Professor Ian Kitchen HonFBPhS

Emeritus Professor of Neuropharmacology



Professor Kitchen is Emeritus Professor of Neuropharmacology in the Faculty of Health and Medical Sciences. He was Associate Dean for Research & Enterprise for a six year period (2007-2013), when he was responsible for leading the research strategy of the Faculty. He also served terms as interim Dean of the Faculty and interim and inaugural Head of the School of Biosciences and Medicine.

Appointed as a Professor of Neuropharmacology in 1997, he was formerly Head of the Pharmacology group and Deputy Head of School of Biomedical and Molecular Sciences at Surrey. He graduated with a 1st Class honours degree in 1977, and gained his PhD in 1980 from the University of London.

In 2006 he was elected a Fellow of the British Pharmacological Society and in 2010 elected a Fellow of the Society of Biology.  He was awarded a lifetime Honorary Fellowship of the British Pharmacological Society in 2019 for his contributions to REF, the Society and to Neuropharmacology. His primary area of research for over 30 years has been in opioid neuropharmacology and he has been a major academic contributor to the opioid field in the UK and world-wide. Surrey has gained international recognition for work on opioid system development in the brain and for neuroanatomical studies in opioid gene knockout mice in relation to furthering our understanding of pain and drug addiction. In collaboration with molecular genetics groups in France we were the first to publish the phenotype of an opioid receptor knockout mouse (Nature 383, 819-823, 1996), and Professor Kitchen has led Euorpean consortia funded by substantial EC grants studying the genomics of drug addiction. At a national level he was Chair of the UK Heads of Pharmacology and Therapeutics from 2010-2013 and has served on MRC advisory and grant boards and is an NC3Rs grant panel member.

He has been a Sub-Panel member on two UK research assessment exercises; on Allied Health Professions and Studies in RAE 2008 and on Allied Health Professions, Dentistry, Nursing and Pharmacy for REF 2014. At an international level he is founder and was President of the European Opioid Conference until 2011, has served three elected terms on the Executive Committee of the International Narcotics Research Conference, and is a member of the IUPHAR opioid receptor nomenclature sub-committee.

Research interests

Professor Kitchen has held research grants from all the major funders (MRC, BBSRC, Wellcome Trust, MoD, EC) as well as pharmaceutical industry. He has supervised over 35 PhD students and still retains active research on developmental neurobiology and his current research project is detailed below. He has published 200 research papers and reviews in leading journals in pharmacology and neuroscience, as well as in the multidisciplinary journals Nature and Cell.


Prof Kitchen has taught CNS pharmacology to undergraduate and postgraduate students on Biochemistry, Pharmacology, Neuroscience, Nursing and Toxicology degree programmes at Surrey.

He has been an external examiner at the University of Sheffield, Glasgow Caledonian University and Aston University.

He has examined at doctoral level at more than 10 Universities in the UK as well as international examining in France, Holland and Australia.


  • 1980-Present British Pharmacological Society (Elected Fellow in 2006, Awarded Honorary Fellowship 2019)
  • 2011-Present Society of Biology (Elected Fellow)

REF Consulting

Professor Kitchen is Chief Executive of the company REF Consulting Limited ( and formerly CEO of REF2020 Consulting (2015-2021). The company provides consultancy advice to Higher Education Institutions in the areas of research assessment and research excellence in preparation for the next UK Research Excellence Framework exercise. The core business of the company include:

  • Reviewing the quality of research areas in the health and biomedical sciences
  • Interactive seminars and presentations (eg):
    • Planning research to deliver more 4* and 3* research outputs
    • How outputs are assessed by REF sub-panels and how to assess your own papers
    • How impact case studies are assessed by REF sub-panels and the art of crafting impact stories
    • How to deliver a high-quality UoA Environment template
  • Strategic advice on appropriate UoA returns
  • Scoring of research outputs
  • Strategic advice on impact case studies
  • Scoring of impact case studies
  • Reviewing impact preparedness
  • Reviewing environment submissions
  • Reviewing impact case studies

Consultancy work for research assessment exercises outside of the UK is also be undertaken, where advice is sought related to the UK Research Excellence Framework.

Professor Kitchen was a Sub-Panel member for UoA 3 (Allied Health Professions, Dentistry, Nursing and Pharmacy) for REF 2014 and a Sub-Panel member for UoA 12 (Allied Health Professions and Studies) for RAE 2008. He was also a member of the cross-main panel feedback evaluation groups for REF 2014. He had lead responsibility at Surrey for large and highly successful RAE submissions in 1992, 1996, 2001 (5* rated) and 2008 (top 5%), and in REF 2014 in health and medical sciences.

Highly cited original articles over the last 25 years

Matthes, H., Maldonado, R., Simonin, F., Valverde, O., Slowe, S., Kitchen, I., Befort, K., Dierich, A., Le Meur, M., Dolle, P., Tzavara, E., Hanoune, J., Roques, B. and Kieffer, B. (1996) Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the µ-opioid receptor gene. Nature. 383, 819-823.


Simonin, F., Valverde, O., Smaje, C., Slowe, S., Kitchen, I., Dolle, P., Dierich, A, Le Meur, M. Roques, B.P., Maldonado, R. and Kieffer, B.L. (1998) Disruption of the -opioid receptor gene in mice impairs hypolocomotor, analgesic and aversive actions of the selective -agonist U-50,488H and attenuates morphine withdrawal. EMBO J. 17, 886-897.


Kitchen, I., Slowe, S., Matthes, H. and Kieffer, B. (1997) Quantitative autoradiographic mapping of mu-, delta and kappa opioid receptors in knockout mice lacking the mu-opioid receptor gene. Brain Res. 778, 73-88.


Guan, J-S., Xu, Z-Z, Gao, H., He, S-Q., Ma, G-Q., Sun, T., Wang, L-H., Zhang, Z-N., Lena, I., Kitchen, I., Elde, R., Zimmer, A., He, C., Pei, G., Bao, L. and Zhang, X. (2005) Interaction with vesicle luminal protachykinin regulates surface expression of δ-opioid receptors and opioid analgesia. Cell, 122, 619-631.


Clarke, S., Zimmer, A. Zimmer, A.M., Hill, R.G. and Kitchen, I. (2003) Region selective up-regulation of m, d and k-opioid receptors but not ORL1 receptors in the brains of enkephalin and dynorphin knockout mice. Neuroscience, 122, 479-489.


Hammers, A., Asselin, M-C., Hinz, R., Kitchen, I., Brooks, D.J., Duncan, J.S. Koepp, M.J. (2007) Upregulation of opioid receptor binding following spontaneous epileptic seizures. Brain, 130, 1009-1016.


Bailey, A., Ledent, C., Kelly, M., Hourani, S.M.O. and Kitchen, I. (2002) Changes in spinal - and -opioid systems in mice deficient in the A2a receptor gene. J. Neurosci. 22, 9210-9220.


Clarke, S., Zimmer, A. Zimmer, A.M., Hill, R.G. and Kitchen, I. (2003) Region selective up-regulation of m, d and k-opioid receptors but not ORL1 receptors in the brains of enkephalin and dynorphin knockout mice. Neuroscience, 122, 479-489.


Bailey, A., Lesscher, H.M.B., Kelly, M., Ledent, C., Davis, L., Hourani, S.M.O. and Kitchen, I. (2004) Enhanced morphine withdrawal and m-opioid receptor G-protein coupling in A2A adenosine receptor knockout mice. J. Neurochem. 88, 827-834.



Anna Borsodi, Michael Bruchas, Girolamo Caló, Charles Chavkin, MacDonald J. Christie, Olivier Civelli, Mark Connor, Brian M. Cox, Lakshmi A. Devi, Christopher Evans, Volker Höllt, Graeme Henderson, Stephen Husbands, Eamonn Kelly, Brigitte Kieffer, Ian Kitchen, Mary-Jeanne Kreek, Lee-Yuan Liu-Chen, Dominique Massot, Jean-Claude Meunier, Philip S. Portoghese, Stefan Schulz, Toni S. Shippenberg, Eric J. Simon, Lawrence Toll, John R. Traynor, Hiroshi Ueda, Yung H. Wong, Nurulain Zaveri, Andreas Zimmer (2019)Opioid receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database, In: IUPHAR/BPS Guide to Pharmacology CITE2019(4)

Opioid and opioid-like receptors are activated by a variety of endogenous peptides including [Met]enkephalin (met), [Leu]enkephalin (leu), β-endorphin (β-end), α-neodynorphin, dynorphin A (dynA), dynorphin B (dynB), big dynorphin (Big dyn), nociceptin/orphanin FQ (N/OFQ); endomorphin-1 and endomorphin-2 are also potential endogenous peptides. The Greek letter nomenclature for the opioid receptors, μ, δ and κ, is well established, and NC-IUPHAR considers this nomenclature appropriate, along with the symbols spelled out (mu, delta, and kappa), and the acronyms, MOP, DOP, and KOP. [116, 96, 88]. The human N/OFQ receptor, NOP, is considered 'opioid-related' rather than opioid because, while it exhibits a high degree of structural homology with the conventional opioid receptors [282], it displays a distinct pharmacology. Currently there are numerous clinically used drugs, such as morphine and many other opioid analgesics, as well as antagonists such as naloxone, however only for the μ receptor.

Panos Zanos, Helen Keyworth, Polymnia Georgiou, Boris Hambsch, David M Otte, Ian Kitchen, Andreas Zimmer, Alexis Bailey (2019)Chronic nicotine administration restores brain region specific upregulation of oxytocin receptor binding levels in a G72 mouse model of schizophrenia, In: The European journal of neuroscience50(3)2255pp. 2255-2263

Nicotine dependence and schizophrenia are two mental health disorders with remarkably high comorbidity. Cigarette smoking is particularly prevalent amongst schizophrenic patients and it is hypothesised to comprise a form of self-medication for relieving cognitive deficits in these patients. Emerging evidence suggests a role of the neurohypophysial peptide oxytocin in the modulation of drug addiction, as well as schizophrenia symptomology; however, the underlying mechanism remains unclear. Therefore, we sought to investigate the effects of chronic nicotine administration on oxytocin receptor (OTR) binding in the brain of a transgenic mouse model of schizophrenia that carries a bacterial artificial chromosome of the human G72/G30 locus (G72Tg). Female wild-type (WT) and heterozygous G72 transgenic CD-1 mice were treated with a chronic nicotine regimen (24 mg/kg/day, osmotic minipumps for 14 days) and quantitative autoradiographic mapping of oxytocin receptors was carried out in brains of these animals. OTR binding levels were higher in the cingulate cortex (CgCx), nucleus accumbens (Acb), and central amygdala (CeA) of saline treated G72Tg mice compared to WT control mice. Chronic nicotine administration reversed this upregulation in the CgCx and CeA. Interestingly, chronic nicotine administration induced an increase in OTR binding in the CeA of solely WT mice. These results indicate that nicotine administration normalises the dysregulated central oxytocinergic system of this mouse model of schizophrenia and may contribute towards nicotine's ability to modulate cognitive deficits which are common symptoms of schizophrenia.

A Bailey, L Davis, HMB Lesscher, MDW Kelly, C Ledent, SMO Hourani, I Kitchen (2004)Enhanced morphine withdrawal and mu-opioid receptor G-protein coupling in A(2A) adenosine receptor knockout ti ice, In: JOURNAL OF NEUROCHEMISTRY88(4)pp. 827-834 BLACKWELL PUBLISHING LTD
Aya Osman, Simone Zuffa, Gemma Walton, Elizabeth Fagbodun, Panos Zanos, Polymnia Georgiou, Ian Kitchen, Jonathan Swann, Alexis Bailey (2021)Post-weaning A1/A2 beta-casein milk intake modulates depressive-like behavior, brain pi-opioid receptors, and the metabolome of rats, In: iScience24(9)103048 Elsevier

The postnatal period is critical for brain and behavioral development and is sensitive to environmental stimuli, such as nutrition. Prevention of weaning from maternal milk was previously shown to cause depressive-like behavior in rats. Additionally, loss of dietary casein was found to act as a developmental trigger for a population of brain opioid receptors. Here, we explore the effect of exposure to milk containing A1 and A2 beta-casein beyond weaning. A1 but not A2 beta-casein milk significantly increased stress-induced immobility in rats, concomitant with an increased abundance of Clostridium histolyticum bacterial group in the caecum and colon of A1 beta-casein fed animals, brain region-specific alterations of m-opioid and oxytocin receptors, and modifications in urinary biochemical profiles. Moreover, urinary gut microbial metabolites strongly correlated with altered brain metabolites. These findings suggest that consumption of milk containing A1 beta-casein beyondweaning agemay affectmood via a possible gut-brain axis mechanism.

A Hammers, M-C Asselin, R Hinz, I Kitchen, DJ Brooks, JS Duncan, MJ Koepp (2007)Upregulation of opioid receptor binding following spontaneous epileptic seizures, In: BRAIN130pp. 1009-1016 OXFORD UNIV PRESS
L Godfrey, I Bailey, NJ Toms, GD Clarke, I Kitchen, SMO Hourani (2007)Paracetamol inhibits nitric oxide synthesis in murine spinal cord slices, In: EUR J PHARMACOL562(1-2)pp. 68-71 ELSEVIER SCIENCE BV

Paracetamol is an effective analgesic but its mechanism of action is unclear. We investigated the effect of paracetamol and the analgesic adjuvant caffeine on the activity of NO synthase in mouse spinal cord and cerebellar slices in vitro, by measuring the conversion of [3H]arginine to [3H]citrulline. Paracetamol (100 μM) had no effect on NO synthase activity in cerebellum, but in the spinal cord both paracetamol (100 μM) and caffeine (30 μM) attenuated glutamate (5 mM)-induced [3H]citrulline production and in combination they abolished it. In conclusion paracetamol inhibits spinal cord NO synthesis and this may be related to its analgesic effects.

A Metaxas, A Bailey, MF Barbano, L Galeote, R Maldonado, I Kitchen (2010)Differential region-specific regulation of alpha 4 beta 2*nAChRs by self-administered and non-contingent nicotine in C57BL/6J mice, In: ADDICT BIOL15(4)pp. 464-479 WILEY-BLACKWELL PUBLISHING, INC

Neuronal nAChR upregulation is the hallmark of chronic nicotine exposure. Neuroplasticity to abused drugs, however, depends on whether their administration is forced by the experimenter or is under the control of the experimental animal. Neuroadaptation to chronic nicotine self-administration was examined with a yoked-control paradigm, using nose-poking as the operating procedure. Freely moving C57BL/6J mice that responded for 0.03 mg/kg/infusion of intravenous nicotine under a continuous schedule of reinforcement (FR-1), had control over the rate and amount of drug intake that a yoked littermate passively received (n = 11). The impact of response dependency on neurobiological changes in nicotinic and dopaminergic systems was subsequently assessed using quantitative autoradiography. Cytisine-sensitive [125I]epibatidine binding, [3H]SCH23390, [3H]raclopride and [3H]mazindol were used to label nAChRs with 4β2* subtype properties, D1 and D2 dopaminergic receptors, and dopamine transporters, respectively. During a period of 12 days, self-administration was reliably initiated and maintained in animals receiving response-contingent nicotine. Region specific changes in the density of 4β2* nAChRs were found to be dependent on the contingency of nicotine treatment. Higher levels of 4β2* receptor binding were observed in the dorsal lateral geniculate nucleus and the ventral tegmental area of self-administering mice, compared to non-contingent animals. Moreover, response-independent increases in D2 binding were observed following chronic nicotine administration. No change in D1 and DAT binding was observed among groups. These findings indicate regional specific alterations in the regulation of the nicotinic cholinergic system following contingent and non-contingent nicotine exposure, and underline the importance of response dependency on the development of nicotine addiction.

D Ribe, D Sawbridge, S Thakur, M Hussey, C Ledent, I Kitchen, S Hourani, J-M Li (2008)Adenosine A(2A) receptor signaling regulation of cardiac NADPH oxidase activity, In: FREE RADICAL BIOLOGY AND MEDICINE44(7)pp. 1433-1442 ELSEVIER SCIENCE INC
VR Brownhill, SMO Hourani, I Kitchen (1996)Differential ontogeny of adenosine receptors in the longitudinal muscle and muscularis mucosae of the rat isolated duodenum, In: EUROPEAN JOURNAL OF PHARMACOLOGY317(2-3)pp. 321-328 ELSEVIER SCIENCE BV
PCS Chung, HL Keyworth, E Martin-Garcia, P Charbogne, E Darcq, A Bailey, D Filliol, A Matifas, G Scherrer, A-M Ouagazzal, C Gaveriaux-Ruff, K Befort, R Maldonado, I Kitchen, BL Kieffer (2015)A Novel Anxiogenic Role for the Delta Opioid Receptor Expressed in GABAergic Forebrain Neurons, In: BIOLOGICAL PSYCHIATRY77(4)pp. 404-415 ELSEVIER SCIENCE INC
VR Brownhill, SMO Hourani, I Kitchen (1997)Ontogeny of P2-purinoceptors in the longitudinal muscle and muscularis mucosae of the rat isolated duodenum, In: BRITISH JOURNAL OF PHARMACOLOGY122(2)pp. 225-232 STOCKTON PRESS
VR Brownhill, SMO Hourani, I Kitchen (1996)Differential distribution of adenosine A(2) receptors in the epididymal and prostatic portions of the rat vas deferens, In: EUROPEAN JOURNAL OF PHARMACOLOGY303(1-2)pp. 87-90 ELSEVIER SCIENCE BV
P Georgiou, P Zanos, M Ehteramyan, S Hourani, I Kitchen, R Maldonado, A Bailey (2015)Differential regulation of mGlu(5)R and MOPr by priming- and cue-induced reinstatement of cocaine-seeking behaviour in mice, In: ADDICTION BIOLOGY20(5)pp. 902-912 WILEY-BLACKWELL
A Osman, I Kitchen, J Swann, A Bailey (2015)Prolonged exposure to milk caseins in early postnatal life increases depressive-like behaviour, In: PROCEEDINGS OF THE NUTRITION SOCIETY74(OCE5)pp. E348-E348 CAMBRIDGE UNIV PRESS
I Lena, S Bradshaw, J Pintar, I Kitchen (2008)Adaptive changes in the expression of central opioid receptors in mice lacking the dopamine D2 receptor gene, In: NEUROSCIENCE153(3)pp. 773-788 PERGAMON-ELSEVIER SCIENCE LTD
J Cabello, A Bailey, I Kitchen, A Clark, J Crooks, R Halsall, M Key-Charriere, S Martin, M Prydderch, R Turchetta, K Wells (2006)Digital Autoradiography using CCD and CMOS Imaging Technology, In: 2006 IEEE Nuclear Science Symposium Conference Record4pp. 2607-2612 Institute of Electrical and Electronics Engineers

CCD and CMOS imaging technologies can be applied to thin tissue Autoradiography as potential imaging alternatives to using conventional film. In this work, we compare two particular devices; a CCD operating in slow scan mode and a CMOS-based Active Pixel sensor, operating at near video rates. Both imaging sensors have been operated at room temperature with images produced from calibrated microscales and radiolabelled tissue samples. We also compare these digital imaging technologies with the use of conventional film. We show first comparative results obtained with 14C calibrated microscales and 35S radiolabelled tissue sections. We also present first results of 3H images produced under direct irradiation of a CCD sensor operating at room temperature. Compared to film, silicon-based imaging technologies exhibit enhanced sensitivity, dynamic range and linearity.

Cocaine addiction has become a major concern in the UK as Britain tops the European 'league table' for cocaine abuse. Despite its devastating health and socio-economic consequences, no effective pharmacotherapy for treating cocaine addiction is available. Identifying neurochemical changes induced by repeated drug exposure is critical not only for understanding the transition from recreational drug use towards compulsive drug abuse but also for the development of novel targets for the treatment of the disease and especially for relapse prevention. This article focuses on the effects of chronic cocaine exposure and withdrawal on each of the endogenous opioid peptides and receptors in rodent models. In addition, we review the studies that utilized opioid peptide or receptor knockout mice in order to identify and/or clarify the role of different components of the opioid system in cocaine-addictive behaviours and in cocaine-induced alterations of brain neurochemistry. The review of these studies indicates a region-specific activation of the µ-opioid receptor system following chronic cocaine exposure, which may contribute towards the rewarding effect of the drug and possibly towards cocaine craving during withdrawal followed by relapse. Cocaine also causes a region-specific activation of the κ-opioid receptor/dynorphin system, which may antagonize the rewarding effect of the drug, and at the same time, contribute to the stress-inducing properties of the drug and the triggering of relapse. These conclusions have important implications for the development of effective pharmacotherapy for the treatment of cocaine addiction and the prevention of relapse.

A Bailey, JH Yoo, I Racz, A Zimmer, I Kitchen (2007)Preprodynorphin mediates locomotion and D-2 dopamine and mu-opioid receptor changes induced by chronic 'binge' cocaine administration, In: JOURNAL OF NEUROCHEMISTRY102(6)pp. 1817-1830 BLACKWELL PUBLISHING
MJ Hussey, GD Clarke, C Ledent, I Kitchen, SM Hourani (2012)Deletion of the adenosine A(2A) receptor in mice enhances spinal cord neurochemical responses to an inflammatory nociceptive stimulus., In: Neurosci Lett506(2)pp. 198-202 Elsevier

Knockout mice lacking the adenosine A(2A) receptor are less sensitive to nociceptive stimuli, and this may be due to the presence of pronociceptive A(2A) receptors on sensory nerves. In support of this hypothesis, we have recently shown that in A(2A) receptor knockout mice there are marked reductions in the changes of two markers of spinal cord neuronal activity, [(3)H]MK801 binding to NMDA receptors and uptake of [(14)C]-2-deoxyglucose, in response to formalin injection. We now report that following a more prolonged inflammatory stimulus, consisting of intraplantar injections of PGE(2) and paw pressure, there was in contrast an increase in [(3)H]MK801 binding and [(14)C]-2-deoxyglucose uptake in the spinal cords of the A(2A) receptor knockout mice which was much greater than in the wild-type mice. This increase suggests that when there is a pronounced inflammatory component to the stimulus, loss of inhibitory A(2A) receptors on inflammatory cells outweighs the loss of pronociceptive A(2A) receptors on peripheral nerves so that overall there is an increase in nociceptive signalling. This implies that although A(2A) antagonists have antinociceptive effects they may have only limited use as analgesics in chronic inflammatory pain.

L Godfrey, L Yan, GD Clarke, C Ledent, I Kitchen, SMO Hourani (2006)Modulation of paracetamol antinociception by caffeine and by selective adenosine A(2) receptor antagonists in mice, In: EUR J PHARMACOL531(1-3)pp. 80-86 ELSEVIER SCIENCE BV

This study investigated the involvement of adenosine receptors in the interaction between paracetamol and caffeine in mice, using the adenosine A2A receptor antagonist 5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH58261) and the adenosine A2B receptor antagonist 1-propyl-8-p-sulfophenylxanthine (PSB1115), in the tail immersion and hot-plate tests. Paracetamol (10–200 mg/kg) was antinociceptive in both tests, but, in contrast to previous studies, caffeine (10 mg/kg) was pronociceptive in the tail immersion test, and reduced the effects of paracetamol in both tests. SCH58261 (3 mg/kg) was antinociceptive in both tests and in its presence paracetamol (50 mg/kg) had no further effect. PSB1115 (10 mg/kg) had little effect alone but potentiated the effect of paracetamol (50 mg/kg) in the hot-plate test and abolished it in the tail immersion test. These results suggest that adenosine A2B receptors may be involved in the action of paracetamol in a pathway-dependent manner, and also support the existence of pronociceptive adenosine A2A receptors

M Kelly, A Bailey, C Ledent, I Kitchen, S Hourani (2004)Characterization of [H-3]ZM 241385 binding in wild-type and adenosine A(2A) receptor knockout mice, In: EUROPEAN JOURNAL OF PHARMACOLOGY504(1-2)pp. 55-59 ELSEVIER SCIENCE BV
A Bailey, EE Kelland, A Thomas, J Biggs, D Crawford, I Kitchen, NJ Toms (2001)Regional mapping of low-affinity kainate receptors in mouse brain using [H-3](2S,4R)-4-methylglutamate autoradiography, In: EUROPEAN JOURNAL OF PHARMACOLOGY431(3)pp. 305-310 ELSEVIER SCIENCE BV
MJ Hussey, GD Clarke, C Ledent, SMO Hourani, I Kitchen (2007)Reduced response to the formalin test and lowered spinal NMDA glutamate receptor binding in adenosine A(2A) receptor knockout mice, In: PAIN129(3)pp. 287-294 ELSEVIER SCIENCE BV
A Castane, L Wells, G Soria, S Hourani, C Ledent, I Kitchen, J Opacka-Juffry, R Maldonado, O Valverde (2008)Behavioural and biochemical responses to morphine associated with its motivational properties are altered in adenosine A(2A) receptor knockout mice, In: BRIT J PHARMACOL155(5)pp. 757-766 NATURE PUBLISHING GROUP

Background and purpose. Purinergic system through the A2A adenosine receptor regulates addiction induced by different drugs of abuse. The aim of the present study was to investigate the specific role of A2A adenosine receptors in behavioral and neurochemical morphine responses related to its addictive properties. Experimental approach. Mice lacking A2A adenosine receptors and wild type littermates were used to evaluate behavioral responses induced by morphine. Antinociception was assessed using the tail-immersion and the hot-plate tests. Place conditioning paradigms were used to evaluate the rewarding effects of morphine and the dysphoric responses of morphine withdrawal. Microdialysis studies were carried out to evaluate changes in the extracellular levels of dopamine in the nucleus accumbens of A2A knockout mice after morphine administration. Key results. The acute administration of morphine induced a similar enhancement of locomotor activity and antinociceptive responses in both genotypes. However, the rewarding effects induced by morphine were completely blocked in A2A knockout mice. Besides, naloxone did not induce place aversion in animals lacking the A2A adenosine receptors. Conclusions and implications. Our findings demonstrate the relevant role played by A2A adenosine receptors in the addictive properties of morphine. Both, rewarding and aversive effects associated to abstinence were abolished in A2A knockout mice, supporting a differential role of the A2A adenosine receptor in somatic and motivational effects of morphine addiction. This study provides evidence about the role of A2A adenosine receptor as a general modulator of the addictive phenomenon.

P Georgiou, P Zanos, J-A Garcia-Carmona, S Hourani, I Kitchen, M-L Laorden, A Bailey (2016)Methamphetamine abstinence induces changes in mu-opioid receptor, oxytocin and CRF systems: Association with an anxiogenic phenotype, In: NEUROPHARMACOLOGY105pp. 520-532 PERGAMON-ELSEVIER SCIENCE LTD
L Fan, D Sawbridge, V George, L Teng, A Bailey, I Kitchen, J-M Li (2009)Chronic Cocaine-Induced Cardiac Oxidative Stress and Mitogen-Activated Protein Kinase Activation: The Role of Nox2 Oxidase, In: JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS328(1)pp. 99-106 AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
P Farshim, G Walton, B Chakrabarti, I Givens, D Saddy, I Kitchen, J Swann, Alexis Bailey (2016)Maternal Weaning Modulates Emotional Behavior and Regulates the Gut-Brain Axis, In: SCIENTIFIC REPORTS6ARTN 21958 NATURE PUBLISHING GROUP

Evidence shows that nutritional and environmental stress stimuli during postnatal period influence brain development and interactions between gut and brain. In this study we show that in rats, prevention of weaning from maternal milk results in depressive-like behavior, which is accompanied by changes in the gut bacteria and host metabolism. Depressive-like behavior was studied using the forced-swim test on postnatal day (PND) 25 in rats either weaned on PND 21, or left with their mother until PND 25 (non-weaned). Non-weaned rats showed an increased immobility time consistent with a depressive phenotype. Fluorescence in situ hybridization showed non-weaned rats to harbor significantly lowered Clostridium histolyticum bacterial groups but exhibit marked stress-induced increases. Metabonomic analysis of urine from these animals revealed significant differences in the metabolic profiles, with biochemical phenotypes indicative of depression in the non-weaned animals. In addition, non-weaned rats showed resistance to stress-induced modulation of oxytocin receptors in amygdala nuclei, which is indicative of passive stress-coping mechanism. We conclude that delaying weaning results in alterations to the gut microbiota and global metabolic profiles which may contribute to a depressive phenotype and raise the issue that mood disorders at early developmental ages may reflect interplay between mammalian host and resident bacteria.

P Zanos, P Georgiou, LR Gonzalez, S Hourani, Y Chen, I Kitchen, BL Kieffer, R Winsky-Sommerer, A Bailey (2016)Emotional Impairment and Persistent Upregulation of mGlu(5) Receptor following Morphine Abstinence: Implications of an mGlu(5)-MOPr Interaction, In: INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY19(7) OXFORD UNIV PRESS
SR Wright, P Zanos, P Georgiou, JH Yoo, C Ledent, SM Hourani, I Kitchen, R Winsky-Sommerer, A Bailey (2015)A critical role of striatal A2A R-mGlu5 R interactions in modulating the psychomotor and drug-seeking effects of methamphetamine., In: ADDICT BIOL WILEY-BLACKWELL PUBLISHING, INC

Addiction to psychostimulants is a major public health problem with no available treatment. Adenosine A2A receptors (A2A R) co-localize with metabotropic glutamate 5 receptors (mGlu5 R) in the striatum and functionally interact to modulate behaviours induced by addictive substances, such as alcohol. Using genetic and pharmacological antagonism of A2A R in mice, we investigated whether A2A R-mGlu5 R interaction can regulate the locomotor, stereotypic and drug-seeking effect of methamphetamine and cocaine, two drugs that exhibit distinct mechanism of action. Genetic deletion of A2A R, as well as combined administration of sub-threshold doses of the selective A2A R antagonist (SCH 58261, 0.01 mg/kg, i.p.) with the mGlu5 R antagonist, 3-((2-methyl-4-thiazolyl)ethynyl)pyridine (0.01 mg/kg, i.p.), prevented methamphetamine- but not cocaine-induced hyperactivity and stereotypic rearing behaviour. This drug combination also prevented methamphetamine-rewarding effects in a conditioned-place preference paradigm. Moreover, mGlu5 R binding was reduced in the nucleus accumbens core of A2A R knockout (KO) mice supporting an interaction between these receptors in a brain region crucial in mediating addiction processes. Chronic methamphetamine, but not cocaine administration, resulted in a significant increase in striatal mGlu5 R binding in wild-type mice, which was absent in the A2A R KO mice. These data are in support of a critical role of striatal A2A R-mGlu5 R functional interaction in mediating the ambulatory, stereotypic and reinforcing effects of methamphetamine but not cocaine-induced hyperlocomotion or stereotypy. The present study highlights a distinct and selective mechanistic role for this receptor interaction in regulating methamphetamine-induced behaviours and suggests that combined antagonism of A2A R and mGlu5 R may represent a novel therapy for methamphetamine addiction.

P Georgiou, P Zanos, J-A Garcia-Carmona, S Hourani, I Kitchen, BL Kieffer, M-L Laorden, A Bailey (2015)The oxytocin analogue carbetocin prevents priming-induced reinstatement of morphine-seeking: Involvement of dopaminergic, noradrenergic and MOPr systems, In: EUROPEAN NEUROPSYCHOPHARMACOLOGY25(12)pp. 2459-2464 ELSEVIER SCIENCE BV
P Zanos, P Georgiou, A Metaxas, I Kitchen, R Winsky-Sommerer, A Bailey (2015)Region-specific up-regulation of oxytocin receptor binding in the brain of mice following chronic nicotine administration, In: NEUROSCIENCE LETTERS600pp. 33-37 ELSEVIER IRELAND LTD

Nicotine addiction is considered to be the main preventable cause of death worldwide. While growing evidence indicates that the neurohypophysial peptide oxytocin can modulate the addictive properties of several abused drugs, the regulation of the oxytocinergic system following nicotine administration has so far received little attention. Here, we examined the effects of long-term nicotine or saline administration on the central oxytocinergic system using [(125)I]OVTA autoradiographic binding in mouse brain. Male, 7-week old C57BL6J mice were treated with either nicotine (7.8 mg/kg daily; rate of 0.5 μl per hour) or saline for a period of 14-days via osmotic minipumps. Chronic nicotine administration induced a marked region-specific upregulation of the oxytocin receptor binding in the amygdala, a brain region involved in stress and emotional regulation. These results provide direct evidence for nicotine-induced neuroadaptations in the oxytocinergic system, which may be involved in the modulation of nicotine-seeking as well as emotional consequence of chronic drug use.

A Bailey, RM Hawkins, SMO Hourani, I Kitchen (2003)Quantitative autoradiography of adenosine receptors in brains of chronic naltrexone-treated mice, In: BRITISH JOURNAL OF PHARMACOLOGY139(6)pp. 1187-1195 NATURE PUBLISHING GROUP
M Connor, I Kitchen (2006)Has the sun set on kappa(3)-opioid receptors?, In: BRITISH JOURNAL OF PHARMACOLOGY147(4)pp. 349-350 NATURE PUBLISHING GROUP
R Al-Hasani, JD Foster, A Metaxas, C Ledent, SM Hourani, I Kitchen, Y Chen (2011)Increased desensitization of dopamine D(2) receptor-mediated response in the ventral tegmental area in the absence of adenosine A(2A) receptors., In: Neuroscience190pp. 103-111 Elsevier

G-protein coupled receptors interact to provide additional regulatory mechanisms for neurotransmitter signaling. Adenosine A(2A) receptors are expressed at a high density in striatal neurons, where they closely interact with dopamine D(2) receptors and modulate effects of dopamine and responses to psychostimulants. A(2A) receptors are expressed at much lower densities in other forebrain neurons but play a more prominent yet opposing role to striatal receptors in response to psychostimulants in mice. It is, therefore, possible that A(2A) receptors expressed at low levels elsewhere in the brain may also regulate neurotransmitter systems and modulate neuronal functions. Dopamine D(2) receptors play an important role in autoinhibition of neuronal firing in dopamine neurons of the ventral tegmental area (VTA) and dopamine release in other brain areas. Here, we examined the effect of A(2A) receptor deletion on D(2) receptor-mediated inhibition of neuronal firing in dopamine neurons in the VTA. Spontaneous activity of dopamine neurons was recorded in midbrain slices, and concentration-dependent effects of the dopamine D(2) receptor agonist, quinpirole, was compared between wild-type and A(2A) knockout mice. The potency of quinpirole applied in single concentrations and the expression of D(2) receptors were not altered in the VTA of the knockout mice. However, quinpirole applied in stepwise escalating concentrations caused significantly reduced maximal inhibition in A(2A) knockout mice, indicating an enhanced agonist-induced desensitization of D(2) receptors in the absence of A(2A) receptors. The A(2A) receptor agonist, CGS21680, did not exert any effect on dopamine neuron firing or response to quinpirole, revealing a novel non-pharmacological interaction between adenosine A(2A) receptors and dopaminergic neurotransmission in midbrain dopamine neurons. Altered D(2) receptor desensitization may result in changes in dopamine neuron firing rate and pattern and dopamine release in other brain areas in response to persistent dopamine release and administration of psychostimulants.

B Hambsch, DM Otte, I Racz, A Zimmer, H Keyworth, J Lind, I Kitchen, A Bailey (2014)Chronic nicotine improves short-term memory selectively in a G72 mouse model of schizophrenia, In: British Journal of Pharmacology171(7)pp. 1758-1771

Background and Purpose The prevalence of smoking in schizophrenia patients is exceptionally high; it is not known why but many researchers suggest that smoking constitutes a form of self-medication. Among the symptoms of schizophrenia that may be improved by nicotine are cognitive deficits. Hence, we studied the effects of long-term nicotine administration on cognition in a genetic animal model of schizophrenia susceptibility, G72-transgenic (G72Tg) mice. Experimental Approach The effect of long-term nicotine or saline, administered by osmotic minipumps, on different cognitive domains was assessed in G72Tg mice and controls using a battery of behavioural tests. To investigate the mechanism underlying phenotypic differences, quantitative autoradiographic mapping of nACh receptor subtypes was performed in forebrain structures to explore effects of chronic nicotine exposure on nACh receptor density in wild-type (WT) and G72Tg mice. Key Results Genotype significantly affected the cognitive effects of chronic nicotine administration. Whereas chronic nicotine disrupted cognitive performance in WT mice, it was effective at restoring impaired prepulse inhibition, working memory and social recognition in G72Tg mice. However, long-term spatial learning was further impaired by nicotine in transgenic animals. In contrast, associative learning was protected by G72-expression against the adverse nicotine effects seen in WT animals. G72-expression did not decisively influence nicotine-induced up-regulation of the α4β2subtype, whereas α7nACh receptor density was differentially altered by genotype or by a genotype·treatment interaction in specific brain areas, most notably hippocampal subregions. Conclusions and Implications Our data support the hypothesis that nicotine self-medication of schizophrenics improves cognitive symptoms, possibly by facilitating nicotine-induced α7nACh receptor activation in the hippocampus. © 2014 The British Pharmacological Society.

A Metaxas, R Al-Hasani, P Farshim, K Tubby, A Berwick, C Ledent, S Hourani, I Kitchen, A Bailey (2013)Genetic deletion of the adenosine A2A receptor prevents nicotine-induced upregulation of α7, but not α4β2* nicotinic acetylcholine receptor binding in the brain., In: Neuropharmacology71pp. 228-236

Considerable evidence indicates that adenosine A2A receptors (A2ARs) modulate cholinergic neurotransmission, nicotinic acetylcholine receptor (nAChR) function, and nicotine-induced behavioural effects. To explore the interaction between A2A and nAChRs, we examined if the complete genetic deletion of adenosine A2ARs in mice induces compensatory alterations in the binding of different nAChR subtypes, and whether the long-term effects of nicotine on nAChR regulation are altered in the absence of the A2AR gene. Quantitative autoradiography was used to measure cytisine-sensitive [(125)I]epibatidine and [(125)I]α-bungarotoxin binding to α4β2* and α7 nAChRs, respectively, in brain sections of drug-naïve (n = 6) or nicotine treated (n = 5-7), wild-type and adenosine A2AR knockout mice. Saline or nicotine (7.8 mg/kg/day; free-base weight) were administered to male CD1 mice via subcutaneous osmotic minipumps for a period of 14 days. Blood plasma levels of nicotine and cotinine were measured at the end of treatment. There were no compensatory developmental alterations in nAChR subtype distribution or density in drug-naïve A2AR knockout mice. In nicotine treated wild-type mice, both α4β2* and α7 nAChR binding sites were increased compared with saline treated controls. The genetic ablation of adenosine A2ARs prevented nicotine-induced upregulation of α7 nAChRs, without affecting α4β2* receptor upregulation. This selective effect was observed at plasma levels of nicotine that were within the range reported for smokers (10-50 ng ml(-1)). Our data highlight the involvement of adenosine A2ARs in the mechanisms of nicotine-induced α7 nAChR upregulation, and identify A2ARs as novel pharmacological targets for modulating the long-term effects of nicotine on α7 receptors.

Understanding the neurobiology of the transition from initial drug use to excessive drug use has been a challenge in drug addiction. We examined the effect of chronic 'binge' escalating dose cocaine administration, which mimics human compulsive drug use, on behavioural responses and the dopaminergic system of mice and compared it with a chronic steady dose (3 x 15 mg/kg/day) 'binge' cocaine administration paradigm. Male C57BL/6J mice were injected with saline or cocaine in an escalating dose paradigm for 14 days. Locomotor and stereotypy activity were measured and quantitative autoradiographic mapping of D(1) and D(2) receptors, dopamine transporters and D(2)-stimulated [(35)S]GTPgammaS binding was performed in the brains of mice treated with this escalating and steady dose paradigm. An initial sensitization to the locomotor effects of cocaine followed by a dose-dependent increase in the duration of the locomotor effect of cocaine was observed in the escalating but not the steady dose paradigm. Sensitization to the stereotypy effect of cocaine and an increase in cocaine-induced stereotypy score was observed from 3 x 20 to 3 x 25 mg/kg/day cocaine. There was a significant decrease in D(2) receptor density, but an increase in D(2)-stimulated G-protein activity and dopamine transporter density in the striatum of cocaine-treated mice, which was not observed in our steady dose paradigm. Our results document that chronic 'binge' escalating dose cocaine treatment triggers profound behavioural and neurochemical changes in the dopaminergic system, which might underlie the transition from drug use to compulsive drug use associated with addiction, which is a process of escalation.

There is growing agreement that genetic factors play an important role in the risk to develop heroin addiction, and comparisons of heroin addiction vulnerability in inbred strains of mice could provide useful information on the question of individual vulnerability to heroin addiction. This study examined the rewarding and locomotor-stimulating effects of heroin in male C57BL/6J and DBA/2J mice. Heroin induced locomotion and sensitisation in C57BL/6J but not in DBA/2J mice. C57BL/6J mice developed conditioned place preference (CPP) to the highest doses of heroin, while DBA/2J showed CPP to only the lowest heroin doses, indicating a higher sensitivity of DBA/2J mice to the rewarding properties of heroin vs C57BL/6J mice. In order to investigate the neurobiological substrate underlying some of these differences, the effect of chronic 'intermittent' escalating dose heroin administration on the opioid, dopaminergic and stress systems was explored. Twofold higher mu-opioid receptor (MOP-r)-stimulated [35S]GTPgammaS binding was observed in the nucleus accumbens and caudate of saline-treated C57BL/6J mice compared with DBA/2J. Heroin decreased MOP-r density in brain regions of C57BL/6J mice, but not in DBA/2J. A higher density of dopamine transporters (DAT) was observed in nucleus accumbens shell and caudate of heroin-treated DBA/2J mice compared with heroin-treated C57BL/6J. There were no effects on D1 and D2 binding. Chronic heroin administration decreased corticosterone levels in both strains with no effect of strain. These results suggest that genetic differences in MOP-r activation and DAT expression may be responsible for individual differences in vulnerability to heroin addiction.

P Zanos, P Georgiou, SR Wright, SM Hourani, I Kitchen, R Winsky-Sommerer, A Bailey (2014)The oxytocin analogue carbetocin prevents emotional impairment and stress-induced reinstatement of opioid-seeking in morphine-abstinent mice, In: Neuropsychopharmacology39(4)pp. 855-865

The main challenge in treating opioid addicts is to maintain abstinence due to the affective consequences associated with withdrawal which may trigger relapse. Emerging evidence suggests a role of the neurohypophysial peptide oxytocin (OT) in the modulation of mood disorders as well as drug addiction. However, its involvement in the emotional consequences of drug abstinence remains unclear. We investigated the effect of 7-day opioid abstinence on the oxytocinergic system and assessed the effect of the OT analogue carbetocin (CBT) on the emotional consequences of opioid abstinence, as well as relapse. Male C57BL/6J mice were treated with a chronic escalating-dose morphine regimen (20-100 mg/kg/day, i.p.). Seven days withdrawal from this administration paradigm induced a decrease of hypothalamic OT levels and a concomitant increase of oxytocin receptor (OTR) binding in the lateral septum and amygdala. Although no physical withdrawal symptoms or alterations in the plasma corticosterone levels were observed after 7 days of abstinence, mice exhibited increased anxiety-like and depressive-like behaviors and impaired sociability. CBT (6.4 mg/kg, i.p.) attenuated the observed negative emotional consequences of opioid withdrawal. Furthermore, in the conditioned place preference paradigm with 10 mg/kg morphine conditioning, CBT (6.4 mg/kg, i.p.) was able to prevent the stress-induced reinstatement to morphine-seeking following extinction. Overall, our results suggest that alterations of the oxytocinergic system contribute to the mechanisms underlying anxiety, depression, and social deficits observed during opioid abstinence. This study also highlights the oxytocinergic system as a target for developing pharmacotherapy for the treatment of emotional impairment associated with abstinence and thereby prevention of relapse.

J-H Yoo, A Bailey, A Borsodi, G Toth, A Matifas, BL Kieffer, I Kitchen (2014)Knockout subtraction autoradiography: A novel ex vivo method to detect heteromers finds sparse KOP receptor/DOP receptor heterodimerization in the brain, In: EUROPEAN JOURNAL OF PHARMACOLOGY731pp. 1-7 ELSEVIER SCIENCE BV
P Zanos, SR Wright, P Georgiou, JH Yoo, SM Hourani, I Kitchen, R Winsky-Sommerer, A Bailey, C Ledent (2014)Chronic methamphetamine treatment induces oxytocin receptor up-regulation in the amygdala and hypothalamus via an adenosine A receptor-independent mechanism, In: Pharmacology Biochemistry and Behavior119pp. 72-79

There is mounting evidence that the neuropeptide oxytocin is a possible candidate for the treatment of drug addiction. Oxytocin was shown to reduce methamphetamine self-administration, conditioned place-preference, hyperactivity and reinstatement in rodents, highlighting its potential for the management of methamphetamine addiction. Thus, we hypothesised that the central endogenous oxytocinergic system is dysregulated following chronic methamphetamine administration. We tested this hypothesis by examining the effect of chronic methamphetamine administration on oxytocin receptor density in mice brains with the use of quantitative receptor autoradiographic binding. Saline (4 ml/kg/day, i.p.) or methamphetamine (1 mg/kg/day, i.p.) was administered daily for 10 days to male, CD1 mice. Quantitative autoradiographic mapping of oxytocin receptors was carried out with the use of [I]-vasotocin in brain sections of these animals. Chronic methamphetamine administration induced a region specific upregulation of oxytocin receptor density in the amygdala and hypothalamus, but not in the nucleus accumbens and caudate putamen. As there is evidence suggesting an involvement of central adenosine A receptors on central endogenous oxytocinergic function, we investigated whether these methamphetamine-induced oxytocinergic neuroadaptations are mediated via an A receptor-dependent mechanism. To test this hypothesis, autoradiographic oxytocin receptor binding was carried out in brain sections of male CD1 mice lacking A receptors which were chronically treated with methamphetamine (1 mg/kg/day, i.p. for 10 days) or saline. Similar to wild-type animals, chronic methamphetamine administration induced a region-specific upregulation of oxytocin receptor binding in the amygdala and hypothalamus of A receptor knockout mice and no genotype effect was observed. These results indicate that chronic methamphetamine use can induce profound neuroadaptations of the oxytocinergic receptor system in brain regions associated with stress, emotionality and social bonding and that these neuroadaptations are independent on the presence of A receptors. These results may at least partly explain some of the behavioural consequences of chronic methamphetamine use. © 2013 Elsevier Inc. All rights reserved.

HMB Lesscher, A Bailey, JPH Burbach, JM van Ree, I Kitchen, MAFM Gerrits (2003)Receptor-selective changes in mu-, delta- and kappa-opioid receptors after chronic naltrexone treatment in mice, In: EUROPEAN JOURNAL OF NEUROSCIENCE17(5)pp. 1006-1012 BLACKWELL PUBLISHING LTD
BJ Martynhak, AL Hogben, P Zanos, P Georgiou, R Andreatini, I Kitchen, SN Archer, M von Schantz, A Bailey, Daan R. van der Veen (2017)Transient anhedonia phenotype and altered circadian timing of behaviour during night-time dim light exposure in Per3-/- mice, but not wildtype mice, In: Scientific Reports740399 Nature Publishing Group

Industrialisation greatly increased human night-time exposure to artificial light, which in animal models is a known cause of depressive phenotypes. Whilst many of these phenotypes are ‘direct’ effects of light on affect, an ‘indirect’ pathway via altered sleep-wake timing has been suggested. We have previously shown that the Period3 gene, which forms part of the biological clock, is associated with altered sleep-wake patterns in response to light. Here, we show that both wild-type and Per3-/- mice showed elevated levels of circulating corticosterone and increased hippocampal Bdnf expression after 3 weeks of exposure to dim light at night, but only mice deficient for the PERIOD3 protein (Per3-/-) exhibited a transient anhedonia-like phenotype, observed as reduced sucrose preference, in weeks 2-3 of dim light at night, whereas WT mice did not. Per3-/- mice also exhibited a significantly smaller delay in behavioural timing than WT mice during weeks 1, 2 and 4 of dim light at night exposure. When treated with imipramine, neither Per3-/- nor WT mice exhibited an anhedonia-like phenotype, and neither genotypes exhibited a delay in behavioural timing in responses to dLAN. While the association between both Per3-/- phenotypes remains unclear, both are alleviated by imipramine treatment during dim night-time light.

Background and purpose: High rates of cigarette smoking occur in cocaine dependent individuals, reflecting an involvement of nicotinic acetylcholine receptors (nAChRs) in cocaine-elicited behaviour. This study was designed to parse the contribution of different nAChR subtypes to the behavioural and neurochemical effects of chronic cocaine treatment. Experimental approach: Cocaine (15 mg/kg, i.p.) was administered to male C57BL/6J mice in a chronic 'binge' paradigm, with and without the co-administration of the α7 preferring antagonist methyllycaconitine (MLA; 5 mg/kg; i.p.) or the β2* nAChR antagonist dihydro-β-erythroidine (DHßE; 2 mg/kg. i.p.). Quantitative autoradiography was used to examine the impact of cocaine exposure on α7 and α4β2* nAChRs, and on the high-affinity choline transporter. Key results: MLA+cocaine administration induced an intense self-grooming behaviour, indicating a likely role for α7 nAChRs in modulating this anxiogenic, compulsive-like effect of cocaine. In the major island of Calleja, a key area of action for neuroleptics, MLA+cocaine reduced choline-transporter binding compared to cocaine (±DHßE) administration. DHßE treatment prevented the induction of stereotypy sensitisation to cocaine, but prolonged locomotor sensitisation, implicating heteromeric β2* nAChRs in the neuroadaptations mediating cocaine-induced behavioural sensitisation. 'Binge' cocaine treatment region-specifically increased α4β2* nAChR binding in the midbrain dopaminergic regions: ventral tegmental area and substantia nigra pars compacta. Conclusions and implications: We show a differential, subtype-selective contribution of nAChRs to the behavioural and neurochemical sequelae of chronic cocaine administration. These data support the clinical utility of targeting specific nAChR subtypes for the alleviation of cocaine-abuse symptomatology. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

J Cabello, A Bailey, I Kitchen, M Prydderch, A Clark, R Turchetta, K Wells (2007)Digital autoradiography using room temperature CCD and CMOS imaging technology., In: Physics in Medicine and Biology52(16)pp. 4993-5011

CCD (charged coupled device) and CMOS imaging technologies can be applied to thin tissue autoradiography as potential imaging alternatives to using conventional film. In this work, we compare two particular devices: a CCD operating in slow scan mode and a CMOS-based active pixel sensor, operating at near video rates. Both imaging sensors have been operated at room temperature using direct irradiation with images produced from calibrated microscales and radiolabelled tissue samples. We also compare these digital image sensor technologies with the use of conventional film. We show comparative results obtained with (14)C calibrated microscales and (35)S radiolabelled tissue sections. We also present the first results of (3)H images produced under direct irradiation of a CCD sensor operating at room temperature. Compared to film, silicon-based imaging technologies exhibit enhanced sensitivity, dynamic range and linearity.

D Fragou, P Zanos, S Kouidou, S Njau, I Kitchen, A Bailey, L Kovatsi (2013)Effect of chronic heroin and cocaine administration on global DNA methylation in brain and liver, In: TOXICOLOGY LETTERS218(3)pp. 260-265 ELSEVIER IRELAND LTD
Helen Keyworth, Polymnia Georgiou, Panos Zanos, Andre Veloso Rueda, Ying Chen, Ian Kitchen, Rosana Camarini, Mark Cropley, Alexis Bailey (2017)Wheel running during chronic nicotine exposure is protective against mecamylamine-precipitated withdrawal and upregulates hippocampal a7 nACh receptors in mice, In: British Journal of Pharmacology175(11)pp. 1928-1943 Wiley

Background and purpose. Evidence suggests that exercise decreases nicotine withdrawal symptoms in humans; however, the mechanisms mediating this effect are unclear. We investigate, in a mouse model, the effect of exercise intensity during chronic nicotine exposure on nicotine withdrawal severity, binding of α4β2*, α7 nicotinic acetylcholine (nAChR), μ-opioid (μ receptors) and D2 dopamine receptors, and on brain-derived neurotrophic factor (BDNF) and plasma corticosterone levels. Experimental approach. Male C57Bl/6J mice treated with nicotine (minipump, 24 mg kg-1 day-1) or saline for 14 days underwent one of three concurrent exercise regimes: 24, 2 or 0 hrs day-1 voluntary wheel running. Mecamylamine-precipitated withdrawal symptoms were assessed on day 14. Quantitative autoradiography of α4β2*, α7 nAChRs, μ receptors and D2 receptor binding was performed in brain sections of these mice. Plasma corticosterone and brain BDNF levels were also measured. Key results. Nicotine-treated mice undertaking 2 or 24 hrs day-1 wheel running displayed a significant reduction of withdrawal symptom severity compared with the sedentary group. Wheel-running induced a significant upregulation of α7 nAChR binding in the CA2/3 area of the hippocampus of nicotine-treated mice. Neither exercise nor nicotine treatment affected μ or D2 receptor binding or BDNF levels. Nicotine withdrawal increased plasma corticosterone levels and α4β2* nAChR binding, irrespective of exercise regimen. Conclusions and implications. We demonstrate for the first time a profound effect of exercise on α7 nAChRs of nicotine-dependent animals, irrespective of exercise intensity. These findings shed light onto the mechanism underlining the protective effect of exercise in the development of nicotine dependence.

L Godfrey, A Morselli, P Bennion, GD Clarke, SMO Hourani, I Kitchen (2005)An investigation of binding sites for paracetamol in the mouse brain and spinal cord, In: EUROPEAN JOURNAL OF PHARMACOLOGY508(1-3)pp. 99-106 ELSEVIER SCIENCE BV
L Wells, J Opacka-Juffry, D Fisher, C Ledent, S Hourani, I Kitchen (2011)In vivo dopaminergic and behavioural responses to acute cocaine are altered in adenosine A(2A) receptor knockout mice., In: Synapse66pp. 382-390 Wiley

Adenosine, acting on A(2A) adenosine receptors, regulates addictive processes induced by drugs of abuse. The present study investigates the role of A(2A) adenosine receptors in neurochemical and behavioural responses to an acute cocaine challenge. Changes in the extracellular levels of dopamine in the nucleus accumbens of mice lacking A(2A) adenosine receptors and wild type littermates after an acute cocaine (20mg/kg) administration were evaluated by in vivo microdialysis studies. Locomotor effects induced by cocaine were measured during the microdialysis procedure. Cocaine-evoked increases in extracellular dopamine were not sustained in mice lacking A(2A) receptors in comparison to wild-type mice (P

JD Foster, I Kitchen, B Bettler, Y Chen (2012)GABA(B) Receptor Subtypes Differentially Modulate Synaptic Inhibition in the Dentate Gyrus to Enhance Granule Cell Output., In: Br J Pharmacol168(8)pp. 1808-1819 Wiley

BACKGROUND AND PURPOSE: Activation of GABA(B) receptors in the dentate gyrus (DG) enhances granule cell (GC) activity by reducing synaptic inhibition imposed by hilar interneurons. This disinhibitory action facilitates signal transfer from the perforant path to the hippocampus. However, as the two main molecular subtypes, GABA(B(1a,2)) and GABA(B(1b,2)) receptors, prefer axonal terminal and dendritic compartments, respectively, they may modulate the hilar pathways at different synaptic localisations. We examined their relative expression and functions in the DG. EXPERIMENTAL APPROACH: The localisation of GABA(B) subtypes was revealed immunohistochemically using subunit-selective antibodies in GABA(B1a) (-/-) and GABA(B1b) (-/-) mice. Effects of subtype activation by the GABA(B) receptor agonist, baclofen, were examined on the perforant path-stimulated GC population activities in brain slices. KEY RESULTS: GABA(B(1a,2)) receptors were concentrated in the inner molecular layer, the neuropil of the hilus and hilar neurons at the border zone; while GABA(B(1b,2)) receptors dominated the outer molecular layer and hilar neurons in the deep layer, showing their differential localisation on GC dendrite and in the hilus. Baclofen enhanced the GC population spike to a larger extent in the GABA(B1b) (-/-) mice, demonstrating exclusively disinhibitory roles of the GABA(B(1a,2)) receptors. Conversely, in the GABA(B1a) (-/-) mice baclofen not only enhanced but also inhibited the population spike during GABA(A) blockade, revealing both disinhibitory and inhibitory effects of GABA(B(1b,2)) receptors. CONCLUSIONS AND IMPLICATIONS: The GABA(B(1a,2)) and GABA(B(1b,2)) receptor subtypes differentially modulate GC outputs via selective axonal terminal and dendritic locations in the hilar pathways. The GABA(B(1a,2)) receptors exclusively mediate disinhibition, thereby playing a greater role in gating signal transfer for hippocampal spatial and pattern learning.

JA Peachey, SMO Hourani, I Kitchen (1999)Ontogeny of adenosine receptors in the longitudinal muscle and muscularis mucosae of the rat distal colon, In: NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY359(2)pp. 140-146 SPRINGER VERLAG
J Cabello, A Holland, K Holland, A Bailey, I Kitchen, K Wells (2009)Betacam: A commercial approach to β- Autoradiography, In: Proceedings of SPIE: Poster Session: Detectors7258

Autoradiography is a well established imaging modality in Biology and Medicine. This aims to measure the location and concentration of labelled molecules within thin tissue sections. The brain is the most anatomically complex organ and identification of neuroanatomical structures is still a challenge particularly when small animals are used for pre-clinical trials. High spatial resolution and high sensitivity are therefore necessary. This work shows the performance and ability of a prototype commercial system, based on a Charged-Couple Device (CCD), to accurately obtain detailed functional information in brain Autoradiography. The sample is placed in contact with the detector enabling direct detection of β- particles in silicon, and the system is run in a range of quasi-room temperatures (17-22 °C) under stable conditions by using a precision temperature controller. Direct detection of β- particles with low energy down to ~5 keV from 3[H] is possible using this room temperature approach. The CCD used in this work is an E2V CCD47-20 frame-transfer device which removes the image smear arising in conventional full-frame imaging devices. The temporal stability of the system has been analyzed by exposing a set of 14[C] calibrated microscales for different periods of time, and measuring the stability of the resultant sensitivity and background noise. The thermal performance of the system has also been analyzed in order to demonstrate its capability of working in other life science applications, where higher working temperatures are required. Once the performance of the system was studied, a set of experiments with biological samples, labelled with typical β- radioisotopes, such as 3[H], has been carried out to demonstrate its application in life sciences.

J Cabello, A Bailey, I Kitchen, A Clark, J Crooks, R Halsall, M Key-Charriere, S Martin, M Prydderch, R Turchetta, K Wells (2006)Digital autoradiography using CCD and CMOS imaging technology, In: 2006 IEEE NUCLEAR SCIENCE SYMPOSIUM CONFERENCE RECORD, VOL 1-6pp. 2607-2612
J Cabello, K Wells, A Metaxas, A Bailey, I Kitchen, A Clark, A Prydderch, R Turchetta (2007)Digital Autoradiography imaging using CMOS technology: First Tritium Autoradiography with a back-thinned CMOS detector and comparison of CMOS imaging performance with autoradiography film, In: 2007 IEEE NUCLEAR SCIENCE SYMPOSIUM CONFERENCE RECORD, VOLS 1-11pp. 3743-3746
J Cabello, K Wells, A Metaxas, A Bailey, I Kitchen (2009)Elastic atlas registration of β- autoradiograms using scattered data interpolators, In: IEEE Nuclear Science Symposium Conference Recordpp. 3700-3704

Autoradiography is a widely extended pre-clinical nuclear imaging modality used in life sciences to investigate and localise radiolabelled biological pathways in thin ex-vivo tissue sections. After the tissue section has been exposed to an ionising radiation detector the resulting labelled regions are subsequently analysed. Typically, the resulting autoradiograms are analysed manually by an expert life scientists using a visual template as reference to measure the different radioligand uptake levels in the different areas of, in our case, mouse brain. This process is extremely time consuming and error prone, with the expertise of the life scientist playing a significant role. In this paper we describe a semi-automatic method to register a template brain atlas on to the brain autoradiogram making the analysis process more efficient, repeatable and independent of the expertise of the life scientist. The method first identifies those regions with high and low level of radioligand uptake by region growing segmentation. Subsequently, the counterpart regions in the corresponding atlas image are manually identified. Finally a set of control points is extracted from each region contour in the autoradiogram and the atlas image to apply a scattered data interpolator. ©2009 IEEE.

J Cabello, A Bailey, I Kitchen, M Guy, K Wells (2009)Segmentation of low contrast-to-noise ratio images applied to functional imaging using adaptive region growing, In: Proceedings of SPIE: Posters: Segmentation7259

Segmentation in medical imaging plays a critical role easing the delineation of key anatomical functional structures in all the imaging modalities. However, many segmentation approaches are optimized with the assumption of high contrast, and then fail when segmenting poor contrast to noise objects. The number of approaches published in the literature falls dramatically when functional imaging is the aim. In this paper a feature extraction based approach, based on region growing, is presented as a segmentation technique suitable for poor quality (low Contrast to Noise Ratio CNR) images, as often found in functional images derived from Autoradiography. The region growing combines some modifications from the typical region growing method, to make the algorithm more robust and more reliable. Finally the algorithm is validated using synthetic images and biological imagery.

J Cabello, K Wells, A Bailey, I Kitchen (2007)Semi-automatic elastic registration applied to a beta-autoradiography brain atlas, In: 2007 IEEE NUCLEAR SCIENCE SYMPOSIUM CONFERENCE RECORD, VOLS 1-11pp. 4303-4307
SR Smith, N Pochani, R Al-Hasani, S Hourani, L Wells, I Kitchen, A Bailey (2011)Metabotropic mGluR5-and adenosine A(2A)-receptor interactions in opioid addiction, In: PHARMACOLOGICAL REPORTS63(1)pp. 225-225 POLISH ACAD SCIENCES INST PHARMACOLOGY
VR Brownhill, SMO Hourani, I Kitchen (1996)Selective enhancement by an adenosine A(1) receptor agonist of agents inducing contraction of the rat vas deferens, In: NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY353(5)pp. 499-504 SPRINGER VERLAG
JA Peachey, SMO Hourani, I Kitchen (1996)Differential development of adenosine A(1) and A(2b) receptors in the rat duodenum, In: BRITISH JOURNAL OF PHARMACOLOGY119(5)pp. 949-958 STOCKTON PRESS
A Bailey, C Ledent, MDW Kelly, I Kitchen, SMO Hourani (2004)Interactions between opioid receptors and the adenosine system, In: FUNDAMENTAL & CLINICAL PHARMACOLOGY18pp. 15-15 WILEY-BLACKWELL
A Bailey, C Ledent, M Kelly, SMO Hourani, I Kitchen (2002)Changes in spinal delta and kappa opioid systems in mice deficient in the A(2A) receptor gene, In: JOURNAL OF NEUROSCIENCE22(21)pp. 9210-9220 SOC NEUROSCIENCE
I Kitchen (2006)Opioid receptors: What, where and how?, In: EPILEPSIA47pp. 222-223
A Bailey, C Ledent, MDW Kelly, I Kitchen, SMO Hourani (2002)Changes in opioid systems in A(2A) receptor knockout mice, In: DRUG DEVELOPMENT RESEARCH56(4)pp. 562-562
JA Peachey, VR Brownhill, SMO Hourani, I Kitchen (1996)The ontogenetic profiles of the pre- and postjunctional adenosine receptors in the rat vas deferens, In: BRITISH JOURNAL OF PHARMACOLOGY117(6)pp. 1105-1110 STOCKTON PRESS
L Godfrey, SMO Hourani, I Kitchen (2003)Quantitative autoradiography of [H-3]paracetamol binding in the mouse brain, In: BRITISH JOURNAL OF PHARMACOLOGY140
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