Neuropharmacology
Neuropharmacology is a discipline that links neuroscience to the pharmacological treatment of psychiatric and neurological disorders.
Research facilities are based in the School of Pharmacy & Pharmaceutical Sciences and Trinity College Institute of Neuroscience (TCIN)
Director of Neuropsychopharmacology Research Group
Andrew Harkin
Associate Professor of Pharmacology
Contact details: Trinity College Institute of Neuroscience and School of Pharmacy and Pharmaceutical Studies, Trinity College Dublin
email: aharkin@tcd.ie
Telephone: 353-01-896-8575 or 896-2807
PhD Opportunities:
Information regarding funding opportunities to undertake a PhD in the group may be obtained in the following link.
See www.pharmacy.tcd.ie/postgraduate/funding.php
For further website information see:
www.pharmacy.tcd.ie
www.neuroscience.tcd.ie
Selected examples of projects are outlined below:
Brain Imaging Return to Health
Marie Curie Initial Training Networks (ITN): FP7-PEOPLE-2012-ITN Brain Imaging Return to Health “reBIRTH” (see http://www.rbirth.eu/) The r’BIRTH consortium is a Marie Curie Initial Training Network that gathers experts on molecular mechanisms of age-associated pathologies including neurodegeneration and depression. They work together to identify stress-regulated molecules provoking neuronal atrophy and hindering neurogenesis, and monitor the consequences of these processes in human brain. At the cellular level, diminished birth of new neurons (neurogenesis) contributes to cognitive decline and increased depressive and anxiety disorders that are associated with ageing. The work is funded by the European Commission (FP7) under the sub-programme PEOPLE (Marie Curie Actions). 16 early stage researchers will be trained in the topics of the programme i.e. molecular imaging (MRI), proteomics, immunotechnology, high content screening, molecular neuroscience, neuropharmacology and patient studies. The training is provided by seven universities, two private companies and one non-profit research organisation from 7 European countries.
Early diagnosis, treatment and prevention of mood disorders targeting the activated inflammatory response system.
A collaborative, large-scale focused research project entitled “Early diagnosis, treatment and prevention of mood disorders targeting the activated inflammatory response system. [Acronym: MOODINFLAME]. A consortium of 14 European Universities/Research Institutes and 4 SMEs have come together for this project with the overall objective of developing biomarker tests for mood disorder patients based on an activated inflammatory response system (IRS) and inflammation-mediated disturbances in tryptophan metabolism. As part of this programme patients are treated with drugs to counteract the consequences of an activated IRS/disturbed metabolism of tryptophan. The project leads to an enhanced understanding of the pathogenesis of inflammation-related mood disorders, and of the mechanism of anti-inflammatory drugs and drugs targeting tryptophan metabolism in treating depressive behaviour.
Neuronal nitric oxide synthase: A novel target for antidepressant activity
Inhibition of N-methyl-D-aspartic acid receptors (NMDA-R) has shown considerable promise as a drug target to produce new antidepressants that work faster, and are more effective than existing antidepressants. However, targeting NMDA-R directly is problematic due to adverse effects. We hypothesise that targeting signalling events down-stream of NMDA-R may provide a more viable approach. nNOS is a down stream target of NMDA-R. We have published a number of original papers demonstrating that 1) NOS inhibitors have antidepressant properties 2) such properties are dependent on endogenous serotonin and 3) NOS inhibitors can augment the effects of conventional antidepressants in preclinical models. Currently our research is assessing the efficacy of nNOS inhibitors as novel antidepressant agents. A future aim is to determine if uncoupling the NMDA-R from nNOS can elicit antidepressant actions. Funded by the Health Research Board
Recreational MDMA (“Ecstasy”) abuse - implications for neuropsychiatric disorders
Our research has demonstrated reduced behavioural and neurochemical responses to the serotonin based antidepressant fluoxetine in tests of antidepressant activity following MDMA-induced serotonin loss in preclinical models. These results have important clinical relevance, suggesting that serotonin reuptake inhibitors may be less effective at treating depression in individuals with a history of MDMA/“Ecstasy” abuse.
Interaction between caffeine and recreational drugs
My research has demonstrated that caffeine profoundly exacerbates the hyperthermia, tachycardia and long-term serotonin loss associated with MDMA administration in an animal model and can induce lethality. More recently we have identified that the neurotransmitter dopamine plays a key role in mediating the ability of caffeine to exacerbate the toxicity of MDMA. Consequently, we aim to determine if the ability of caffeine to augment MDMA-induced toxicity generalizes to other dopaminergic enhancers such as d-amphetamine, cocaine and bupropion. The project will elucidate the mechanism underlying a serious drug interaction, and clarify risks associated with the concurrent consumption of caffeine with drugs which increase dopaminergic transmission. This work is supported by the Health Research Board.
Selected Research Publications
Morgese MG, Colaianna M, Mhillaj E, Zotti M, Schiavone S, D'Antonio P, Harkin A, Gigliucci V, Campolongo P, Trezza V, De Stradis A, Tucci P, Cuomo V, Trabace L. (2015) Soluble beta amyloid evokes alteration in brain norepinephrine levels: role of nitric oxide and interleukin-1. Front Neurosci. 9:428. eCollection 2015.
Doucet MV, O'Toole E, Connor T, Harkin A. (2015) Small-molecule inhibitors at the PSD-95/nNOS interface protect against glutamate-induced neuronal atrophy in primary cortical neurons. Neuroscience. 301: 421 - 38.
Murray C, Griffin EW, O'Loughlin E, Lyons A, Sherwin E, Ahmed S, Stevenson NJ, Harkin A, Cunningham C. (2015) Interdependent and independent roles of type I interferons and IL-6 in innate immune, neuroinflammatory and sickness behaviour responses to systemic poly I:C. Brain Behav Immun. 48: 274 - 86.
Harkin A. (2015) Muscling in on depression. N Engl J Med. 371(24): 2333 - 4.
Rouine J, Kelly ME, Jennings-Murphy C, Duffy P, Gorman I, Gormley S, Kerskens CM, Harkin A. (2015) Investigation of the mechanisms mediating MDMA "Ecstasy"-induced increases in cerebro-cortical perfusion determined by btASL MRI. Psychopharmacology (Berl). 232(9): 1501 - 13.
Frodl T, Carballedo A, Frey EM, O'Keane V, Skokauskas N, Morris D, Gill M, Hughes MM, Harkin A, Connor T. (2014) Expression of glucocorticoid inducible genes is associated with reductions in cornu ammonis and dentate gyrus volumes in patients with major depressive disorder. Dev Psychopathol. 26(4 Pt 2): 1209 - 17.
Cuartero MI, Ballesteros I, de la Parra J, Harkin AL, Abautret-Daly A, Sherwin E, Fernández-Salguero P, Corbí AL, Lizasoain I, Moro MA. (2014) L-kynurenine/aryl hydrocarbon receptor pathway mediates brain damage after experimental stroke. Circulation. 2014 Dec 2;130(23): 2040 - 51.
Gigliucci V, Gormley S, Gibney S, Rouine J, Kerskens C, Connor TJ, Harkin A. (2014) Characterisation of the antidepressant properties of nitric oxide synthase inhibitors in the olfactory bulbectomised rat model of depression. Eur Neuropsychopharmacol. 24(8): 1349 - 61.
O'Donovan S, Dalton V, Harkin A, McLoughlin DM. (2014) Effects of brief pulse and ultrabrief pulse electroconvulsive stimulation on rodent brain and behaviour in the corticosterone model of depression. Int J Neuropsychopharmacol. 17(9):1477-86.
Gibney SM, Fagan EM, Waldron AM, O'Byrne J, Connor TJ, Harkin A. (2014) Inhibition of stress-induced hepatic tryptophan 2,3-dioxygenase exhibits antidepressant activity in an animal model of depressive behaviour. Int J Neuropsychopharmacol. 17(6):917-28.
Day JS, O'Neill E, Cawley C, Aretz NK, Kilroy D, Gibney SM, Harkin A, Connor TJ. (2014) Noradrenaline acting on astrocytic β₂-adrenoceptors induces neurite outgrowth in primary cortical neurons. Neuropharmacology. 77:234-48.
Pertl MM, Hevey D, Boyle NT, Hughes MM, Collier S, O'Dwyer AM, Harkin A, Kennedy MJ, Connor TJ (2013) C-reactive protein predicts fatigue independently of depression in breast cancer patients prior to chemotherapy. Brain Behav Immun. 34:108-19.
Ryan KJ, Griffin É, Yssel JD, Ryan KM, McNamee EN, Harkin A, Connor TJ. (2013)
Stimulation of central β2-adrenoceptors suppresses NFκB activity in rat brain: a role for IκB. Neurochem Int.63:368-78.
Rouine J, Gobbo OL, Campbell M, Gigliucci V, Ogden I, McHugh Smith K, Duffy P, Behan B, Byrne D, Kelly ME, Blau CW, Kerskens CM, Harkin A. (2013) MDMA 'ecstasy' increases cerebral cortical perfusion determined by bolus-tracking arterial spin labelling (btASL) MRI. Br J Pharmacol. 169(5):974-87.
Gigliucci V, O'Dowd G, Casey S, Egan D, Gibney S, Harkin A. (2013) Ketamine elicits sustained antidepressant-like activity via a serotonin-dependent mechanism.
Psychopharmacology (Berl). 228(1):157-66.
Doucet MV, Levine H, Dev KK, Harkin A. (2013) Small-molecule inhibitors at the PSD-95/nNOS interface have antidepressant-like properties in mice. Neuropsychopharmacology. 38(8):1575-84.
Gibney SM, McGuinness B, Prendergast C, Harkin A, Connor TJ. (2013) Poly I:C-induced activation of the immune response is accompanied by depression and anxiety-like behaviours, kynurenine pathway activation and reduced BDNF expression. Brain Behav Immun. 28:170-81.
Beumer W, Gibney SM, Drexhage RC, Pont-Lezica L, Doorduin J, Klein HC, Steiner J, Connor TJ, Harkin A, Versnel MA, Drexhage HA. (2012) The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes.
J Leukoc Biol. 92(5):959-75.
Hughes MM, Carballedo A, McLoughlin DM, Amico F, Harkin A, Frodl T, Connor TJ. (2012) Tryptophan depletion in depressed patients occurs independent of kynurenine pathway activation. Brain Behav Immun. 26(6):979-87.
Vanattou-Saïfoudine N, McNamara R, Harkin A. (2012) Caffeine provokes adverse interactions with 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') and related psychostimulants: mechanisms and mediators. Br J Pharmacol. 167(5):946-59.
Doucet MV, Harkin A, Dev KK. (2012) The PSD-95/nNOS complex: new drugs for depression? Pharmacol Ther. 133(2):218-29. Review.
Vanattou-Saïfoudine N, Behan B, Harkin A. (2012) Dopamine D1 receptor-mediated intracellular responses in the hypothalamus after co-administration of caffeine with MDMA. Basic Clin Pharmacol Toxicol. 110(3):283-9.
Vanattou-Saïfoudine N, Gossen A, Harkin A (2011) A role for adenosine A(1) receptor blockade in the ability of caffeine to promote MDMA "Ecstasy"-induced striatal dopamine release. Eur J Pharmacol. 650(1):220-8.
Gleeson LC, Ryan KJ, Griffin EW, Connor TJ, Harkin A. (2010) The beta(2)-adrenoceptor agonist clenbuterol elicits neuroprotective, anti-inflammatory and neurotrophic actions in the kainic acid model of excitotoxicity. Brain Behav Immun. 24: 1354-61
Vanattou-Saïfoudine N, McNamara R, Harkin A. (2010) Mechanisms mediating the ability of caffeine to influence MDMA ('Ecstasy')-induced hyperthermia in rats. Br J Pharmacol. 160(4):860-877.
Vanattou-Saïfoudine N, McNamara R, Harkin A. (2010) Caffeine promotes dopamine D1 receptor-mediated body temperature, heart rate and behavioural responses to MDMA ('ecstasy'). Psychopharmacology (Berl). 211(1):15-25.
McNamee EN, Griffin EW, Ryan KM, Ryan KJ, Heffernan S, Harkin A, Connor TJ. (2010) Noradrenaline acting at beta-adrenoceptors induces expression of IL-1beta and its negative regulators IL-1ra and IL-1RII, and drives an overall anti-inflammatory phenotype in rat cortex. Neuropharmacology. 59(1-2):37-48.
McNamee EN, Ryan KM, Griffin EW, González-Reyes RE, Ryan KJ, Harkin A, Connor TJ. (2010) Noradrenaline acting at central beta-adrenoceptors induces interleukin-10 and suppressor of cytokine signaling-3 expression in rat brain: Implications for neurodegeneration. Brain Behav Immun. 24(4):660-671.
O'Sullivan JB, Ryan KM, Harkin A, Connor TJ. (2010) Noradrenaline reuptake inhibitors inhibit expression of chemokines IP-10 and RANTES and cell adhesion molecules VCAM-1 and ICAM-1 in the CNS following a systemic inflammatory challenge. J Neuroimmunol. 220(1-2):34-42.
Gigliucci V, Buckley KN, Nunan J, O'Shea K, Harkin A. (2010) A role for serotonin in the antidepressant activity of NG-Nitro-L-arginine, in the rat forced swimming test.
Pharmacol Biochem Behav. 94(4):524-533.
O'Sullivan JB, Ryan KM, Curtin NM, Harkin A, Connor TJ. (2009) Noradrenaline reuptake inhibitors limit neuroinflammation in rat cortex following a systemic inflammatory challenge: implications for depression and neurodegeneration.
Int J Neuropsychopharmacol. 12(5):687-699.
Durkin S, Prendergast A, Harkin A. (2008) Reduced efficacy of fluoxetine following MDMA ("Ecstasy")-induced serotonin loss in rats. Prog Neuropsychopharmacol Biol Psychiatry. 32(8):1894-1901.
Connor TJ, Starr N, O'Sullivan JB, Harkin A. (2008) Induction of indolamine 2,3-dioxygenase and kynurenine 3-monooxygenase in rat brain following a systemic inflammatory challenge: A role for IFN-g? Neuroscience Letters 441: 29-34.
McNamara R., Maginn M., Harkin A. (2007) Caffeine induces a profound and persistent tachycardia in response to MDMA ("Ecstasy") administration. European Journal of Pharmacology 555: 194-198.
Garland MR, Hallahan B, McNamara M, Carney PA, Grimes H, Hibbeln JR, Harkin A, Conroy RM (2007) Lipids and essential fatty acids in patients presenting with self-harm. British Journal of Psychiatry. 190: 112-117.
Roche M, Harkin A, Kelly JP (2007) Chronic fluoxetine treatment attenuates stressor-induced changes in temperature, heart rate, and neuronal activation in the olfactory bulbectomized rat. Neuropsychopharmacology 32: 1312-1320.
McNamara R, Kerans A, O'Neill B and Harkin A. (2006) Caffeine promotes hyperthermia and serotonergic loss following co-administration of the substituted amphetamines, MDMA (“Ecstasy”) and MDA (“Love”) Neuropharmacology 50: 69-80.
Harkin A, Connor TJ, Burns MP and Kelly JP (2004) Nitric oxide synthase inhibitors augment the effect of serotonin re-uptake inhibitors in the mouse forced swimming test. European Neuropsychopharmacology 14: 274-281.
Harkin A, Shanahan E, Kelly JP and Connor TJ (2003) Methylenedioxyamphetamine produces serotonergic nerve terminal loss and diminished behavioral and neurochemical responses to the antidepressant fluoxetine. European Journal of Neuroscience 18: 1021-1027.
Harkin A, Connor TJ, Walsh M, St. John, N. and Kelly JP (2003) Serotonergic mediation of the antidepressant-like effects of nitric oxide synthase inhibitors. Neuropharmacology 44: 616-623.
Current Research Projects & Funding
2013-2017: Marie Curie Initial Training Networks (ITN): FP7-PEOPLE-2012-ITN
Brain Imaging Return to Health “reBIRTH” (http://www.rbirth.eu/)
2012-2015 Higher Education Authority of Ireland and the Programme for Research in Third Level Institutions MolCellBio programme.
Early diagnosis, treatment and prevention of mood disorders targeting the activated inflammatory response system. [Acronym: MOODINFLAME ] 2008-2013. Type of funding: A collaborative, large-scale focused research project
FP7- HEALTH-2007-2.2.1-8: From mood disorders to experimental models
The laboratory has also received support from SFI, Enterprise Ireland, Health Research Board & IRCSET
Members of the Research Group
Prof. Andrew Harkin (PI)
Dr. Allison McIntosh (Post-doctoral researcher)
Justin Yssel (with Prof. Thomas Connor)
Eimear O’Neill (with Prof. Thomas Connor)
Eoin Sherwin
Eileen O’Toole
Katherine O’Farrell
Elaine Dempsey
Jennifer David
Chloe Farrell (with Prof. Veronica O’Keane)
Kelly Doolin (with Prof. Veronica O’Keane)
Eoiin O’Neill
Lab Alumni
Dr. Sinead Gibney (Post-doctoral)
Dr. Alessia Piazza (Post-doctoral)
Dr. Ruth McNamara (2005, NUI Galway)
Dr. Natacha Vanattou-Saifoudine (2010, TCD)
Dr. Lorna Gleeson (2010, TCD)
Dr. Jennifer Rouine (2012, TCD)
Dr. Aine Abautret-Daly (2013, TCD)
Dr. Valentina Gigliucci (2013, TCD)
Dr. Marika Doucet (2013, TCD)
Dr. Martina Hughes (2014, TCD with Prof. Thomas Connor)
Dr. Barry McGuinness (2014, TCD with Prof. Thomas Connor)
Dr. Eimear Fagan (2014, TCD with Prof. Thomas Connor)
Dr. Shane Gormley (2015, TCD)
TCD Collaborators
Dr. Christian Kerskens, Trinity College Institute of Neuroscience
Prof. Arun Bodke, Trinity College Institute of Neuroscience
Prof. Declan McLoughlin, Trinity College Institute of Neuroscience
Prof. Thomas Frodl, Trinity College Institute of Neuroscience
Prof. Veronica O’Keane, Trinity College Institute of Neuroscience
Prof. Carlos Medina, School of Pharmacy & Pharmaceutical Sciences, TCD
Dr. Neil Docherty, Department of Physiology, School of Medicine, TCD
Prof. Colm Cunningham, Trinity College Institute of Neuroscience
National and International Collaborators
ReBirth EU collaborative network
MOODINFLAME EU collaborative network
Prof. Luigia Trabace and Dr. Marilena Colaianna, University of Foggia, Italy
Dr. Marjan Versnel, Erasmus MC, Rotterdam, The Netherlands
Prof. Maria Moro, Complutense University, Madrid, Spain