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Depression: HELP
Articles by Andrew Harkin
Based on 26 articles published since 2010
(Why 26 articles?)
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Between 2010 and 2020, A. Harkin wrote the following 26 articles about Depression.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Gut-brain actions underlying comorbid anxiety and depression associated with inflammatory bowel disease. 2018

Abautret-Daly, Áine / Dempsey, Elaine / Parra-Blanco, Adolfo / Medina, Carlos / Harkin, Andrew. ·1Neuropsychopharmacology Research Group,Trinity College Institute of Neuroscience,Trinity College,Dublin,Ireland. · 3Department of Gastroenterology,Hospital Central de Asturias,Oviedo,Spain. ·Acta Neuropsychiatr · Pubmed #28270247.

ABSTRACT: IntroductionInflammatory bowel disease (IBD) is a chronic relapsing and remitting disorder characterised by inflammation of the gastrointestinal tract. There is a growing consensus that IBD is associated with anxiety- and depression-related symptoms. Psychological symptoms appear to be more prevalent during active disease states with no difference in prevalence between Crohn's disease and ulcerative colitis. Behavioural disturbances including anxiety- and depression-like symptoms have also been observed in animal models of IBD. RESULTS: The likely mechanisms underlying the association are discussed with particular reference to communication between the gut and brain. The close bidirectional relationship known as the gut-brain axis includes neural, hormonal and immune communication links. Evidence is provided for a number of interacting factors including activation of the inflammatory response system in the brain, the hypothalamic-pituitary-adrenal axis, and brain areas implicated in altered behaviours, changes in blood brain barrier integrity, and an emerging role for gut microbiota and response to probiotics in IBD.DiscussionThe impact of psychological stress in models of IBD remains somewhat conflicted, however, it is weighted in favour of stress or early stressful life events as risk factors in the development of IBD, stress-induced exacerbation of inflammation and relapse. CONCLUSION: It is recommended that patients with IBD be screened for psychological disturbance and treated accordingly as intervention can improve quality of life and may reduce relapse rates.

2 Review Recent Advances in Translational Magnetic Resonance Imaging in Animal Models of Stress and Depression. 2017

McIntosh, Allison L / Gormley, Shane / Tozzi, Leonardo / Frodl, Thomas / Harkin, Andrew. ·Institute of Neuroscience, Trinity College DublinDublin, Ireland. · Universitätsklinikum A.ö.R, Universitätsklinik für Psychiatrie und Psychotherapie, Medizinische Fakultät, Otto von Guericke UniversitätMagdeburg, Germany. · School of Pharmacy and Pharmaceutical sciences, Trinity College DublinDublin, Ireland. ·Front Cell Neurosci · Pubmed #28596724.

ABSTRACT: Magnetic resonance imaging (MRI) is a valuable translational tool that can be used to investigate alterations in brain structure and function in both patients and animal models of disease. Regional changes in brain structure, functional connectivity, and metabolite concentrations have been reported in depressed patients, giving insight into the networks and brain regions involved, however preclinical models are less well characterized. The development of more effective treatments depends upon animal models that best translate to the human condition and animal models may be exploited to assess the molecular and cellular alterations that accompany neuroimaging changes. Recent advances in preclinical imaging have facilitated significant developments within the field, particularly relating to high resolution structural imaging and resting-state functional imaging which are emerging techniques in clinical research. This review aims to bring together the current literature on preclinical neuroimaging in animal models of stress and depression, highlighting promising avenues of research toward understanding the pathological basis of this hugely prevalent disorder.

3 Review Stress-Related Immune Markers in Depression: Implications for Treatment. 2016

Hughes, Martina M / Connor, Thomas J / Harkin, Andrew. ·Neuroimmunology Research Group, Department of Physiology, School of Medicine & Trinity College Institute of Neuroscience (Drs Hughes and Connor), and Neuropsychopharmacology Research Group, School of Pharmacy and Pharmaceutical Sciences & Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland (Dr Harkin). · Neuroimmunology Research Group, Department of Physiology, School of Medicine & Trinity College Institute of Neuroscience (Drs Hughes and Connor), and Neuropsychopharmacology Research Group, School of Pharmacy and Pharmaceutical Sciences & Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland (Dr Harkin). aharkin@tcd.ie. ·Int J Neuropsychopharmacol · Pubmed #26775294.

ABSTRACT: Major depression is a serious psychiatric disorder; however, the precise biological basis of depression still remains elusive. A large body of evidence implicates a dysregulated endocrine and inflammatory response system in the pathogenesis of depression. Despite this, given the heterogeneity of depression, not all depressed patients exhibit dysregulation of the inflammatory and endocrine systems. Evidence suggests that inflammation is associated with depression in certain subgroups of patients and that those who have experienced stressful life events such as childhood trauma or bereavement may be at greater risk of developing depression. Consequently, prolonged exposure to stress is thought to be a key trigger for the onset of a depressive episode. This review assesses the relationship between stress and the immune system, with a particular interest in the mechanisms by which stress impacts immune function, and how altered immune functioning, in turn, may lead to a feed forward cascade of multiple systems dysregulation and the subsequent manifestation of depressive symptomology. The identification of stress-related immune markers and potential avenues for advances in therapeutic intervention is vital. Changes in specific biological markers may be used to characterize or differentiate depressive subtypes or specific symptoms and may predict treatment response, in turn facilitating a more effective, targeted, and fast-acting approach to treatment.

4 Review The PSD-95/nNOS complex: new drugs for depression? 2012

Doucet, Marika V / Harkin, Andrew / Dev, Kumlesh K. ·Molecular Neuropharmacology, Department of Physiology, Trinity College, Dublin 2, Ireland. ·Pharmacol Ther · Pubmed #22133842.

ABSTRACT: Drug treatment of major depressive disorder is currently limited to the use of agents which influence monoaminergic neuronal transmission including inhibitors of presynaptic transporters and monoamine oxidase. Typically improvement in depressive symptoms only emerges after several weeks of treatment, suggesting that downstream neuronal adaptations rather than the elevation in synaptic monoamine levels are responsible for antidepressant effects. In recent years, the NMDA receptor has emerged as a promising target for treating CNS disorders including stroke, pain and depression. In this review, we outline the molecular mechanisms underlying NMDA receptor signalling in neurons and in particular provide an overview of the role of the NMDAR/PSD-95/nNOS complex in CNS disorders. We discuss novel drug developments made that suggest the NMDAR/PSD-95/nNOS complex as a potential target for the treatment of depression. The review also provides examples of how PDZ-based protein-protein interactions can be exploited as novel drug targets for disease.

5 Article Tryptophan metabolite concentrations in depressed patients before and after electroconvulsive therapy. 2020

Ryan, Karen M / Allers, Kelly A / McLoughlin, Declan M / Harkin, Andrew. ·Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland; Department of Psychiatry, St. Patrick's University Hospital, Trinity College Dublin, Dublin, Ireland. · Central Nervous System Disease Research, Boehringer Ingelheim Pharma GmbH + Co. KG, Birkendorferstrabe 65, Biberach a.d. Riss, Germany. · Neuropsychopharmacology Research Group, School of Pharmacy and Pharmaceutical Sciences & Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland. Electronic address: aharkin@tcd.ie. ·Brain Behav Immun · Pubmed #31606477.

ABSTRACT: Tryptophan and kynurenine pathway (KP) metabolites are implicated in the pathophysiology of depression. We aimed to investigate their plasma concentrations in medicated patients with depression (n = 94) compared to age- and sex-matched healthy controls (n = 57), and in patients with depression after electroconvulsive therapy (ECT) in a real-world clinical setting, taking account of co-variables including ECT modality and heterogenous psychopathology. Depression severity was assessed using the Hamilton Depression Rating Scale (HAM-D24). Tryptophan (TRP) and kynurenine (KYN) metabolite concentrations [anthranilic acid (AA), 3-hydroxyanthranilic acid (3HAA), picolinic acid (PA), kynurenic acid (KYNA), and xanthurenic acid (XA)] and KYNA/KYN and KYNA/quinolinic acid (QUIN) ratios were lower in patients compared to controls. For the total group there was no significant change in KP metabolites post-ECT or correlations with mood ratings. However, improvements in mood score were correlated with increased KYN, 3-hydroxykynurenine (3HK), 3HAA, QUIN, and KYN/TRP in a subgroup of unipolar depressed patients. Additionally, in remitters baseline KYN, 3HK, and QUIN were associated with baseline HAM-D24 scores, and changes in 3HK and 3HAA concentrations post-ECT correlated with improvement in mood. KYN, KYNA, AA, 3HK, XA, PA, and QUIN were increased in a smaller 3-month follow-up group (n = 19) compared to pre-ECT concentrations. Overall, the results indicate that ECT mobilizes the KP, where a moderate association between selected metabolites and treatment response in unipolar depressed patients is evident.

6 Article L-alpha-amino adipic acid provokes depression-like behaviour and a stress related increase in dendritic spine density in the pre-limbic cortex and hippocampus in rodents. 2019

David, J / Gormley, S / McIntosh, A L / Kebede, V / Thuery, G / Varidaki, A / Coffey, E T / Harkin, A. ·Trinity College Institute of Neuroscience and School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland. · Turku Centre for Biotechnology, Åbo Akademi University and University of Turku, Turku, Finland. · Trinity College Institute of Neuroscience and School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland. Electronic address: aharkin@tcd.ie. ·Behav Brain Res · Pubmed #30639510.

ABSTRACT: Astrocyte dysfunction is implicated in clinical depression. There is a paucity of animal models to assess the role of astrocytes in depression pathogenesis. Refinement of an existing model is described here. Administration of the astrocytic toxin L-alpha aminoadipic acid (L-AAA) to the pre-limbic cortex (PLC) was assessed in rats and mice in tests of anxiety and depression related behaviours. Delivery of L-AAA to the PLC of Wistar rats produced an increase in immobility in the forced swimming test (FST) and reduced exploration in the open field. Delivery to the CA3 subfield of the hippocampus produced a deficit in the novel object relocation task. Delivery of single or two successive doses of L-AAA to the PLC of C57Bl6/J mice was sufficient to induce an increase in immobility in the mouse tail suspension (TST) and FST independently of administration of anaesthetic agent or the surgical procedure. In both mice and rats, L-AAA produced a reduction in immunoreactivity of the astrocytic marker glial fibrillary acidic protein (GFAP) for up to 72 h. L-AAA provoked an increase in the density of apical and basal dendritic spines in mice exposed to the FST when compared to non-FST controls. In summary, L-AAA provokes a region-dependent change in behaviour, a reduction in GFAP immunoreactivity and FST-provoked increased in dendritic spine density in the PLC. This model may be further employed to assess the impact of astroglial integrity on the structural plasticity of neurons and the effect of antidepressant agents on L-AAA-related changes.

7 Article Ketamine and depression: A special kase for kynurenic acid? 2019

Harkin, Andrew / McLoughlin, Declan M. ·Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland. · Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland; Dept of Psychiatry, Trinity College Dublin, St. Patrick's University Hospital, Dublin 8, Ireland. Electronic address: d.mcloughlin@tcd.ie. ·Brain Behav Immun · Pubmed #30399405.

ABSTRACT: -- No abstract --

8 Article DNA methylation differences at the glucocorticoid receptor gene in depression are related to functional alterations in hypothalamic-pituitary-adrenal axis activity and to early life emotional abuse. 2018

Farrell, Chloё / Doolin, Kelly / O' Leary, Niamh / Jairaj, Chaitra / Roddy, Darren / Tozzi, Leonardo / Morris, Derek / Harkin, Andrew / Frodl, Thomas / Nemoda, Zsófia / Szyf, Moshe / Booij, Linda / O'Keane, Veronica. ·Department of Psychiatry, School of Medicine, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland. Electronic address: farrelc6@tcd.ie. · Department of Psychiatry, School of Medicine, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland. · Department of Psychiatry and Psychotherapy, Otto von Guericke University Magdeburg, Magdeburg, Germany. · Discipline of Biochemistry, NUI Galway, Galway, Ireland. · School of Pharmacy and Pharmaceutical Studies, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland. · Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary. · Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada. · Department of Psychology, Concordia University, Montreal, Quebec, Canada; Sainte-Justine Hospital Research Centre, Montreal, Quebec, Canada. · Department of Psychiatry, School of Medicine, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland; Trinity Centre for Health Sciences, AMNCH (Tallaght Hospital), Tallaght, Dublin 24, Ireland. ·Psychiatry Res · Pubmed #29793048.

ABSTRACT: Depression is associated with alterations in hypothalamic-pituitary-adrenal (HPA) axis activity. A proposed mechanism to explain these alterations are changes in DNA methylation levels, secondary to early life adversity (ELA), at stress-related genes. Two gene regions that have been implicated in the literature, the glucocorticoid receptor gene (NR3C1) exon 1F and the FKBP5 gene intron 7 were examined in 67 individuals (33 depressed patients and 34 controls). We investigated whether cortisol concentrations, evaluated in 25 depressed patients and 20 controls, and measures of ELA were associated with the degree of methylation at these candidate gene regions. Mean NR3C1 exon 1F DNA methylation levels were significantly increased in the depressed cohort and the degree of methylation was found to be positively associated with morning cortisol concentrations. DNA methylation levels at specific CG sites within the NR3C1 exon 1F were related to childhood emotional abuse severity. DNA methylation at CG38 was related to both HPA axis and childhood emotional abuse measures in the depressed group. No FKBP5 differences were revealed. Our findings suggest that hypermethylation at the NR3C1 exon 1F may occur in depression. This locus-specific epigenetic change is associated with higher basal HPA axis activity, possibly reflecting acquired glucocorticoid receptor resistance.

9 Article Altered tryptophan catabolite concentrations in major depressive disorder and associated changes in hippocampal subfield volumes. 2018

Doolin, Kelly / Allers, Kelly A / Pleiner, Sina / Liesener, Andre / Farrell, Chloe / Tozzi, Leonardo / O'Hanlon, Erik / Roddy, Darren / Frodl, Thomas / Harkin, Andrew / O'Keane, Veronica. ·Trinity College Institute of Neuroscience and School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland. · Boehringer Ingelheim Pharma GmbH & Co. KG, CNS Diseases Research, and DMPK, Biberach an der Riss, Germany. · Trinity College Institute of Neuroscience and School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland; Department of Psychiatry and Psychotherapy, University Hospital Otto von Guerick University, 39120 Magdeburg, Germany. · Department of Psychiatry and Psychotherapy, University Hospital Otto von Guerick University, 39120 Magdeburg, Germany; German Centre for Neurogenerative Diseases (DZNE), Leipzigerstr. 44, 39120 Magdeburg, Germany. · Trinity College Institute of Neuroscience and School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland. Electronic address: aharkin@tcd.ie. · Trinity College Institute of Neuroscience and School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland; Trinity Centre for Health Sciences, Tallaght Hospital, Tallaght, Dublin 24, Ireland. ·Psychoneuroendocrinology · Pubmed #29787958.

ABSTRACT: BACKGROUND: Tryptophan depletion is a well-replicated biological finding in Major Depressive Disorder (MDD). The kynurenine pathway (KP) and its rate-limiting tryptophan degrading enzyme, indolamine 2,3 dioxygenase (IDO), have been implicated in the pathogenesis of depression. IDO expression is driven by inflammatory cytokines, providing a putative link between inflammation and neuropathology. This study examined circulating concentrations of C-reactive protein (CRP), plasma tryptophan, kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QUIN) and whole blood mRNA expression of IDO in patients with major depressive disorder (MDD) compared with healthy controls (HC). METHODS: A diagnosis of major depression was made according to DSM-IV. Depression severity was assessed using the Hamilton depression (HAM-D) rating scale. 74 MDD patients, 39 with a first presentation of MDD (fpMDD) and 35 with chronic or recurrent episodes (rMDD), and 37 HC were recruited to the study. Whole blood and plasma samples were collected. Expression of markers in whole blood were measured by PCR, circulating CRP by ELISA and KP metabolites by LC-MS/MS. Hippocampal cornu ammonis (CA) and subiculum volumes were determined by MRI and calculated using FreeSurfer. RESULTS: Tryptophan concentrations were significantly reduced in MDD compared to HC. There was a positive correlation between QUIN and both CRP concentrations and whole blood IDO1 in MDD. KYNA concentrations were reduced in MDD patients presenting with a first episode (fpMDD) compared to those presenting with recurrent depression (rMDD) and HC. By contrast QUIN concentrations were elevated in rMDD compared to fpMDD and HC. KYNA/QUIN was reduced in MDD and rMDD but not fpMDD compared to HC. Hippocampal subfield volumes were smaller in MDD patients than HC for CA1 (left only), CA2/3 (left and right) and CA4 (right only). CRP and CA1 volumes were negatively correlated bilaterally in MDD patients. KYNA and subiculum volume were positively correlated bilaterally. DISCUSSION: This study found evidence of KP metabolism imbalance in MDD patients in addition to tryptophan reduction and mild immune activation. Relationships between CRP and KYNA with some hippocampal subfield volumes in MDD patients suggest that this inflammatory signature may be associated with reduced hippocampal subfield volumes in depression.

10 Article Diurnal Hypothalamic-Pituitary-Adrenal Axis Measures and Inflammatory Marker Correlates in Major Depressive Disorder. 2017

Doolin, Kelly / Farrell, Chloe / Tozzi, Leonardo / Harkin, Andrew / Frodl, Thomas / O'Keane, Veronica. ·Trinity College Institute of Neuroscience, Dublin 2, Ireland. doolink@tcd.ie. · Trinity College Institute of Neuroscience, Dublin 2, Ireland. farrelc6@tcd.ie. · Trinity College Institute of Neuroscience, Dublin 2, Ireland. leo.tozzi88@gmail.com. · Department of Psychiatry, Otto von Guerick University, 39106 Magdeburg, Germany. leo.tozzi88@gmail.com. · Trinity College Institute of Neuroscience, Dublin 2, Ireland. aharkin@tcd.ie. · Department of Psychiatry, Otto von Guerick University, 39106 Magdeburg, Germany. thomas.frodl@med.ovgu.de. · Trinity College Institute of Neuroscience, Dublin 2, Ireland. vokeane@tcd.ie. · Trinity Centre for Health Sciences, Tallaght Hospital, Tallaght, Dublin 24, Ireland. vokeane@tcd.ie. ·Int J Mol Sci · Pubmed #29064428.

ABSTRACT: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and inflammatory systems is a consistent finding in patients with Major Depressive Disorder (MDD). Cortisol is often assessed by measurement of the cortisol awakening response (CAR) and/or diurnal cortisol levels. Some methods of cortisol measurement overestimate cortisol concentration due to detection of other glucocorticoids including the relatively inert cortisone, therefore this study aimed to assess the presence of both cortisol and cortisone, and the cortisol-cortisone catalyzing enzyme 11β-hydroxysteroiddehydrogenase type 1 (11β-HSD1), in depressed patients and controls. Because the HPA axis is known to regulate the body's immune system, relationships between measures of cytokines and cortisol were also assessed. Saliva samples were collected from 57 MDD patients and 40 healthy controls at five post-wakening time points (0, +30, +60, +720 and +750 min). Glucocorticoid concentrations were measured by liquid chromatography mass spectrometry. Whole blood mRNA expression of several inflammatory markers was measured by quantitative polymerase chain reaction. This study replicated the common finding of elevated morning cortisol and reduced CAR reactivity in MDD and found no differences in cortisone or 11β-HSD1 mRNA measures. There was a negative association between interleukin 1-β (IL-1β) mRNA and morning cortisol reactivity within the depressed group, indicating that dysregulation of the HPA axis and immune system may be interconnected.

11 Article Association between psychological measures with inflammatory anddisease-related markers of inflammatory bowel disease. 2017

Abautret-Daly, Áine / Dempsey, Elaine / Riestra, Sabino / de Francisco-García, Ruth / Parra-Blanco, Adolfo / Rodrigo, Luis / Medina, Carlos / Connor, Thomas J / Harkin, Andrew. ·a Neuropsychopharmacology Research Group, Trinity College Institute of Neuroscience, Trinity College , Dublin 2 , Ireland. · b School of Pharmacy and Pharmaceutical Sciences, Trinity College , Dublin 2 , Ireland. · c Department of Gastroenterology , Hospital Central de Asturias , Oviedo , Spain. · d Trinity Biomedical Sciences Institute, Trinity College , Dublin 2 , Ireland. · e Neuroimmunology Research Group, School of Medicine and Trinity College Institute of Neuroscience, Trinity College , Dublin 2 , Ireland. ·Int J Psychiatry Clin Pract · Pubmed #28353360.

ABSTRACT: OBJECTIVE: This study aimed at investigating the associations between inflammatory mediators, symptoms and psychological disturbances in inflammatory bowel disease (IBD) patients. METHODS: IBD patients and patient controls were examined during a single visit to a gastroenterology clinic. Disease activity was assessed using the Mayo index for ulcerative colitis (UC), inflammatory bowel disease questionnaire (IBDQ), Crohn's disease activity index (CDAI) and Crohn's disease endoscopic index of severity (CDEIS). Gene expression of inflammatory mediators were measured in intestinal biopsies and whole blood samples along with circulating concentrations of interleukin (IL)-6, interferon (IFN)γ, C-reactive protein (CRP), kynurenine and tryptophan. Validated depression, anxiety and quality of life scores were used to assess psychological well-being. RESULTS: Patients who were symptomatic had the highest depression and anxiety scores, together with increased intestinal expression of IL-1β, IL-6 and matrix metalloproteinase-9, increased circulating IL-6 and CRP, and an increased circulating kynurenine:tryptophan ratio. Increased Hamilton depression (HAM-D) scores in IBD patients were observed independent of the psychological impact of acute symptoms. CONCLUSIONS: Active IBD is associated with symptoms of depression and anxiety and with a raised circulating inflammatory mediator profile. Patients with active IBD exhibiting psychological symptoms should undergo psychological evaluation to ensure the psychological aspects of the condition are considered and addressed.

12 Article Regional specific modulation of neuronal activation associated with nitric oxide synthase inhibitors in an animal model of antidepressant activity. 2017

Sherwin, Eoin / Gigliucci, Valentina / Harkin, Andrew. ·Department of Physiology, School of Medicine, Trinity College Dublin, Ireland; Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland. · School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Ireland; Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland. · School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Ireland; Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland. Electronic address: aharkin@tcd.ie. ·Behav Brain Res · Pubmed #27569181.

ABSTRACT: OBJECTIVE: The regional specific modulation of neuronal activation following drug administration is of interest to determine brain areas involved in the behavioural effects of experimental test compounds. In the current investigation the effects of the L-arginine related NOS inhibitor N METHODS: Male Sprague-Dawley rats (n=5- 6 per group) were treated with the irreversible tryptophan hydroxylase inhibitor, DL-4-p-chlorophenylalanine (pCPA, 150mg/kg, i.p.), to achieve central serotonin-depletion followed by repeated exposures to restraint stress and were then subjected to the FST. 24, 5 and 1h prior to the test, animals were treated with either L-NA (10mg/kg, i.p.), TRIM (50mg/kg, i.p.) or saline vehicle (1mg/kg i.p). RESULTS: pCPA treatment coupled with restraint stress increased immobility in the FST compared to naïve controls. Both NOS inhibitors decreased immobility time in 5-HT depleted and stressed animals only in keeping with their antidepressant-like properties. Brain regions analyzed for c-FOS immunoreactivity included the pre-limbic cortex, lateral septum (LS), nucleus accumbens, paraventricular hypothalamic nucleus (PVN), central amygdala, hippocampus (dorsal dentate gyrus and ventral CA1), and the dorsal raphe nucleus (DRN). Exposure to the FST increased c-FOS immunoreactivity in the LS, PVN, dentate gyrus, vCA1 and the DRN when compared to non-FST exposed controls. FST-induced c-FOS immunoreactivity was further increased in the LS following treatment with L-NA or TRIM when compared to vehicle-treated FST controls. By contrast, FST-induced c-FOS immunoreactivity was reduced in dorsal dentate gyrus, vCA1 and the DRN following treatment with L-NA or TRIM when compared to vehicle-treated FST controls. There was no difference observed in FST-induced expression of c-FOS between naïve animals and animals exposed to pCPA and restraint stress. This combination however provoked an increase in FosB/ΔFosB immunoreactivity in the infra-limbic cortex and nucleus accumbens with a concomitant reduction in the lateral septum, suggesting alterations to long-term, adaptive neuronal activation. CONCLUSION: This study identified a pattern of enhanced and reduced FST-related c-FOS immunoreactivity indicative of a NO-regulated network where inhibition of NO leads to activation of the septum with concomitant inhibition of the hippocampus, and the DRN. No link between FST-induced regional expression of c-FOS and increased immobility in the FST was observed in animals exposed to pCPA and stress. However, the 5-HT depletion regime combined with restraint stress provoked regional changes in the expression of ΔFosB which may relate to increased immobility in the FST.

13 Article Ketamine for depression relapse prevention following electroconvulsive therapy: protocol for a randomised pilot trial (the KEEP-WELL trial). 2016

Finnegan, Martha / Ryan, Karen / Shanahan, Enda / Harkin, Andrew / Daly, Leslie / McLoughlin, Declan M. ·Department of Psychiatry and Trinity College Institute of Neuroscience, St. Patrick's University Hospital, James' St., Dublin 8, Ireland. · Trinity College Institute of Neuroscience, Trinity College Dublin, College Green, Dublin 2, Ireland. · School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, College Green, Dublin 2, Ireland. · Centre for Training and Research in Analysis and Research, University College Dublin, Belfield, Dublin 4, Ireland. ·Pilot Feasibility Stud · Pubmed #27965856.

ABSTRACT: BACKGROUND: Major depressive disorder is a common debilitating illness that is the second leading contributor to the global burden of disease. Unfortunately, about 30 % of patients do not respond to adequate trials of antidepressants and/or psychotherapies. About 45-60 % of such treatment-resistant patients will remit with electroconvulsive therapy (ECT). However, relapse rates are high following ECT-38 % after 6 months. There is a need for better relapse prevention strategies. One possibility is to use ketamine, a competitive glutamate receptor antagonist used for anaesthesia. A recent paradigm shift in treating depression and understanding its biology has been the finding that ketamine has a robust, rapid-onset, though short-lived, antidepressant effect that is possibly mediated through neuroplastic effects. However, ketamine has not previously been reported on for relapse prevention. METHODS/DESIGN: The main objective of this study is to conduct a randomised controlled pilot trial ( DISCUSSION: This is the first registered trial (NCT02414932, https://clinicaltrials.gov/ct2/show/NCT02414932) of ketamine for depression relapse prevention, an important possible use of this agent. The primary focus of the pilot trial is on feasibility. However, a 95 % confidence interval will be determined for the difference between ketamine and midazolam groups in 6-month relapse rates to help inform a future definitive trial. TRIAL REGISTRATION: https://clinicaltrials.gov/ NCT02414932 Secondary Identifying numbers: EudraCT number: 2014-000339-18 Sponsors' Reference, Sponsor: St. Patrick's Mental Health Services: 05/14 Research Ethics Committee Reference, Joint REC of St James' and Tallaght Hospitals, Dublin: 2014-08-19.

14 Article Glial fibrillary acidic protein (GFAP) immunoreactivity correlates with cortical perfusion parameters determined by bolus tracking arterial spin labelling (bt-ASL) magnetic resonance (MR) imaging in the Wistar Kyoto rat. 2016

Gormley, Shane / Rouine, Jennifer / McIntosh, Allison / Kerskens, Christian / Harkin, Andrew. ·Neuropsychopharmacology Research Group, School of Pharmacy & Pharmaceutical Sciences, Dublin, Ireland. Electronic address: sgormley@tcd.ie. · Neuropsychopharmacology Research Group, School of Pharmacy & Pharmaceutical Sciences, Dublin, Ireland; Trinity College Institute of Neuroscience, Dublin, Ireland. · Trinity College Institute of Neuroscience, Dublin, Ireland. · Neuropsychopharmacology Research Group, School of Pharmacy & Pharmaceutical Sciences, Dublin, Ireland; Trinity College Institute of Neuroscience, Dublin, Ireland. Electronic address: aharkin@tcd.ie. ·Physiol Behav · Pubmed #27068181.

ABSTRACT: Alterations in astrocyte number and function have been implicated in the pathophysiology of a number of psychiatric disorders. The development of magnetic resonance imaging (MRI) as a tool in the animal laboratory has enabled an investigation of the relationship between pathological and neuroimaging markers in animal models. However the physiological processes which underlie these markers and their role in mediating behavioural deficits is still poorly understood. Rodent models have provided us with important insights into physiological and cellular mechanisms which may mediate anxiety and depression-related behaviours. The Wistar-Kyoto (WKY) rat is a strain which endogenously expresses highly anxious and depressive-like behaviours and has previously been reported to exhibit alterations in immunoreactivity for the astrocytic marker glial fibrillary acidic protein (GFAP) in brain sub-regions relative to more stress resilient out-bred strains. Here we report that the depressive and anxiety-like behaviours exhibited by the WKY rat strain are associated with alterations in brain morphology including a decrease in hippocampal volume, coupled with reduced resting state frontal cortical perfusion as assessed by MR bolus tracking arterial spin labelling (bt-ASL) relative to the out-bred Wistar strain. Pre-limbic cortical GFAP immunoreactivity and astrocyte cell number were positively correlated with cortical blood perfusion in the WKY strain. These experiments provide a link between pathological and neuroimaging markers of aberrant astrocytic function and add validity to the WKY rat as a model for co-morbid anxiety and depression.

15 Article Clenbuterol activates the central IL-1 system via the β2-adrenoceptor without provoking inflammatory response related behaviours in rats. 2016

Ryan, Karen M / Griffin, Éadaoin W / Ryan, Katie J / Tanveer, Riffat / Vanattou-Saifoudine, Natacha / McNamee, Eoin N / Fallon, Emer / Heffernan, Sheena / Harkin, Andrew / Connor, Thomas J. ·Neuroimmunology Research Group, Trinity College Institute of Neuroscience, Department of Physiology & School of Medicine, Trinity College, Dublin 2, Ireland. · Neuropsychopharmacology Research Group, School of Pharmacy and Pharmaceutical Sciences & Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland. · Neuropsychopharmacology Research Group, School of Pharmacy and Pharmaceutical Sciences & Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland. Electronic address: aharkin@tcd.ie. ·Brain Behav Immun · Pubmed #26928198.

ABSTRACT: The long-acting, highly lipophilic, β2-adrenoceptor agonist clenbuterol may represent a suitable therapeutic agent for the treatment of neuroinflammation as it drives an anti-inflammatory response within the CNS. However, clenbuterol is also known to increase the expression of IL-1β in the brain, a potent neuromodulator that plays a role in provoking sickness related symptoms including anxiety and depression-related behaviours. Here we demonstrate that, compared to the immunological stimulus lipopolysaccharide (LPS, 250μg/kg), clenbuterol (0.5mg/kg) selectively up-regulates expression of the central IL-1 system resulting in a mild stress-like response which is accompanied by a reduction in locomotor activity and food consumption in rats. We provide further evidence that clenbuterol-induced activation of the central IL-1 system occurs in a controlled and selective manner in tandem with its negative regulators IL-1ra and IL-1RII. Furthermore, we demonstrate that peripheral β2-adrenoceptors mediate the suppression of locomotor activity and food consumption induced by clenbuterol and that these effects are not linked to the central induction of IL-1β. Moreover, despite increasing central IL-1β expression, chronic administration of clenbuterol (0.03mg/kg; twice daily for 21days) fails to induce anxiety or depressive-like behaviour in rats in contrast to reports of the ability of exogenously administered IL-1 to induce these symptoms in rodents. Overall, our findings suggest that clenbuterol or other selective β2-adrenoceptor agonists could have the potential to combat neuroinflammatory or neurodegenerative disorders without inducing unwanted symptoms of depression and anxiety.

16 Article Interdependent and independent roles of type I interferons and IL-6 in innate immune, neuroinflammatory and sickness behaviour responses to systemic poly I:C. 2015

Murray, Carol / Griffin, Éadaoin W / O'Loughlin, Elaine / Lyons, Aoife / Sherwin, Eoin / Ahmed, Suaad / Stevenson, Nigel J / Harkin, Andrew / Cunningham, Colm. ·School of Biochemistry and Immunology, Trinity College Dublin, Ireland; Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland. · Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland. · School of Biochemistry and Immunology, Trinity College Dublin, Ireland. · School of Biochemistry and Immunology, Trinity College Dublin, Ireland; Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland. Electronic address: colm.cunningham@tcd.ie. ·Brain Behav Immun · Pubmed #25900439.

ABSTRACT: Type I interferons (IFN-I) are expressed in the brain during many inflammatory and neurodegenerative conditions and have multiple effects on CNS function. IFN-I is readily induced in the brain by systemic administration of the viral mimetic, poly I:C (synthetic double-stranded RNA). We hypothesised that IFN-I contributes to systemically administered poly I:C-induced sickness behaviour, metabolic and neuroinflammatory changes. IFN-I receptor 1 deficient mice (IFNAR1(-/-)) displayed significantly attenuated poly I:C-induced hypothermia, hypoactivity and weight loss compared to WT C57BL/6 mice. This amelioration of sickness was associated with equivalent IL-1β and TNF-α responses but much reduced IL-6 responses in plasma, hypothalamus and hippocampus of IFNAR1(-/-) mice. IFN-β injection induced trivial IL-6 production and limited behavioural change and the poly I:C-induced IFN-β response did not preceed, and would not appear to mediate, IL-6 induction. Rather, IFNAR1(-/-) mice lack basal IFN-I activity, have lower STAT1 levels and show significantly lower levels of several inflammatory transcripts, including stat1. Basal IFN-I activity appears to play a facilitatory role in the full expression of the IL-6 response and activation of the tryptophan-kynurenine metabolism pathway. The deficient IL-6 response in IFNAR1(-/-) mice partially explains the observed incomplete sickness behaviour response. Reconstitution of circulating IL-6 revealed that the role of IFNAR in burrowing activity is mediated via IL-6, while IFN-I and IL-6 have additive effects on hypoactivity, but the role of IFN-I in anorexia is independent of IL-6. Hence, we have demonstrated both interdependent and independent roles for IFN-I and IL-6 in systemic inflammation-induced changes in brain function.

17 Article Muscling in on depression. 2014

Harkin, Andrew. · ·N Engl J Med · Pubmed #25494274.

ABSTRACT: -- No abstract --

18 Article Expression of glucocorticoid inducible genes is associated with reductions in cornu ammonis and dentate gyrus volumes in patients with major depressive disorder. 2014

Frodl, Thomas / Carballedo, Angela / Frey, Eva-Maria / O'Keane, Veronica / Skokauskas, Norbert / Morris, Derrek / Gill, Michael / Hughes, Martina Mary / Harkin, Andrew / Connor, Thomas. ·Trinity College Dublin. · University of Regensburg. ·Dev Psychopathol · Pubmed #25422956.

ABSTRACT: Alterations of the glucocorticoid system and of hippocampal volumes have consistently been reported in patients with major depressive disorders (MDD). The aim of the present study was to investigate whether the messenger RNA (mRNA) expression of glucocorticoid inducible genes is associated with changes in the cornu ammonis (CA) and dentate gyrus subfields. Forty-three patients with MDD and 43 healthy controls were recruited and investigated with high resolution magnetic resonance imaging. Hippocampal subfields were measured using freesurfer. Measurement of whole blood mRNA expression of glucocorticoid inducible genes serum and glucocorticoid-regulated kinase 1 (SGK1), FK506 binding protein 5 (FKBP5), and glucocorticoid induced leucine zipper (GILZ) was performed. Patients with MDD had significantly smaller volumes of CA1, CA2/3, CA4/DG, and subiculum compared to healthy controls. In the regression analysis, the factor diagnosis had a significant moderating effect on the association of SGK1 and hippocampal volumes. Patients with low expression of SGK1 had significantly smaller CA2/3 and CA4/DG volumes compared to patients with high expression of SGK1 mRNA and to healthy controls with low/high expression of SGK1, respectively. Therefore, a lack of mRNA expression of glucocorticoid inducible genes in patients with MDD that seems to correspond to a blunted cortisol response is associated with smaller hippocampal CA and dentate gyrus volumes. SGK1 seems to be particularly relevant for stress-related mental disorders.

19 Article Characterisation of the antidepressant properties of nitric oxide synthase inhibitors in the olfactory bulbectomised rat model of depression. 2014

Gigliucci, Valentina / Gormley, Shane / Gibney, Sinead / Rouine, Jennifer / Kerskens, Christian / Connor, Thomas J / Harkin, Andrew. ·Neuropsychopharmacology Research Group, School of Pharmacy & Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland; Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland. Electronic address: gigliucv@tcd.ie. · Neuropsychopharmacology Research Group, School of Pharmacy & Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland; Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland. Electronic address: sgormley@tcd.ie. · Neuropsychopharmacology Research Group, School of Pharmacy & Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland; Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland; Neuroimmunology Research Group, Department of Physiology, School of Medicine, Trinity College, Dublin 2, Ireland. Electronic address: gibneysi@tcd.ie. · Neuropsychopharmacology Research Group, School of Pharmacy & Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland; Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland. Electronic address: rouinej@tcd.ie. · Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland. Electronic address: kerskenc@tcd.ie. · Neuroimmunology Research Group, Department of Physiology, School of Medicine, Trinity College, Dublin 2, Ireland. · Neuropsychopharmacology Research Group, School of Pharmacy & Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland; Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland. Electronic address: aharkin@tcd.ie. ·Eur Neuropsychopharmacol · Pubmed #24931298.

ABSTRACT: Nitric oxide synthase (NOS) inhibitors possess antidepressant-like properties in preclinical tests and in the current investigation the brain penetrant NOS inhibitor N(ω)-nitro-L-arginine (l-NA) and the preferential inhibitor of neuronal NOS (nNOS) 1-(2-trifluoromethylphenyl) imidazole (TRIM) were assessed in the olfactory bulbectomised (OB) rat, a well-established animal model of depression. Magnetic resonance imaging (MRI) was employed to assess regional brain volumes, blood perfusion and T1 and T2 relaxometry times both with and without drug treatment. l-NA (10 mg/kg, once daily p.o. for 10 days) attenuated OB-related hyperactivity in the "open field" test in a comparable fashion to the tricyclic antidepressant imipramine (20 mg/kg, once daily p.o. for 14 days) indicative of an antidepressant-like response in the model. Treatment with TRIM (50 mg/kg, once daily s.c.) attenuated OB-related hyperactivity following 7 days of treatment when compared to vehicle treated controls. OB is associated with enlarged ventricular volume, increased periventicular perfusion and a decrease in T2 relaxation times in cortical and hippocampal regions, with enhanced perfusion and reduced T2 times attenuated by L-NA treatment. L-NA treatment was also associated with an increase in T1 relaxation times in limbic and cortical regions and found to reduce resting state hippocampal blood perfusion in OB animals. Behavioural observations are consistent with an antidepressant action of NOS inhibitors where associated changes in perfusion and T2 relaxation times may be related to the antidepressant action of L-NA in the model.

20 Article Effects of brief pulse and ultrabrief pulse electroconvulsive stimulation on rodent brain and behaviour in the corticosterone model of depression. 2014

O'Donovan, Sinead / Dalton, Victoria / Harkin, Andrew / McLoughlin, Declan M. ·Trinity College Institute of Neuroscience,Trinity College Dublin, Dublin 2,Ireland. · School of Pharmacy & Pharmaceutical Sciences & Trinity College Institute of Neuroscience,Trinity College Dublin, Dublin 2,Ireland. · St. Patrick's University Hospital & Trinity College Institute of Neuroscience,Trinity College Dublin,Ireland. ·Int J Neuropsychopharmacol · Pubmed #24607259.

ABSTRACT: Brief pulse electroconvulsive therapy (BP ECT; pulse width 0.5-1.5 ms) is the most effective treatment available for severe depression. However, its use is associated with side-effects. The stimulus in ultrabrief pulse ECT (UBP ECT; pulse width 0.25-0.3 ms) is more physiological and has been reported to be associated with less cognitive side-effects, but its antidepressant effectiveness is not yet well established. Using electroconvulsive stimulation (ECS), the animal model of ECT, we previously reported UBP ECS to be significantly less effective than well-established BP ECS in eliciting behavioural, molecular and cellular antidepressant-related effects in naïve rats. We have now compared the effects of BP and UBP ECS in an animal model of depression related to exogenous supplementation with the stress-induced glucocorticoid hormone, corticosterone. Corticosterone administration resulted in an increase in immobility time in the forced swim test (FST) (p < 0.01) and decreases in the expression of brain-derived neurotrophic factor (BDNF) (p < 0.05) and glial fibrillary acidic protein (GFAP) (p < 0.001) in the hippocampus and frontal cortex. There was no significant difference in the duration or type of seizure induced by BP (0.5 ms) or UBP (0.3 ms) ECS. UBP ECS proved to be as effective as BP ECS at inducing a behavioural antidepressant response in the FST with a significant decrease (p < 0.001) in immobility seen following administration of ECS. Both forms of ECS also induced significant increases in BDNF protein (p < 0.01) expression in the hippocampus. BP ECS (p < 0.05) but not UBP ECS induced a significant increase in GFAP levels in the hippocampus and frontal cortex. Overall, UBP ECS effectively induced antidepressant-related behavioural and molecular responses in the corticosterone supplementation model, providing the first preclinical data on the potential role of this form of ECS to treat a depression phenotype related to elevated corticosterone.

21 Article Inhibition of stress-induced hepatic tryptophan 2,3-dioxygenase exhibits antidepressant activity in an animal model of depressive behaviour. 2014

Gibney, Sinead M / Fagan, Eimear M / Waldron, Ann-Marie / O'Byrne, Jordan / Connor, Thomas J / Harkin, Andrew. ·Neuropsychopharmacology Research Group, School of Pharmacy and Pharmaceutical Sciences & Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland. · Neuroimmunology Research Group, Department of Physiology, School of Medicine & Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland. ·Int J Neuropsychopharmacol · Pubmed #24472498.

ABSTRACT: The role of hepatic tryptophan 2,3 dioxygenase (TDO) was assessed in the provocation of stress-induced depression-related behaviour in the rat. TDO drives tryptophan metabolism via the kynurenine pathway (KP) and leads to the production of neuroactive metabolites including kynurenine. A single 2 h period of restraint stress in adult male Sprague-Dawley rats provoked an increase in circulating concentrations of the glucocorticoid corticosterone and induction of hepatic TDO expression and activity. Repeated exposure to stress (10 d of 2 h restraint each day) provoked an increase in immobility in the forced swimming test (FST) indicative of depression-related behaviour. Immobility was accompanied by an increase in the circulating corticosterone concentrations, expression and activity of hepatic TDO and increase in the expression of TDO in the cerebral cortex. Increased TDO activity was associated with raised circulating kynurenine concentrations and a reduction in circulating tryptophan concentrations indicative of KP activation. Co-treatment with the TDO inhibitor allopurinol (20 mg/kg, i.p.), attenuated the chronic stress-related increase in immobility in the FST and the accompanying increase in circulating kynurenine concentrations. These findings indicate that stress-induced corticosterone and consequent activation of hepatic TDO, tryptophan metabolism and production of kynurenine provoke a depression-related behavioural phenotype. Inhibition of stress-related hepatic TDO activity promotes antidepressant activity. TDO may therefore represent a promising target for the treatment of depression associated with stress-related disorders in which there is evidence for KP activation.

22 Article C-reactive protein predicts fatigue independently of depression in breast cancer patients prior to chemotherapy. 2013

Pertl, Maria M / Hevey, David / Boyle, Noreen T / Hughes, Martina M / Collier, Sonya / O'Dwyer, Anne-Marie / Harkin, Andrew / Kennedy, M John / Connor, Thomas J. ·School of Psychology, Trinity College, Dublin 2, Ireland. Electronic address: pertlm@tcd.ie. ·Brain Behav Immun · Pubmed #23928287.

ABSTRACT: Heightened inflammatory activity has been proposed as a mechanism for the development of cancer-related fatigue (CRF), a common and distressing condition that can negatively affect quality of life. Inflammation is also implicated in the pathogenesis of depression, and depression is a strong predictor of CRF. Thus, the role of the pro-inflammatory cytokine network in CRF may be mediated by depression or both conditions may share similar underlying physiological processes. The current study investigated associations between fatigue, depression and inflammatory cytokine (IFN-γ, IL-6, TNF-α) and CRP concentrations, as well as kynurenine pathway (KP) activation, in 61 breast cancer patients prior to chemotherapy. Changes in inflammatory markers and KP activation over time were also explored, and associations with changes in fatigue and depression were examined. Higher levels of CRP were significantly correlated with fatigue and depression before chemotherapy; nevertheless, CRP predicted fatigue independently of depression. Although greater kynurenine concentrations were associated with increased immune activation, there was no evidence that the KP played a role in fatigue or depression. Furthermore, no relationships emerged between either fatigue or depression and IFN-γ, IL-6, or TNF-α before chemotherapy. Nevertheless, kynurenine levels pre- and post-treatment significantly predicted changes in depression, suggesting that heightened KP activation may contribute to depressive symptoms in patients treated for cancer. In addition, IL-6 significantly covaried with fatigue. These preliminary findings provide some support for the idea that low-grade inflammation contributes to the development of CRF, independently of depression; however, there was no evidence that this is mediated by KP activity.

23 Article Ketamine elicits sustained antidepressant-like activity via a serotonin-dependent mechanism. 2013

Gigliucci, Valentina / O'Dowd, Grainne / Casey, Sheena / Egan, Danielle / Gibney, Sinead / Harkin, Andrew. ·Neuropsychopharmacology Research Group, School of Pharmacy & Pharmaceutical Sciences and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland. ·Psychopharmacology (Berl) · Pubmed #23455595.

ABSTRACT: RATIONALE: Behavioural antidepressant-like effects of ketamine have been reported in the forced swimming test (FST). The mechanisms mediating such effects are unknown. OBJECTIVES: As serotonin (5-HT) is an important transmitter mediating antidepressant responsiveness in the FST, the influence of 5-HT depletion on the antidepressant-like effect of ketamine was assessed. METHODS: The effect of ketamine (25 mg/kg, i.p., 1 or 24 h prior to test) was assessed in the FST in naive rats or animals subjected to 5-HT depletion, repeated stress or following a combination of 5-HT depletion and stress. Endogenous 5-HT was depleted using the tryptophan hydroxylase inhibitor para-chlorophenylalanine (3 × 150 mg/kg, i.p.). Stress was induced by physical restraint (2 h/day for 10 days). RESULTS: In naive rats, ketamine administered 24 or 1 h prior to test produced a characteristic antidepressant-like reduction in immobility time in the FST. Depletion of 5-HT blocked this reduction in immobility when ketamine was administered 24 h prior FST, indicative of 5-HT dependency. The increase in immobility provoked by repeated restraint stress (2 h/day for 10 days) was blocked by ketamine when administered 24 h prior to FST, but this effect dissipated when animals were subjected to 5-HT depletion. CONCLUSIONS: These observations are consistent with a role for 5-HT in mediating sustained antidepressant activity of ketamine in the FST. Molecular and cellular changes induced by ketamine may produce a rapid adaptation of 5-HT transmission which underlies the antidepressant response.

24 Article Small-molecule inhibitors at the PSD-95/nNOS interface have antidepressant-like properties in mice. 2013

Doucet, Marika V / Levine, Hester / Dev, Kumlesh K / Harkin, Andrew. ·Neuropsychopharmacology Research Group, School of Pharmacy and Pharmaceutical Sciences and Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland. ·Neuropsychopharmacology · Pubmed #23446451.

ABSTRACT: Previous studies have demonstrated that nitric oxide (NO) synthase inhibitors are as efficacious as tricyclic antidepressants in preclinical antidepressant screening procedures and in attenuating behavioural deficits associated with animal models of depression. The N-methyl-D-aspartate receptor (NMDA-R) complex gates Ca(2+), which interacts with calmodulin to subsequently activate NO synthase. We hypothesised that uncoupling neuronal nitric oxide synthase (nNOS) from the NMDA-R through the scaffolding protein postsynaptic density protein 95 (PSD-95) would produce behavioural antidepressant effects similar to NO synthase inhibitors. Small-molecule inhibitors of the PSD-95/nNOS interaction, IC87201 (0.01-2 mg/kg) and ZL006 (10 mg/kg) were tested for antidepressant properties in tests of antidepressant activity namely the tail suspension and forced swim tests in mice. We now report that IC87201 and ZL006 produce antidepressant-like responses in the forced swimming test (FST) and tail suspension test (TST) following a single administration in mice. By contrast to the tricyclic antidepressant imipramine (25 mg/kg), the effects are not observed 1 h following drug administration but are apparent 24 and 72 h later. Furthermore prior exposure to the TST or FST is required in order to observe the antidepressant-related activity. Similar delayed and sustained antidepressant-like effects were observed following TRIM (50 mg/kg) and ketamine (30 mg/kg) in the TST. The antidepressant-like effects of ZL006 also generalise to IC87201 in the TST. IC87201 was devoid of effects on locomotor activity and step-through latency in the passive avoidance cognition test. These data support the hypothesis that targeting the PSD-95/nNOS interaction downstream of NMDA-R produces antidepressant effects and may represent a novel class of therapeutics for major depressive disorders.

25 Article Poly I:C-induced activation of the immune response is accompanied by depression and anxiety-like behaviours, kynurenine pathway activation and reduced BDNF expression. 2013

Gibney, Sinead M / McGuinness, Barry / Prendergast, Christine / Harkin, Andrew / Connor, Thomas J. ·Neuroimmunology Research Group, Department of Physiology, School of Medicine & Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland. ·Brain Behav Immun · Pubmed #23201589.

ABSTRACT: In this study we characterised the ability of the viral mimetic poly I:C to induce a neuroinflammatory response and induce symptoms of depression and anxiety in rats. Furthermore, the ability of poly I:C to deplete central tryptophan and serotonin via induction of indolamine 2,3 dioxygenase (IDO), and also the ability of poly I:C to impact upon expression of the neurotrophin BDNF and its receptor TrkB were examined as potential mechanisms to link inflammation to depression. Poly I:C induced a neuroinflammatory response characterised by increased expression of IL-1β, IL-6, TNF-α and CD11b in frontal cortex and hippocampus. In the first 24h following poly I:C administration rats displayed sickness behaviour characterised by reduced locomotor activity and weight gain. Anhedonia measured using the saccharin preference test was used as an indicator of depressive behaviour, and poly I:C induced depressive behaviour that persisted for up to 72h following administration. Anxiety was measured using the open field test and anxious behaviour was observed 24h following poly I:C, a time-point when sickness behaviour had resolved. These behavioural changes were accompanied by decreased expression of BDNF and TrkB in hippocampus and frontal cortex. In addition, poly I:C increased central IDO expression and increased concentrations of tryptophan, and its metabolite kynurenine. However this activation of the kynurenine pathway did not result in reduced central serotonin concentrations. These findings suggest that depressive and anxiety-like behaviours elicited by poly I:C are associated with a reduction in BDNF signalling, and activation of the kynurenine pathway, but not a reduction in serotonin.

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