G B Baker

University of Alberta, Edmonton, Alberta, Canada

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Publications (424)1424.91 Total impact

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    ABSTRACT: Multiple sclerosis (MS) is classically defined by motor deficits, but it is also associated with the secondary symptoms of pain, depression and anxiety. Up to this point modifying these secondary symptoms has been difficult. There is evidence that both MS and the animal model experimental autoimmune encephalomyelitis (EAE), commonly used to study the pathophysiology of the disease, can be modulated by exercise. To examine whether limited voluntary wheel running could modulate EAE disease progression and the co-morbid symptoms of pain, mice with EAE were allowed access to running wheels for 1hour every day. Allowing only 1hour every day of voluntary running led to a significant delay in the onset of clinical signs of the disease. The development of mechanical allodynia was assessed using Von Frey hairs and indicated that wheel running had a modest positive effect on the pain hypersensitivity associated with EAE. These behavioural changes were associated with reduced numbers of cFOS and phosphorylated NR1 positive cells in the dorsal horn of the spinal cord compared to no-run EAE controls. In addition, within the dorsal horn, voluntary wheel running reduced the number of infiltrating CD3(+) T-cells and reduced the overall levels of Iba1 immunoreactivity. Using high performance liquid chromatography (HPLC), we observed that wheel-running lead to significant changes in the spinal cord levels of the antioxidant glutathione. Oxidative stress has separately been shown to contribute to EAE disease progression and neuropathic pain. Together these results indicate that in mice with EAE, voluntary motor activity can delay the onset of clinical signs and reduce pain symptoms associated with the disease. Copyright © 2015. Published by Elsevier Inc.
    Experimental Neurology 05/2015; DOI:10.1016/j.expneurol.2015.05.017 · 4.62 Impact Factor
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    ABSTRACT: A significant number of people who experience chronic pain also complain of depression and sleep problems. The comorbidities and bidirectional relationships that exist between these ailments are not unheralded, as all three involve similar alterations in structural and functional neurobiology, and share common pathophysiological mechanisms. Comparable changes are seen in levels of serotonin (5-hydroxytryptamine, 5-HT), pro-inflammatory cytokines, brain-derived neurotrophic factor (BDNF) and other transmitters. This review is unique, as it attempts to cast a broader net over the common neurobiological correlates that exist among these three conditions. Perspective This review article highlights important neurophysiological similarities, and key neurobiological links, underlying chronic pain, depression, and sleep problems. Greater awareness of the connections between these conditions may prompt clinicians to actively seek and treat symptoms of all three when one presents, and may provide a rationale for better treatment choices as a result.
    The Clinical journal of pain 05/2015; DOI:10.1097/AJP.0000000000000260 · 2.70 Impact Factor
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    ABSTRACT: Neurodegenerative diseases are characterized by chronic and progressive structural or functional loss of neurons. Limitations related to the animal models of these human diseases have impeded the development of effective drugs. This emphasizes the need to establish disease models using human-derived cells. The discovery of induced pluripotent stem cell (iPSC) technology has provided novel opportunities in disease modeling, drug development, screening, and the potential for "patient-matched" cellular therapies in neurodegenerative diseases. In this study, with the objective of establishing reliable tools to study neurodegenerative diseases, we reprogrammed human umbilical vein endothelial cells (HUVECs) into iPSCs (HiPSCs). Using a novel and direct approach, HiPSCs were differentiated into cells of central nervous system (CNS) lineage, including neuronal, astrocyte and glial cells, with high efficiency. HiPSCs expressed embryonic genes such as nanog, sox2 and Oct-3/4, and formed embryoid bodies that expressed markers of the 3 germ layers. Expression of endothelial-specific genes was not detected in HiPSCs at RNA or protein levels. HiPSC-derived neurons possess similar morphology but significantly longer neurites compared to primary human fetal neurons. These stem cell-derived neurons are susceptible to inflammatory cell-mediated neuronal injury. HiPSC-derived neurons express various amino acids that are important for normal function in the CNS. They have functional receptors for a variety of neurotransmitters such as glutamate and acetylcholine. HiPSC-derived astrocytes respond to ATP and acetylcholine by elevating cytosolic Ca2+ concentrations. In summary, this study presents a novel technique to generate differentiated and functional HiPSC-derived neurons and astrocytes. These cells are appropriate tools for studying the development of the nervous system, the pathophysiology of various neurodegenerative diseases and the development of potential drugs for their treatments.
    PLoS ONE 03/2015; 10(3):e0119617. DOI:10.1371/journal.pone.0119617 · 3.53 Impact Factor
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    ABSTRACT: Background Better treatments for schizophrenia are urgently needed. The therapeutic use of the nitric oxide (NO)-donor sodium nitroprusside (SNP) in patients with schizophrenia has shown promising results. The role of NO in schizophrenia is still unclear, and NO modulation is unexplored in ketamine (KET) animal models to date. In the present study, we compared the behavioral effects of pre- and post-treatment with SNP, glyceryl trinitrate (GTN), and methylene blue (MB) in the acute KET animal model of schizophrenia. The present study was designed to test whether acute SNP, GTN, and MB treatment taken after (therapeutic effect) or before (preventive effect) a single KET injection would influence the behavior of rats in the sucrose preference test, object recognition task and open field. Results The results showed that KET induced cognitive deficits and hyperlocomotion. Long- term memory improvement was seen with the therapeutic GTN and SNP treatment, but not with the preventive one. MB pretreatment resulted in long-term memory recovery. GTN pre-, but not post-treatment, tended to increase vertical and horizontal activity in the KET model. Therapeutic and preventive SNP treatment consistently decreased KET-induced hyperlocomotion. Conclusion NO donors – especially SNP – are promising new pharmacological candidates in the treatment of schizophrenia. In addition, we showed that the potential impact of NO-related compounds on KET-induced behavioral changes may depend on the temporal window of drug administration.
    BMC Neuroscience 03/2015; 16:1-9. DOI:10.1186/s12868-015-0149-3 · 2.85 Impact Factor
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    ABSTRACT: B y modulating the "glutamate-NO (nitric oxide)-cGMP" pathway," a new paradigm for the treatment of schizophrenia seems to arise. Indeed, our group has recently pub-lished a double-blind placebo (PLB) con-trolled trial showing that an infusion of sodium nitroprusside (SNP), a nitric oxide donor, improved positive, negative, anxiety, and depressive symptoms of schizophrenic patients in a matter of hours. 1 During this study, it seemed of interest to test the idea that SNP might also be effective in treating cognitive symptoms found in schizophrenia. For this purpose, it was performed, in the same subjects just mentioned, a pilot study where the patients were evaluated by a battery of cognitive tests on 2 occasions: 1 hour be-fore the start of SNP or PLB infusion and at 8 hours after the end of SNP or PLB infusion. Twenty-four patients agreed to partici-pate and were assessed for eligibility; 4 sub-jects subsequently refused to participate, and 20 individuals were randomized to receive either SNP or placebo. Two subjects from the SNP group refused to participate in the sec-ond cognitive evaluation (cognitive evaluation at 8 hours after the end of the SNP infusion). The other 18 participants who were random-ized completed all the study procedures. The SNP was administered as an endovenous infusion of 0 . 5 μg/kg per min-ute for 4 hours. The placebo was a 5% glu-cose solution that was endovenous infused over the same length of time. The following cognitive tests were con-ducted: (a) Stroop Color Word Test (SCWT) is a test to assess selective attention. Two cards instead of the 3 cards originally pro-posed by Stroop were used, following the procedure used by Liddle and Morris. 2 On the first card 100 words designating 5 colors, printed in black, were used; and on the sec-ond card, 100 words for the same colors, printed in colors incongruent with the des-ignation were used. The task was to read card 1 and designate the colors of card 2. Time spent on the task was measured in seconds and number of errors committed, according to the method proposed by Seabra (1987). (b) N-Back is a test to assess work-ing memory. It lasts about 6 minutes and consists of examining a series of numbers where it is required, at varying intervals, to report the number seen "n" positions back in the sequence. A printed version of the test on laminated cards was used in this study, with 2 distinct blocks presented in-terchangeably. The first and the third blocks contain 5 questions each about the last num-ber seen ("0-Back," task control), and the sec-ond and fourth blocks contain 5 questions each about which number was submitted before the last 2 cards ("2-Back"). The num-ber of errors made during the task was com-puted. (c) FAS (the Verbal Fluency Test) is a test widely used in the literature to measure verbal fluency, which is known to be impaired in schizophrenic patients. The task consists of a period of 3 minutes (1 minute for each letter—F, A, and S) where the volunteer must produce the largest number of words begin-ning with those letters. Brand names, proper names, or variations from the same root (eg, words like fall and fallen) are not allowed. Data were analyzed using the Statistical Package for the Social Sciences (SPSS 17·0). For the SCWT, N-Back, and the FAS scores, separate analyses of variance (ANOVAs) for repeated measures were carried out, with treatment (SNP/PLB) and time (every point of evaluation) as factors. If the ANOVAs were significant, a paired 2-tailed t test was per-formed, considering the groups independently. The following results were found: (a) SCWT—the ANOVA for repeated mea-sures concerning card 1 reading time showed an effect of the time factor (F = 6.98, df = 1–15, P = 0.02), but not drug (F = 1.46, df = 1–15, P = 0.24) and no interaction between time and drug (F = 0.03, df = 1–15, P = 0.85). The analysis of the number of errors on card 1 showed no effect of time (F = 2.4, df = 1–15, P = 0.14), drug (F = 0.18, df = 1–15, P = 0.68), or interaction between time and drug (F = 0.03, df = 1–15, P = 0.86). An interac-tion between time and drug was found for the number of errors on naming incongru-ent colors on card 2 (F = 5.54, df = 1–15, P = 0.03), but no effect of time (F = 0.57, df = 1–15, P = 0.46) or of drug alone (F = 0.03, df = 1–15, P = 0.85). Regarding the time for naming incongruent colors, the ANOVA for repeated measures showed no effect of time (F = 0.02, df = 1–15, P = 0.89), drug (F = 0.71, df = 1–15, P = 0.42), or in-teraction between them (F = 2.32, df = 1–15, P = 0.15). In situations where the ANOVA for repeated measures identified some in-teraction, the paired t test was performed, considering the groups independently. The paired t test for the 2 groups individually (SNP and PLB) showed that those patients who received SNP made fewer errors in the second evaluation of naming incongruent colors, but those who received PLB did not. (b) FAS—the ANOVA for repeated measures showed an effect of time (F = 9.37, df = 1–16, P = 0.01), but not of drug (F = 0.08, df = 1–16, P = 0.78) and no interaction between time and drug (F = 0.03, df = 1–16, P = 0.85). (c) N-Back—the ANOVA for repeated mea-sures identified an effect of time (F = 7.63, df = 1–14, P = 0·01), drug (F = 7.76, df = 1–14, P = 0.01), and also an interaction be-tween these 2 (F = 15.24, df = 1–14, P < 0.01). Thus, the paired t test was conducted for the SNP and PLB groups alone, which showed that those who received the SNP infusion pre-sented significant improvement in congnitive performance, whereas those who received the PLB infusion did not (Table 1). To our knowledge, this is the first time that improvements on executive functions that are frequently impaired in patients with schizophrenia were shown after SNP admin-istration. The improvement in SCWT and N-back performance that was observed in the SNP group, but not in the PLB group, suggests that treatment with SNP had an impact on patients cognitive functioning by improving selective attention 3 and work-ing memory 4 deficits. These beneficial effects could be ex-plained through SNP capacity, as a NO do-nor, to act by increasing the concentrations of the second messenger cGMP and medi-ating the neuronal communication in the CNS (central nervous system). 5,6 In this way, NO has been shown to influence learning and memory. 7 NO donors such as SNP have been found to stimulate neuronal growth in vitro 8 and have been proposed as potential new drugs to treat patients with age-related neurodegenerative disease such as Alzheimer disease. 9,10 On the other hand, too much NO could produce neurotoxicity due to accumu-lation of its toxic metabolite, peroxynitrite. 11 The small amount of patients studied is the limitation of this work. Future studies with a larger number of patients are needed. The usual NPS safe dose rate used to treat hypertension is 0.5 to 10 μg/kg per minute. Therefore, we decide to work with its low-est dose to minimize cardiovascular effects. Indeed, no clear effect of NPS on the vascu-lar system was observed (these results have been discussed elsewhere). 1 Further works should investigate the effects of multiple and different doses of SNP and other rele-vant issues like how frequently do we have to administer SNP to sustain its effect in long-term. To minimize possible learning effects, cognitive tests were performed only on 2 occasions. To avoid confounding LETTER TO THE EDITORS Journal of Clinical Psychopharmacology • Volume 35, Number 1, February 2015 www.psychopharmacology.com 1 Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. factors from demographic and clinical vari-ables, the selection and pairing of subjects were performed carefully and showed no differences between the 2 groups in any of the parameters evaluated (these results have been discussed elsewhere). 1 Despite the cognitive deficits being considered as the strongest predictors of long-term functional recovery in patients with schizophrenia, they have been among the symptoms most refractory to the treat-ment by both second-and first-generation antipsychotics. 12,13 Perhaps, the develop-ment of drugs that enhance NO levels, such as SNP, could be a productive target to pur-sue in the development of the next genera-tion of antipsychotic drugs. However, the findings here reported are modest and need to be confirmed for future studies. ACKNOWLEDGMENTS The authors thank their respective universities for the continuous support and Dr Judy Baker for the editorial and secretarial assistance.
    Journal of clinical psychopharmacology 02/2015; 35(1):1. DOI:10.1097/JCP.0000000000000258 · 3.76 Impact Factor
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    ABSTRACT: Recently, we found a rapid and long-lasting improvement of symptoms in schizophrenic patients on antipsychotics after a single four-hour infusion of sodium nitroprusside (SNP), a nitric oxide (NO) donor with a short half-life. This improvement persisted for up to 4 weeks. Because these patients remained on antipsychotics after infusion of SNP was finished, the question arises about whether this improvement was due to SNP itself. We have now investigated whether SNP, alone, can produce preventive antipsychotic effects in rats treated with ketamine (KET). 56 adult rats divided into 7 groups were infused with SNP 4 mg/kg, KET 25 mg/kg, or saline as follows: group1 — saline, group2 — SNP, group3 — KET, group4 — KET 12 h after SNP, group5 — KET 1 day after SNP, group6 — KET 2 days after SNP, and group7 — KET 1 week after SNP. The animals were filmed in an open field arena for 30 min and the videos were later analyzed by ANY-Maze software to measure activity and stereotypy. SNP significantly prevented the emergence of hyperactivity induced by KET when it was administered for up to 1 week before KET, and prevented the emergence of stereotypies when it was administered for up to 1 day before KET. These findings in rats, which have an even faster metabolic rate than humans, suggest that the long-lasting effects observed in our clinical trial with SNP in humans could have been due to SNP itself, and indicate for the first time that SNP may present preventive antipsychotic effects.
    Schizophrenia Research 01/2015; 162(1-3). DOI:10.1016/j.schres.2014.12.035 · 4.43 Impact Factor
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    ABSTRACT: Increasing evidence suggests that the tetracycline antibiotic minocycline has neuroprotective effects and is a potential treatment for schizophrenia. However, the mechanisms of action of minocycline in the CNS remain elusive. The aim of this study was to investigate the effects of minocycline on brain morphology and cerebral perfusion in patients with recent-onset schizophrenia after 12 months of a randomized double-blind, placebo-controlled clinical trial of minocycline add-on treatment. This study included 24 outpatients with recent-onset schizophrenia randomized for 12 months of adjuvant treatment with minocycline (200 mg/d) or placebo. MRI (1.5 T) and [ 99m Tc]-ECD SPECT brain scans were performed at the end of the 12-month of trial. Between-condition comparisons of SPECT and MRI brain images were performed using statistical parametric mapping and analyzed by voxel-based morphometry (VBM). Minocycline adjuvant treatment significantly reduced positive and negative symptoms when compared with placebo. The VBM analysis of MRI scans showed that the patients in the placebo group had significant lower gray matter volumes in the midposterior cingulate cortex and in the precentral gyrus in comparison with the patients in the minocycline group. In addition, a decreased ECD uptake in the minocycline condition was observed in fronto-temporal areas. These results suggest that minocycline may protect against gray matter loss and modulate fronto-temporal areas involved in the pathophysiology of schizophrenia. Furthermore, minocycline add-on treatment may be a potential treatment in the early stages of schizophrenia and may ameliorate clinical deterioration and brain alterations observed in this period.
    Schizophrenia Research 12/2014; 161(2-3). DOI:10.1016/j.schres.2014.11.031 · 4.43 Impact Factor
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    ABSTRACT: ZET: fiizofreni için yeni tedavi stratejileri olarak nitrik oksit modülasyonu Antipsikotik ilaç gelifltirilmesindeki son ilerlemelere ra¤-men, flizofreninin farmakolojik yönetimi görece yetersiz kalmaktad›r. Santral nitrik oksit modülasyonuna dair artan kan›tlar flizofreni tedavisi için yeni bir tedavi stratejisi suna-bilir. Bu nedenle, bu editöryal yaz›da flizofreni ve antipsiko-tik ilaçlar›n mekanizmas› ile santral nitrik oksit patofizyolo-jisi iliflkisi anlat›lmaya çal›fl›lmaktad›r. Nitrik oksit modülas-yonunun yeni stratejileri flizofreni için potansiyel bir farma-koterapi yöntemi olarak karfl›m›zda durmaktad›r.
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    Schizophrenia Research 11/2014; 159(2-3). DOI:10.1016/j.schres.2014.08.020 · 4.43 Impact Factor
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    Journal of clinical psychopharmacology 09/2014; DOI:10.1097/JCP.0000000000000217 · 3.76 Impact Factor
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    ABSTRACT: Primary human fetal neurons and astrocytes (HFNs and HFAs, respectively) provide relevant cell types with which to study in vitro the mechanisms involved in various human neurological diseases, such as multiple sclerosis, Parkinson's disease, and Alzheimer's disease. However, the limited availability of human fetal cells poses a significant problem for the study of these diseases when a human cell model system is required. Thus, generating a readily available alternative cell source with the essential features of human neurons and astrocytes is necessary. The human teratoma-derived NTera2/D1 (NT2) cell line is a promising tool from which both neuronal and glial cells can be generated. Nevertheless, a direct comparison of NT2 neurons and primary HFNs in terms of their morphology physiological and chemical properties is still missing. This study directly compares NT2-derived neurons and primary HFNs using immunocytochemistry, confocal calcium imaging, high-performance liquid chromatography, and high-content analysis techniques. We investigated the morphological similarities and differences, levels of relevant amino acids, and internal calcium fluctuations in response to certain neurotransmitters/stimuli. We also compared NT2-derived astrocytes and HFAs. In most of the parameters tested, both neuronal and astrocytic cell types exhibited similarities to primary human fetal neurons and astrocytes. NT2-derived neurons and astrocytes are reliable in vitro tools and a renewable cell source that can serve as a valid alternative to HFNs/HFAs for mechanistic studies of neurological diseases. © 2014 Wiley Periodicals, Inc.
    Journal of Neuroscience Research 09/2014; 92(9). DOI:10.1002/jnr.23399 · 2.73 Impact Factor
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    ABSTRACT: Background Neuropsychiatric disorders during HIV/AIDS are common although the contribution of HIV-1 infection within the brain, and in particular individual HIV-1 proteins, to the development of these brain disorders is unknown. Herein, an in vivo transgenic mouse model was generated in which the HIV-1 Nef protein was expressed in microglia cells, permitting investigation of neurobehavioral phenotypes and associated cellular and molecular properties. Methods Transgenic (Tg) mice that expressed full length HIV-1 nef under the control of the c-fms promoter and wildtype (Wt) littermates were investigated using different measures of neurobehavioral performance including locomotory, forced swim (FST), elevated plus maze (EPM) and T-maze tests. Host gene and transgene expression were assessed by RT-PCR, immunoblotting, enzymatic activity and immunohistochemistry. Biogenic amine levels were measured by HPLC with electrochemical detection. Results Tg animals exhibited Nef expression in brain microglia and cultured macrophages. Tg males displayed hyperactive behaviors including augmented locomotor activity, decreased immobility in the FST and increased open-arm EPM exploration compared to Wt littermates (p<0.05). Tg animals showed increased CCL2 expression with concurrent IFN-α suppression in striatum compared with Wt littermates (p<0.05). Dopamine levels, MAO activity and the dopamine transporter (DAT) expression were reduced in the striatum of Tg animals (p<0.05). Conclusions HIV-1 Nef expression in microglia induced CCL2 expression together with disrupting striatal dopaminergic transmission, resulting in hyperactive behaviors which are observed in mania and other psychiatric comorbidities among HIV-infected persons. These findings emphasize the selective effects of individual viral proteins in the brain and their participation in neuropathogenesis.
    Brain Behavior and Immunity 08/2014; DOI:10.1016/j.bbi.2014.02.016 · 6.13 Impact Factor
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    ABSTRACT: The progesterone derivative allopregnanolone (ALLO) is one of the most widely studied compounds among neurosteroids. Through interactions with GABA-A receptors expressed by neurons and glial cells, ALLO has been shown to affect diverse aspects of neural cell physiology, including cell proliferation and survival, migration, and gene expression. Recent data point to important roles for ALLO in different neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis (MS). Dysregulation in ALLO biosynthesis pathways has been reported in brain tissue from MS patients as well as in the central nervous system (CNS) tissue derived from MS animal models. Administration of ALLO has been shown to ameliorate neurobehavioral deficits together with neuropathology and inflammation in the CNS of animals with autoimmune demyelination. These findings are in line with previous reports indicating growth- and differentiation-promoting actions of ALLO on neurons and glial cells as well as its neuroprotective effects in the context of other CNS diseases. Nonetheless, these findings have also raised the possibility that ALLO might influence leukocyte biology and associated neuroinflammatory mechanisms independent of its neuroregenerative properties. Herein, we review the current knowledge regarding the role of ALLO in the pathogenesis of MS, and discuss the potential cellular and molecular pathways that might be influenced by ALLO in the context of disease.
    Frontiers in Cellular Neuroscience 06/2014; 8:134. DOI:10.3389/fncel.2014.00134 · 4.18 Impact Factor
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    ABSTRACT: Interactions between neurotransmitters and the immune system represent new prospects for understanding neuroinflammation and subsequent neurological disease. γ-amino butyric acid (GABA) is the chief inhibitory neurotransmitter but its actions on immune pathways in the brain are unclear. In the present study, we investigated GABAergic transport in conjunction with neuroinflammation in models of multiple sclerosis (MS). Protein and mRNA levels of γ-amino butyric acid transporter 2 (GAT-2) were examined in cerebral white matter from MS and control (Non-MS) patients, in cultured human macrophages, microglia and astrocytes, and in spinal cords from mice with and without experimental autoimmune encephalomyelitis (EAE) using western blotting, immunocytochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). GABA levels were measured by HPLC. The GAT-2's expression was increased in multiple sclerosis (MS) patients' (n=6) white matter, particularly in macrophage lineage cells, compared to Non-MS patients (n=6) (p<0.05). Interferon-γ (IFN-γ) stimulation of human macrophage lineage cells induced GAT-2 expression and reduced extracellular GABA levels (p<0.05) but soluble GABA treatment suppressed HLA-DRα, GAT-2 and XBP-1/s expression in stimulated macrophage lineage cells (p<0.05). Similarly, the synthetic allopregnanolone analogue, ganaxolone (GNX), repressed GAT-2, JAK-1 and STAT-1 expression in activated macrophage lineage cells (p<0.05). In vivo GNX treatment reduced Gat-2, Cd3ε, MhcII, and Xbp-1/s expression in spinal cords following EAE induction (p<0.05), which was correlated with improved neurobehavioral outcomes and reduced neuroinflammation, demyelination and axonal injury. These findings highlight altered GABAergic transport through GAT-2 induction during neuroinflammation. GABA transport and neuroinflammation are closely coupled but regulated by GNX, pointing to GABAergic pathways as therapeutic targets in neuroinflammatory diseases.
    Neuroscience 05/2014; 273. DOI:10.1016/j.neuroscience.2014.04.037 · 3.33 Impact Factor
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    ABSTRACT: Despite decades of study, the etiology and physiopathology of schizophrenia remain unknown. Recent evidence suggests that nitric oxide (NO) may be implicated in schizophrenia. NO is a gas that mediates the release of neurotransmitters, learning, memory, and neurodevelopment. Studies investigating the role of NO in patients with schizophrenia found evidence that points to a disruption in NO-mediated neurotransmission. Therefore, we investigated the effects of sodium nitroprusside, a NO donor, as an add- on treatment for patients with schizophrenia.
    Schizophrenia Research 04/2014; 153(1):1-384. DOI:10.1016/S0920-9964(14)70258-0 · 4.43 Impact Factor
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    ABSTRACT: Phenelzine, a non-selective irreversible inhibitor of monoamine oxidase (MAO), has been used in the treatment of depression and anxiety disorders for several decades. It is a unique inhibitor of MAO as it is also a substrate for MAO, with one of the metabolites being β-phenylethylidenehydrazine (PEH), and it also inhibits several transaminases (e.g. GABA transaminase) in the brain when administered i.p. to rats. Administration of either phenelzine or PEH to rats has been reported to produce dramatic increases in rat brain levels of GABA and alanine while reducing levels of glutamine; these effects are abolished for phenelzine, but not for PEH, when the animals are pre-treated with another MAO inhibitor, suggesting that they are mediated by the MAO-catalyzed formation of PEH from phenelzine. In the present report, we have found that phenelzine and E-and Z- geometric isomers of PEH significantly increased rat whole brain concentrations of L-tyrosine. In a time-response study, acute administration of phenelzine, E-PEH and Z-PEH (30mg/kgi.p.) elevated rat whole brain L-tyrosine levels at 3 and 6hours following injection, reaching approximately 265-305% of vehicle-treated controls at 3hours. To determine whether the effect on L-tyrosine is MAO-dependent, animals were pre-treated with the non-selective MAO inhibitor tranylcypromine (1mg/kgi.p.) prior to administration of phenelzine, racemic PEH or vehicle controls. This pre-treatment reversed the effects of phenelzine, but not of PEH, on brain L-tyrosine levels, suggesting that the tyrosine-elevating property of phenelzine is largely the result of its active metabolite PEH. These results are discussed in relation to possible therapeutic applications of these drugs.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 03/2014; 53. DOI:10.1016/j.pnpbp.2014.02.011 · 4.03 Impact Factor
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    ABSTRACT: Converging evidence from clinical, preclinical, neuroimaging, and genetic research implicates dopamine neurotransmission in the pathophysiology of attention deficit hyperactivity disorder(ADHD). In-vivo neuroreceptor imaging evidence also suggests alterations in the dopamine system in ADHD, however, the nature and behavioural significance of those have not yet been established. Here, we investigated striatal dopaminergic function in ADHD using [(11)C]raclopride PET with a d-amphetamine challenge. We also examined the relationship of striatal dopamine responses to ADHD symptoms and neurocognitive function. Fifteen treatment-free, non-comorbid adult males with ADHD (age: 29.87±8.65) and 18 healthy male controls (age: 25.44±6.77) underwent two PET scans: one following a lactose placebo and the other following d-amphetamine (0.3 mg/kg, p.o.), administered double-blind and in random order counterbalanced across groups. In a separate session without a drug, participants performed a battery of neurocognitive tests. Relative to the healthy controls, the ADHD patients, as a group, showed greater d-amphetamine-induced decreases in striatal [(11)C]raclopride binding and performed more poorly on measures of response inhibition. Across groups, a greater magnitude of d-amphetamine-induced change in [(11)C]raclopride binding potential was associated with poorer performance on measures of response inhibition and ADHD symptoms. Our findings suggest an augmented striatal dopaminergic response in treatment-naïve ADHD. Though in contrast to results of a previous study, this finding appears consistent with a model proposing exaggerated phasic dopamine release in ADHD. A susceptibility to increased phasic dopamine responsivity may contribute to such characteristics of ADHD as poor inhibition and impulsivity.Neuropsychopharmacology accepted article preview online, 30 December 2013. doi:10.1038/npp.2013.349.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 12/2013; DOI:10.1038/npp.2013.349 · 7.83 Impact Factor
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    ABSTRACT: Not everyone who tries addictive drugs develops a substance use disorder. One of the best predictors of risk is a family history (FH) of substance use problems. In part, this might reflect perturbed mesolimbic dopamine responses. We measured amphetamine-induced changes in [(11)C]raclopride binding in 1) high-risk young adults with a multigenerational FH of substance use disorders (n = 16); 2) stimulant drug-naïve healthy control subjects with no known risk factors for addiction (n = 17); and 3) subjects matched to the high-risk group on personal drug use but without a FH of substance use problems (n = 15). Compared with either control group, the high-risk young adults with a multigenerational FH of substance use disorders exhibited smaller [(11)C]raclopride responses, particularly within the right ventral striatum. Past drug use predicted the dopamine response also, but including it as a covariate increased the group differences. Together, the results suggest that young people at familial high risk for substance use disorders have decreased dopamine responses to an amphetamine challenge, an effect that predates the onset of addiction.
    Biological psychiatry 10/2013; 76(1). DOI:10.1016/j.biopsych.2013.08.033 · 9.47 Impact Factor
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    ABSTRACT: Spinal cord transection leads to the elimination of the brainstem-derived monoamine fibres that normally synthesize most of the monoamines in the spinal cord, including serotonin (5-HT) that is synthesized from tryptophan by the enzymes tryptophan hydroxylase (TPH, synthesizing 5-hydroxytryptophan, 5-HTP) and aromatic L-amino acid decarboxylase (AADC, synthesizing 5-HT from 5-HTP). Here we examine whether the spinal cord of transected rats remains able to manufacture and metabolize 5-HT. Immunolabelling for AADC reveals that, while most AADC is confined to brainstem-derived monoamine fibres in spinal cords from normal rats, caudal to a transection AADC is primarily in blood vessel endothelial cells and pericytes, as well as in a novel group of neurons (NeuN positive and GFAP negative), all of which strongly upregulate AADC with injury. However, immunolabelling for 5-HT reveals that there is no detectable endogenous 5-HT synthesis in any structure in the spinal cord caudal to a chronic transection, including in AADC containing vessels and neurons, consistent with a lack of TPH. In contrast, when we applied exogenous 5-HTP (in vitro or in vivo), AADC-containing vessels and neurons synthesized 5-HT, which contributed to increased motoneuron activity and muscle spasms (long-lasting reflexes, LLRs), by acting on 5-HT2 receptors (SB206553-sensitive) located on motoneurons (TTX-resistant). Blocking monoamine oxidase (MAO) markedly increased the sensitivity of the motoneurons (LLR) to 5-HTP. In summary, after spinal cord injury AADC is upregulated in vessels, pericytes and neurons, but does not produce 5-HT that affects motoneurons unless exogenous 5-HTP is administered.
    Journal of Neurophysiology 09/2013; 111(1). DOI:10.1152/jn.00508.2013 · 3.04 Impact Factor
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    ABSTRACT: The meso-striatal dopamine system influences responses to rewards and the motivation to seek them out. Marked individual differences in these responses are seen in laboratory animals, related in part to input from the prefrontal cortex. Here we measured the relation between cortical morphology and drug-induced striatal dopamine release in healthy young people. Participants were 24 (17 male, 7 female; age 23.0 ± 6.2 years) stimulant drug-naive subjects who underwent PET [(11)C]raclopride scans with 0.3 mg/kg d-amphetamine orally and placebo, and an anatomical MRI scan for measuring cortical thickness. As expected, d-amphetamine produced significant reductions in [(11)C]raclopride binding potential in the striatum as a percentage of the value in the placebo condition. There was substantial individual variability in this response, which was correlated with cortical thickness in the frontal lobe as a whole. The association was strongest in the anterior part of the right lateral prefrontal cortex and bilateral supplementary motor area. A thicker cortex was correlated with a smaller dopamine response. Together, this work demonstrates in humans an association between cortical thickness and the striatal dopamine response to drugs of abuse. Although prefrontal regulation of striatal function has been well studied, it was unclear whether the thickness of the prefrontal cortex was an acceptable proxy to the function of that region. These results suggest it is.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 09/2013; 33(38):15285-94. DOI:10.1523/JNEUROSCI.5029-12.2013 · 6.75 Impact Factor

Publication Stats

7k Citations
1,424.91 Total Impact Points

Institutions

  • 1980–2015
    • University of Alberta
      • • Department of Psychiatry
      • • Faculty of Pharmacy and Pharmaceutical Sciences
      • • Division of Neurosurgery
      Edmonton, Alberta, Canada
  • 2009
    • University of Arkansas for Medical Sciences
      • Department of Psychiatry
      Little Rock, Arkansas, United States
  • 2008
    • University of Saskatchewan
      • Department of Physiology
      Saskatoon, Saskatchewan, Canada
  • 1999–2007
    • McGill University
      • Department of Psychiatry
      Montréal, Quebec, Canada
  • 2003
    • Gracie Square Hospital, New York, NY
      New York City, New York, United States
  • 2002
    • University of Toronto
      • Department of Psychiatry
      Toronto, Ontario, Canada
  • 2000
    • National Defense Medical Center
      • Tri-Service General Hospital
      Taipei, Taipei, Taiwan
  • 1986–1996
    • The University of Western Ontario
      • Department of Psychology
      London, Ontario, Canada
  • 1991–1995
    • The Ohio State University
      • Department of Psychiatry
      Columbus, OH, United States
  • 1989
    • TEC Edmonton
      Edmonton, Alberta, Canada