Neuropharmacology is a discipline that links neuroscience to the pharmacological treatment of psychiatric and neurological disorders. Our research is primarily focused in the thematic areas of depression and drug abuse. Research facilities are based in the School of Pharmacy & Pharmaceutical Sciences and Trinity College Institute of Neuroscience (TCIN)
PhD Opportunities:Information regarding funding opportunities to undertake a PhD in the group may be obtained in the following link.
For further website information see:
Selected examples of projects in these areas are outlined below:
The Neuropharmacology research group is funded under EU FP7 as part of a collaborative, large-scale 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 4 year 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 will be treated with drugs to counteract the consequences of an activated IRS/disturbed metabolism of tryptophan. The project will lead 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.
Antidepressant-induced adaptation to the glutamate NMDA receptor (NMDA-R), a locus for antidepressant activity
Antidepressants effect changes to the ligand binding properties of NMDA-R. The antidepressant desipramine reduces the potency of glycine at the NMDA-R and this adaptation is dependent on the neurotransmitter noradrenaline. Antidepressants with a dual action on the neurotransmitters noradrenaline and serotonin produce a more rapid adaptation at the NMDA-R than antidepressants that target either neurotransmitter alone. The inter-relationship between noradrenaline, serotonin and glutamate in the brain provides insight into the molecular mechanisms of antidepressant drugs.
Neuronal nitric oxide synthase (nNOS): a novel target for antidepressant action
Inhibition of 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. The experiments will identify brain regions involved in the antidepressant-like properties of nNOS inhibitors, and determine if nNOS inhibitors can protect the brain from the deleterious effects of stress. These studies will further our understanding of the neurobiological role of nNOS, and its potential as a novel therapeutic target for stress-related disorders such as depression. This work is funded by the Health research board. An immediate future aim is to determine if uncoupling the NMDA-R from nNOS can elicit antidepressant actions in animal models of depression. This will be achieved by delivery of a competitive peptide that disrupts the coupling of nNOS to NMDA-R using a viral vector. This work is being carried out in collaboration with Prof. Kumlesh Dev (TCIN).
Antidepressants as novel neuroprotectants
We hypothesise that antidepressant-induced adaptation to NMDA-R will confer neuroprotective benefits in the brain. In addition, antidepressants and/or drugs which influence monoamine neurotransmission may possess anti-inflammatory properties which contribute to their therapeutic actions. This research is of particular significance in light of evidence that depression is associated with inflammation and neuronal atrophy and that untreated depression may predispose to neurodegenerative disorders. Initially funded by IRCSET, this project has lead to my laboratory participating in an EU FP7-funded project entitled MOODINFLAME.
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.
On the basis of animal experiments, recreational “Ecstasy” use could have important and serious long-term health consequences for users. We are currently employing magnetic resonance imaging (MRI) studies of the rodent brain to bridge our work to the clinic. In a recent MRI study we have found increased brain perfusion associated with an acute regimen of MDMA. We are currently progressing this work further by developing functional MRI to assess neuronal activation in response to antidepressant treatment following MDMA-induced serotonin loss. This research is being undertaken in collaboration with Dr. Christian Kerskens in the MRI unit in TCIN.
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 buproprion. 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.
Head of Research Group
Members of the Research Group
Dr. Sinead Gibney
Lab AlumniDr. Ruth McNamara (2005, NUI Galway)
Dr. Natacha Vanattou-Saifoudine (2010, TCD)
Dr. Lorna Gleeson (2010, 2010)
Prof. Thomas Connor, Trinity College Institute of Neuroscience
Dr. Christian Kerskens, Trinity College Institute of Neuroscience
Prof. Kumlesh Dev, Trinity College Institute of Neuroscience
Prof. Declan McLoughlin, Trinity College Institute of Neuroscience
Prof. Thomas Frodl, Trinity College Institute of Neuroscience
Dr. Carlos Medina, School of Pharmacy & Pharmaceutical Sciences, TCD
Dr. Neil Docherty, Department of Physiology, School of Medicine, TCD
Dr. Julie Kelly, School of Biochemistry & Immunology, TCD
National and International Collaborators
MOODINFLAME EU collaborative network
Dr. Amy Mu Myint, Ludwig Maximillian University, Muenchen, Germany
Prof. Ian Paul, University of Mississippi Medical Centre, Jackson MS, USA.
Current Research Projects & Funding
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
Neuronal nitric oxide synthase: A novel target for antidepressant activity Health Research Board (HRB), Project grant 2008-2012.
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.