.doi.org/10.1038/s41598-017-12810-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622135PMC
September 2017

Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food.

Biol Psychiatry 2017 05 26;81(9):778-788. Epub 2016 Dec 26.

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Illkirch; Douglas Mental Health Institute, Department of Psychiatry, McGill University, Montreal, Quebec, Canada. Electronic address:

Background: Mu opioid receptors (MORs) are central to pain control, drug reward, and addictive behaviors, but underlying circuit mechanisms have been poorly explored by genetic approaches. Here we investigate the contribution of MORs expressed in gamma-aminobutyric acidergic forebrain neurons to major biological effects of opiates, and also challenge the canonical disinhibition model of opiate reward.

Methods: We used Dlx5/6-mediated recombination to create conditional Oprm1 mice in gamma-aminobutyric acidergic forebrain neurons. We characterized the genetic deletion by histology, electrophysiology, and microdialysis; probed neuronal activation by c-Fos immunohistochemistry and resting-state functional magnetic resonance imaging; and investigated main behavioral responses to opiates, including motivation to obtain heroin and palatable food.

Results: Mutant mice showed MOR transcript deletion mainly in the striatum. In the ventral tegmental area, local MOR activity was intact, and reduced activity was only observed at the level of striatonigral afferents. Heroin-induced neuronal activation was modified at both sites, and whole-brain functional networks were altered in live animals. Morphine analgesia was not altered, and neither was physical dependence to chronic morphine. In contrast, locomotor effects of heroin were abolished, and heroin-induced catalepsy was increased. Place preference to heroin was not modified, but remarkably, motivation to obtain heroin and palatable food was enhanced in operant self-administration procedures.

Conclusions: Our study reveals dissociable MOR functions across mesocorticolimbic networks. Thus, beyond a well-established role in reward processing, operating at the level of local ventral tegmental area neurons, MORs also moderate motivation for appetitive stimuli within forebrain circuits that drive motivated behaviors.
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http://dx.doi.org/10.1016/j.biopsych.2016.12.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386808PMC
May 2017

Interhemispheric regulation of the rat medial prefrontal cortical glutamate stress response: role of local GABA- and dopamine-sensitive mechanisms.

Psychopharmacology (Berl) 2017 Feb 7;234(3):353-363. Epub 2016 Nov 7.

Department of Psychiatry, McGill University, Montréal, Québec, H4H 1R3, Canada.

Rationale: We previously reported that stressors increase medial prefrontal cortex (PFC) glutamate (GLU) levels as a result of activating callosal neurons located in the opposite hemisphere and that this PFC GLU stress response is regulated by GLU-, dopamine- (DA-), and GABA-sensitive mechanisms (Lupinsky et al. 2010).

Objectives: Here, we examine the possibility that PFC DA regulates the stress responsivity of callosal neurons indirectly by acting at D and D receptors located on GABA interneurons.

Methods: Microdialysis combined with drug perfusion (reverse dialysis) or microinjections was used in adult male Long-Evans rats to characterize D, D, and GABA receptor-mediated regulation of the PFC GABA response to tail-pinch (TP) stress.

Results: We report that TP stress reliably elicited comparable increases in extracellular GABA in the left and right PFCs. SCH23390 (D antagonist; 100 μM perfusate concentration) perfused by reverse microdialysis attenuated the local GABA stress responses equally in the left and right PFCs. Intra-PFC raclopride perfusion (D antagonist; 100 μM) had the opposite effect, not only potentiating the local GABA stress response but also causing a transient elevation in basal (pre-stress) GABA. Moreover, unilateral PFC raclopride microinjection (6 nmol) attenuated the GLU response to TP stress in the contralateral PFC. Finally, intra-PFC baclofen perfusion (GABA agonist; 100 μM) inhibited the local GLU and GABA stress responses.

Conclusions: Taken together, these findings implicate PFC GABA interneurons in processing stressful stimuli, showing that local D, D, and GABA receptor-mediated changes in PFC GABA transmission play a crucial role in the interhemispheric regulation of GLU stress responsivity.
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http://dx.doi.org/10.1007/s00213-016-4468-6DOI Listing
February 2017

Resilience to chronic stress is mediated by noradrenergic regulation of dopamine neurons.

Nat Neurosci 2016 Apr 15;19(4):560-3. Epub 2016 Feb 15.

Department of Psychiatry, Douglas Mental Health Research Center, McGill University, Montreal, Quebec, Canada.

Dopamine (DA) neurons in the ventral tegmental area (VTA) help mediate stress susceptibility and resilience. However, upstream mechanisms controlling these neurons remain unknown. Noradrenergic (NE) neurons in the locus coeruleus, implicated in the pathophysiology of depression, have direct connections within the VTA. Here we demonstrate that NE neurons regulate vulnerability to social defeat through inhibitory control of VTA DA neurons.
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http://dx.doi.org/10.1038/nn.4245DOI Listing
April 2016

Selective genetic disruption of dopaminergic, serotonergic and noradrenergic neurotransmission: insights into motor, emotional and addictive behaviour.

J Psychiatry Neurosci 2016 04;41(3):169-81

From the Department of Psychiatry, Douglas Mental Health research center, McGill University, Montreal, Que., Canada (Isingrini, Perret, Rainer, Sagueby, Moquin, Gratton, Giros); and ISERM, UMRS 1130; CNRS, UMR 8246; Sorbonne University UPMC, Neuroscience Paris-Seine, F-75005, Paris, France (Giros).

Background: The monoaminergic transmitters dopamine (DA), noradrenaline (NE) and serotonin (5-HT) modulate cerebral functions via their extensive effects in the brain. Investigating their roles has led to the creation of vesicular monoaminergic transporter-2 (VMAT2) knockout (KO) mice. While this mutation results in postnatal death, VMAT2-heterozygous (HET) mice are viable and show a complex behavioural phenotype. However, the simultaneous alteration of the 3 systems prevents investigations into their individual functions.

Methods: To assess the specific role of NE, 5-HT and DA, we genetically disrupted their neurotransmission by creating conditional VMAT2-KO mice with targeted recombination. These specific recombinations were obtained by breeding VMAT2(lox/lox) mice with DBHcre, SERTcre and DATcre mice, respectively. We conducted a complete neurochemical and behavioural characterization of VMAT2-HET animals in each system.

Results: Conditional VMAT2-KO mice revealed an absence of VMAT2 expression, and a specific decrease in the whole brain levels of each monoamine. Although NE- and 5-HT-depleted mice are viable into adulthood, DA depletion results in postnatal death before weaning. Interestingly, alteration of the DA transmission fully accounted for the increased amphetamine response formerly observed in the VMAT2-HET mice, whereas alteration of the 5-HT system was solely responsible for the increase in cocaine response.

Limitations: We used VMAT2-HET mice that displayed a mild phenotype. Because the VMAT2-KO in DA neurons is lethal, it precluded a straightforward comparison of the full KOs in the 3 systems.

Conclusion: Given the intermingled functions of NE, 5-HT and DA in regulating cognitive and affective functions, this model will enhance understanding of their respective roles in the pathophysiology of psychiatric disorders.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853208PMC
http://dx.doi.org/10.1503/jpn.150028DOI Listing
April 2016

Chronic stress alters the dendritic morphology of callosal neurons and the acute glutamate stress response in the rat medial prefrontal cortex.

Stress 2015 12;18(6):654-67. Epub 2015 Sep 12.

a Department of Psychiatry , Douglas Hospital Research Centre, McGill University , Montréal, Québec , Canada.

We have previously reported that interhemispheric regulation of medial prefrontal cortex (PFC)-mediated stress responses is subserved by glutamate (GLU)- containing callosal neurons. Evidence of chronic stress-induced dendritic and spine atrophy among PFC pyramidal neurons led us to examine how chronic restraint stress (CRS) might alter the apical dendritic morphology of callosal neurons and the acute GLU stress responses in the left versus right PFC. Morphometric analyses of retrogradely labeled, dye-filled PFC callosal neurons revealed hemisphere-specific CRS-induced dendritic retraction; whereas significant dendritic atrophy occurred primarily within the distal arbor of left PFC neurons, it was observed within both the proximal and distal arbor of right PFC neurons. Overall, CRS also significantly reduced spine densities in both hemispheres with the greatest loss occurring among left PFC neurons, mostly at the distal extent of the arbor. While much of the overall decrease in dendritic spine density was accounted by the loss of thin spines, the density of mushroom-shaped spines, despite being fewer in number, was halved. Using microdialysis we found that, compared to controls, basal PFC GLU levels were significantly reduced in both hemispheres of CRS animals and that their GLU response to 30 min of tail-pinch stress was significantly prolonged in the left, but not the right PFC. Together, these findings show that a history of chronic stress alters the dendritic morphology and spine density of PFC callosal neurons and suggest a mechanism by which this might disrupt the interhemispheric regulation of PFC-mediated responses to subsequent stressors.
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http://dx.doi.org/10.3109/10253890.2015.1073256DOI Listing
June 2016

Resilience to amphetamine in mouse models of netrin-1 haploinsufficiency: role of mesocortical dopamine.

Psychopharmacology (Berl) 2015 Oct 12;232(20):3719-29. Epub 2015 Aug 12.

Integrated Program in Neuroscience, McGill University, Montréal, Québec, Canada.

Rationale: Signaling through the netrin-1 receptor, deleted in colorectal cancer (DCC), in dopamine neurons controls the extent of their innervation to the medial prefrontal cortex (mPFC) during adolescence. In mice, dcc haploinsufficiency results in increased mPFC dopamine innervation and concentrations in adulthood. In turn, dcc haploinsufficiency leads to resilience to the effects of stimulant drugs of abuse on dopamine release in the nucleus accumbens and behavior.

Objectives: First, we set out to determine whether increased mPFC dopamine innervation causes blunted behavioral responses to amphetamine in adult dcc haploinsufficient mice. Second, we investigated whether unc5c, another netrin-1 receptor expressed by dopamine neurons, is involved in these effects. Third, we assessed whether haploinsufficiency of netrin-1 itself leads to blunted behavioral responding to amphetamine, whether this phenotype emerges before or after adolescence and whether increased mPFC dopamine input is the underlying mechanism.

Results: Adult, but not adolescent, dcc, unc5c and netrin-1 haploinsufficient mice exhibit blunted behavioral responses to amphetamine. Furthermore, adult dcc, unc5c, and netrin-1 haploinsufficient mice have exaggerated mPFC dopamine concentrations in comparison to their wild-type littermates. Importantly, resilience to amphetamine-induced behavioral activation in all the three mouse models is abolished by selective dopamine depletion in the medial prefrontal cortex.

Conclusions: dcc, unc5c, or netrin-1 haploinsufficiency leads to increased dopamine content in the mPFC and to resilience against amphetamine-induced behavioral activation. Our findings raise the hypothesis that DCC, UNC5C, and netrin-1 act in concert to organize the adolescent development of mesocortical dopamine innervation and, in turn, determine behavioral responses to drugs of abuse.
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http://dx.doi.org/10.1007/s00213-015-4032-9DOI Listing
October 2015

Imaging in vivo glutamate fluctuations with [(11)C]ABP688: a GLT-1 challenge with ceftriaxone.

J Cereb Blood Flow Metab 2015 Jul 25;35(7):1169-74. Epub 2015 Mar 25.

1] Translational Neuroimaging Laboratory (TNL), McGill Center for Studies in Aging, Douglas Mental Health University Institute, Verdun, Quebec, Canada [2] Alzheimer's Disease Research Unit, McGill Centre for Studies in Aging, McGill University, Montreal, Quebec, Canada [3] Montreal Neurological Institute (MNI), Montreal, Quebec, Canada.

Molecular imaging offers unprecedented opportunities for investigating dynamic changes underlying neuropsychiatric conditions. Here, we evaluated whether [(11)C]ABP688, a positron emission tomography (PET) ligand that binds to the allosteric site of the metabotropic glutamate receptor type 5 (mGluR5), is sensitive to glutamate fluctuations after a pharmacological challenge. For this, we used ceftriaxone (CEF) administration in rats, an activator of the GLT-1 transporter (EAAT2), which is known to decrease extracellular levels of glutamate. MicroPET [(11)C]ABP688 dynamic acquisitions were conducted in rats after a venous injection of either saline (baseline) or CEF 200 mg/kg (challenge). Binding potentials (BP(ND)) were obtained using the simplified reference tissue method. Between-condition statistical parametric maps indicating brain regions showing the highest CEF effects guided placement of microdialysis probes for subsequent assessment of extracellular levels of glutamate. The CEF administration increased [(11)C]ABP688 BP(ND) in the thalamic ventral anterior (VA) nucleus bilaterally. Subsequent microdialysis assessment revealed declines in extracellular glutamate concentrations in the VA. The present results support the concept that availability of mGluR5 allosteric binding sites is sensitive to extracellular concentrations of glutamate. This interesting property of mGluR5 allosteric binding sites has potential applications for assessing the role of glutamate in the pathogenesis of neuropsychiatric conditions.
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http://dx.doi.org/10.1038/jcbfm.2015.35DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4640271PMC
July 2015

A highly tunable dopaminergic oscillator generates ultradian rhythms of behavioral arousal.

Elife 2014 Dec 29;3. Epub 2014 Dec 29.

Department of Psychiatry, McGill University, Montreal, Canada.

Ultradian (~4 hr) rhythms in locomotor activity that do not depend on the master circadian pacemaker in the suprachiasmatic nucleus have been observed across mammalian species, however, the underlying mechanisms driving these rhythms are unknown. We show that disruption of the dopamine transporter gene lengthens the period of ultradian locomotor rhythms in mice. Period lengthening also results from chemogenetic activation of midbrain dopamine neurons and psychostimulant treatment, while the antipsychotic haloperidol has the opposite effect. We further reveal that striatal dopamine levels fluctuate in synchrony with ultradian activity cycles and that dopaminergic tone strongly predicts ultradian period. Our data indicate that an arousal regulating, dopaminergic ultradian oscillator (DUO) operates in the mammalian brain, which normally cycles in harmony with the circadian clock, but can desynchronize when dopamine tone is elevated, thereby producing aberrant patterns of arousal which are strikingly similar to perturbed sleep-wake cycles comorbid with psychopathology.
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http://dx.doi.org/10.7554/eLife.05105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337656PMC
December 2014

Presynaptic D2 dopamine receptors control long-term depression expression and memory processes in the temporal hippocampus.

Biol Psychiatry 2015 Mar 20;77(6):513-25. Epub 2014 Mar 20.

Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada; Institut national de la santé et de la recherche médicale, Unité Mixte de Recherche en Santé 1130, and Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8246, Sorbonne University Université Pierre et Marie Curie, Neuroscience Paris Seine, Paris, France. Electronic address:

Background: Dysfunctional mesocorticolimbic dopamine signaling has been linked to alterations in motor and reward-based functions associated with psychiatric disorders. Converging evidence from patients with psychiatric disorders and use of antipsychotics suggests that imbalance of dopamine signaling deeply alters hippocampal functions. However, given the lack of full characterization of a functional mesohippocampal pathway, the precise role of dopamine transmission in memory deficits associated with these disorders and their dedicated therapies is unknown. In particular, the positive outcome of antipsychotic treatments, commonly antagonizing D2 dopamine receptors (D2Rs), on cognitive deficits and memory impairments remains questionable.

Methods: Following pharmacologic and genetic manipulation of dopamine transmission, we performed anatomic, neurochemical, electrophysiologic, and behavioral investigations to uncover the role of D2Rs in hippocampal-dependent plasticity and learning. Naïve mice (n = 4-21) were used in the different procedures.

Results: Dopamine modulated both long-term potentiation and long-term depression in the temporal hippocampus as well as spatial and recognition learning and memory in mice through D2Rs. Although genetic deletion or pharmacologic blockade of D2Rs led to the loss of long-term potentiation expression, the specific genetic removal of presynaptic D2Rs impaired long-term depression and performances on spatial memory tasks.

Conclusions: Presynaptic D2Rs in dopamine fibers of the temporal hippocampus tightly modulate long-term depression expression and play a major role in the regulation of hippocampal learning and memory. This direct role of mesohippocampal dopamine input as uncovered here adds a new dimension to dopamine involvement in the physiology underlying deficits associated with neuropsychiatric disorders.
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http://dx.doi.org/10.1016/j.biopsych.2014.03.013DOI Listing
March 2015

Interhemispheric regulation of the medial prefrontal cortical glutamate stress response in rats.

J Neurosci 2010 Jun;30(22):7624-33

Douglas Hospital Research Centre, Department of Psychiatry, McGill University, Montréal, Québec, Canada.

While stressors are known to increase medial prefrontal cortex (PFC) glutamate (GLU) levels, the mechanism(s) subserving this response remain to be elucidated. We used microdialysis and local drug applications to investigate, in male Long-Evans rats, whether the PFC GLU stress response might reflect increased interhemispheric communication by callosal projection neurons. We report here that tail-pinch stress (20 min) elicited comparable increases in GLU in the left and right PFC that were sodium and calcium dependent and insensitive to local glial cystine-GLU exchanger blockade. Unilateral ibotenate-induced PFC lesions abolished the GLU stress response in the opposite hemisphere, as did contralateral mGlu(2/3) receptor activation. Local dopamine (DA) D(1) receptor blockade in the left PFC potently enhanced the right PFC GLU stress response, whereas the same treatment applied to the right PFC had a much weaker effect on the left PFC GLU response. Finally, the PFC GLU stress response was attenuated and potentiated, respectively, following alpha(1)-adrenoreceptor blockade and GABA(B) receptor activation in the opposite hemisphere. These findings indicate that the PFC GLU stress response reflects, at least in part, activation of callosal neurons located in the opposite hemisphere and that stress-induced activation of these neurons is regulated by GLU-, DA-, norepinephrine-, and GABA-sensitive mechanisms. In the case of DA, this control is asymmetrical, with a marked regulatory bias of the left PFC DA input over the right PFC GLU stress response. Together, these findings suggest that callosal neurons and their afferentation play an important role in the hemispheric specialization of PFC-mediated responses to stressors.
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http://dx.doi.org/10.1523/JNEUROSCI.1187-10.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6632388PMC
June 2010

Interhemispheric regulation of the medial prefrontal cortical glutamate stress response in rats.

J Neurosci 2010 Jun;30(22):7624-33

Douglas Hospital Research Centre, Department of Psychiatry, McGill University, Montréal, Québec, Canada.

While stressors are known to increase medial prefrontal cortex (PFC) glutamate (GLU) levels, the mechanism(s) subserving this response remain to be elucidated. We used microdialysis and local drug applications to investigate, in male Long-Evans rats, whether the PFC GLU stress response might reflect increased interhemispheric communication by callosal projection neurons. We report here that tail-pinch stress (20 min) elicited comparable increases in GLU in the left and right PFC that were sodium and calcium dependent and insensitive to local glial cystine-GLU exchanger blockade. Unilateral ibotenate-induced PFC lesions abolished the GLU stress response in the opposite hemisphere, as did contralateral mGlu(2/3) receptor activation. Local dopamine (DA) D(1) receptor blockade in the left PFC potently enhanced the right PFC GLU stress response, whereas the same treatment applied to the right PFC had a much weaker effect on the left PFC GLU response. Finally, the PFC GLU stress response was attenuated and potentiated, respectively, following alpha(1)-adrenoreceptor blockade and GABA(B) receptor activation in the opposite hemisphere. These findings indicate that the PFC GLU stress response reflects, at least in part, activation of callosal neurons located in the opposite hemisphere and that stress-induced activation of these neurons is regulated by GLU-, DA-, norepinephrine-, and GABA-sensitive mechanisms. In the case of DA, this control is asymmetrical, with a marked regulatory bias of the left PFC DA input over the right PFC GLU stress response. Together, these findings suggest that callosal neurons and their afferentation play an important role in the hemispheric specialization of PFC-mediated responses to stressors.
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http://dx.doi.org/10.1523/JNEUROSCI.1187-10.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6632388PMC
June 2010

Effect of oral glucosamine on cartilage degradation in a rabbit model of osteoarthritis.

Arthritis Rheum 2005 Apr;52(4):1118-28

Faculté de Médecine Vétérinaire, Université de Montréal, St. Hyacinthe, Quebec, Canada.

Objective: To determine whether oral glucosamine alleviates cartilage degradation in an animal model of osteoarthritis (OA).

Methods: The effect of 8 weeks of daily oral glucosamine hydrochloride on degeneration of articular cartilage was evaluated in rabbits in which anterior cruciate ligament transection (ACLT) was performed to induce OA. Animals were treated with glucosamine (n = 16) or a placebo (n = 16) and necropsied at 11 weeks. Seven unoperated rabbits served as controls. The articular cartilage was evaluated macroscopically and histologically and analyzed for total type II collagen and glycosaminoglycan (GAG) content.

Results: Histologic analysis revealed that loss of proteoglycan, based on Safranin O-fast green staining, was significantly reduced in the lateral tibial plateau cartilage of ACL-transected limbs in the glucosamine group compared with ACL-transected limbs in the placebo group, with a similar, but not significant, trend for the lateral femoral condylar cartilage. Likewise, macroscopic analysis of cartilage showed that the lateral tibial plateau alone had a significantly lower rate of disease in the glucosamine group, which was consistent with the results of the independent histologic assessment. However, no significant treatment effect was detected when composite histologic scores were analyzed. A significant reduction in GAG content was observed in the femoral condyles of placebo-treated ACL-transected joints, but not in the same region of glucosamine-treated ACL-transected joints, compared with their respective contralateral unoperated joints.

Conclusion: Oral administration of glucosamine had a detectable, site-specific, partial disease-modifying effect in this model of OA. From a clinical perspective, the administration of glucosamine did not prevent fibrillation and/or erosions of the articular cartilage in all of the treated animals, and no effects were detected in the medial joint compartments.
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http://dx.doi.org/10.1002/art.20951DOI Listing
April 2005
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