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Professor Ian Kitchen

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. 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.

Maternal influences on the development of opioid systems in the brain

Twenty years ago we showed, in rats, that the biologically protective response of stress-induced analgesia was affected by the age that mothers were removed from their pups. We showed that the removal of maternal milk influenced the development of opioid receptors in the brain, and specifically that the process of weaning from maternal milk activates the development of the delta opioid receptor. Subsequently we demonstrated this activation was dependent on the loss of dietary milk casein, which is known to produce opioid peptide fragments. More recently the delta opioid receptor system has been shown to play an important role in mediating mood and social behavior, and gene knockout mice lacking the delta opioid receptor exhibit depressive and anxiogenic phenotypes. We have now shown that delaying weaning causes depression and the key nutritional influence in this effect is dietary casein. In addition, studies on the gut microbiome show marked differences in gut microorganism responses to stress, accompanied by urinary metabolite profiles that suggest marked dysfunction of the metabonome in pups that are left with their mothers. Also, oxytocin receptors in mood-related areas in the brain are insensitive to stress-induced changes when weaning is delayed. Given the widespread differences in milk and casein consumption, through maternal or other sources, an important contribution of casein ingestion to neurobehavioural development is highly likely. The studies raise the issue of how long maternal and non-maternal sources of milk should be given for optimal brain development?


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 is currently an examiner at 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)
  • 2011-Present Society of Biology (Elected Fellow)

REF 2020 consulting

Professor Kitchen is CEO of the company REF2020 Consulting Limited ( The company provides consultancy advice to Higher Education Institutions in the following areas in preparation for the next UK Research Excellence Framework exercise (REF2020). The core business of the company include:

  • Reviewing the quality of research areas in preparation for REF 2020
  • Presentations (eg):
    • The REF2014 exercise: outcome and panel processes
    • Lessons from REF2014 for REF2020
    • What makes a 3* and 4* paper?
    • What makes 3* and 4* impact case studies?
  • 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
  • Impact case study workshops

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.

He 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 is also a member of the cross-main panel feedback evaluation groups for REF 2014. In addition, he had lead responsibility 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 at his own institution.

Highly cited original articles over the last 20 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.

My publications


Al-Hasani R, Foster JD, Metaxas A, Ledent C, Hourani SM, Kitchen I, Chen Y (2011) Increased desensitization of dopamine D(2) receptor-mediated response in the ventral tegmental area in the absence of adenosine A(2A) receptors., Neuroscience 190 pp. 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.
Fan L, Sawbridge D, Bailey A, Kitchen I, Li J-M (2008) The role of NADPH oxidase in cocaine-induced cardiac oxidative stress and redox signalling, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY 44 (4) pp. 713-713 ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
Hambsch B, Keyworth H, Lind J, Otte DM, Racz I, Kitchen I, Bailey A, Zimmer A (2014) Chronic nicotine improves short-term memory selectively in a G72 mouse model of schizophrenia, BRITISH JOURNAL OF PHARMACOLOGY 171 (7) pp. 1758-1771 WILEY-BLACKWELL
Metaxas A, Keyworth HL, Yoo JH, Chen Y, Kitchen I, Bailey A (2012) The stereotypy-inducing and OCD-like effects of chronic 'binge' cocaine are modulated by distinct subtypes of nicotinic acetylcholine receptors., Br J Pharmacol
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 ±7 preferring antagonist methyllycaconitine (MLA; 5 mg/kg; i.p.) or the ²2* nAChR antagonist dihydro-²-erythroidine (DHßE; 2 mg/kg. i.p.). Quantitative autoradiography was used to examine the impact of cocaine exposure on ±7 and ±4²2* nAChRs, and on the high-affinity choline transporter. Key results: MLA+cocaine administration induced an intense self-grooming behaviour, indicating a likely role for ±7 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 ²2* nAChRs in the neuroadaptations mediating cocaine-induced behavioural sensitisation. 'Binge' cocaine treatment region-specifically increased ±4²2* 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.
Zanos P, Georgiou P, Metaxas A, Kitchen I, Winsky-Sommerer R, Bailey A (2015) Region-specific up-regulation of oxytocin receptor binding in the brain of mice following chronic nicotine administration., Neurosci Lett 600 pp. 33-37
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 ¼l 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.
Lena I, Bradshaw S, Pintar J, Kitchen I (2008) Adaptive changes in the expression of central opioid receptors in mice lacking the dopamine D2 receptor gene, NEUROSCIENCE 153 (3) pp. 773-788 PERGAMON-ELSEVIER SCIENCE LTD
Osman A, Kitchen I, Swann J, Bailey A (2015) Prolonged exposure to milk caseins in early postnatal life increases depressive-like behaviour, PROCEEDINGS OF THE NUTRITION SOCIETY 74 (OCE5) pp. E348-E348 CAMBRIDGE UNIV PRESS
Bailey A, Yoo JH, Racz I, Zimmer A, Kitchen I (2007) Preprodynorphin mediates locomotion and D-2 dopamine and mu-opioid receptor changes induced by chronic 'binge' cocaine administration, JOURNAL OF NEUROCHEMISTRY 102 (6) pp. 1817-1830 BLACKWELL PUBLISHING
Connor M, Kitchen I (2006) Has the sun set on kappa(3)-opioid receptors?, BRITISH JOURNAL OF PHARMACOLOGY 147 (4) pp. 349-350 NATURE PUBLISHING GROUP
Zanos P, Georgiou P, Wright SR, Hourani SM, Kitchen I, Winsky-Sommerer R, Bailey A (2013) The Oxytocin Analogue Carbetocin Prevents Emotional Impairment and Stress-Induced Reinstatement of Opioid-Seeking in Morphine-Abstinent Mice., Neuropsychopharmacology
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.Neuropsychopharmacology advance online publication, 4 December 2013; doi:10.1038/npp.2013.285.
Georgiou P, Zanos P, Garcia-Carmona J-A, Hourani S, Kitchen I, Laorden M-L, Bailey A (2016) Methamphetamine abstinence induces changes in mu-opioid receptor, oxytocin and CRF systems: Association with an anxiogenic phenotype, NEUROPHARMACOLOGY 105 pp. 520-532 PERGAMON-ELSEVIER SCIENCE LTD
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.
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.
Smith SR, Pochani N, Al-Hasani R, Hourani S, Wells L, Kitchen I, Bailey A (2011) Metabotropic mGluR5-and adenosine A(2A)-receptor interactions in opioid addiction, PHARMACOLOGICAL REPORTS 63 (1) pp. 225-225 POLISH ACAD SCIENCES INST PHARMACOLOGY
Zanos P, Alshehri M, Sahabandu T, Winsky-Sommerer R, Kitchen I, Bailey A (2011) Persistent brain region-specific upregulation of vasopressin (V1ar) and oxytocin receptors in chronic intermittent escalating dose morphine administration in mice, PHARMACOL REP 63 (1) pp. 252-252 POLISH ACAD SCIENCES INST PHARMACOLOGY
Metaxas A, Bailey A, Barbano MF, Galeote L, Maldonado R, Kitchen I (2010) Differential region-specific regulation of alpha 4 beta 2*nAChRs by self-administered and non-contingent nicotine in C57BL/6J mice, ADDICT BIOL 15 (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 4²2* 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 4²2* nAChRs were found to be dependent on the contingency of nicotine treatment. Higher levels of 4²2* 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.
Kitchen I (2006) Gene knockouts and the neuroscience of addiction, ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH 30 (9) pp. 45A-45A BLACKWELL PUBLISHING
Martynhak BJ, Hogben AL, Zanos P, Georgiou P, Andreatini R, Kitchen I, Archer SN, von Schantz M, Bailey A, Van Der Veen DR (2017) Transient anhedonia phenotype and altered circadian timing of behaviour during night-time dim light exposure in Per3-/- mice, but not wildtype mice, Scientific Reports 7 40399 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.
Georgiou P, Zanos P, Garcia-Carmona J-A, Hourani S, Kitchen I, Kieffer BL, Laorden M-L, Bailey A (2015) The oxytocin analogue carbetocin prevents priming-induced reinstatement of morphine-seeking: Involvement of dopaminergic, noradrenergic and MOPr systems, EUROPEAN NEUROPSYCHOPHARMACOLOGY 25 (12) pp. 2459-2464 ELSEVIER SCIENCE BV
Metaxas A, Al-Hasani R, Farshim P, Tubby K, Berwick A, Ledent C, Hourani S, Kitchen I, Bailey A (2013) Genetic deletion of the adenosine A2A receptor prevents nicotine-induced upregulation of ±7, but not ±4²2* nicotinic acetylcholine receptor binding in the brain., Neuropharmacology 71 pp. 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]±-bungarotoxin binding to ±4²2* and ±7 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 ±4²2* and ±7 nAChR binding sites were increased compared with saline treated controls. The genetic ablation of adenosine A2ARs prevented nicotine-induced upregulation of ±7 nAChRs, without affecting ±4²2* 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 ±7 nAChR upregulation, and identify A2ARs as novel pharmacological targets for modulating the long-term effects of nicotine on ±7 receptors.
Fragou D, Zanos P, Kouidou S, Njau S, Kitchen I, Bailey A, Kovatsi L (2013) Effect of chronic heroin and cocaine administration on global DNA methylation in brain and liver, Toxicology Letters 218 (3) pp. 260-265
Drug abuse is associated with epigenetic changes, such as histone modifications and DNA methylation. The purpose of the present study was to examine the effect of chronic cocaine and heroin administration on global DNA methylation in brain and liver. Male, 8 week old, C57BL/6. J mice received heroin in a chronic 'intermittent' escalating dose paradigm, or cocaine in a chronic escalating dose 'binge' paradigm, which mimic the human pattern of opioid or cocaine abuse respectively. Following sacrifice, livers and brains were removed and DNA was extracted from them. The extracted DNA was hydrolyzed and 2'-deoxycytidine and 5-methyl-2'-deoxycytidine were determined by HPLC-UV. The % 5-methyl-2'-deoxycytidine content of DNA was significantly higher in the brain compared to the liver.There were no differences between the control animals and the cocaine or heroin treated animals in neither of the tissues examined, which is surprising since cocaine administration induced gross morphological changes in the liver. Moreover, there was no difference in the % 5-methyl-2'-deoxycytidine content of DNA between the cocaine and the heroin treated animals. The global DNA methylation status in the brain and liver of mice chronically treated with cocaine or heroin remains unaffected, but this finding cannot exclude the existence of anatomical region or gene-specific methylation differences. This is the first time that global DNA methylation in the liver and whole brain has been studied following chronic cocaine or heroin treatment. © 2013 Elsevier Ireland Ltd.
Cabello J, Wells K, Metaxas A, Bailey A, Kitchen I, Clark A, Prydderch A, Turchetta R (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, 2007 IEEE NUCLEAR SCIENCE SYMPOSIUM CONFERENCE RECORD, VOLS 1-11 pp. 3743-3746 IEEE
Ribe D, Sawbridge D, Thakur S, Hussey M, Ledent C, Kitchen I, Hourani S, Li J-M (2008) Adenosine A(2A) receptor signaling regulation of cardiac NADPH oxidase activity, FREE RADICAL BIOLOGY AND MEDICINE 44 (7) pp. 1433-1442 ELSEVIER SCIENCE INC
Zanos P, Georgiou P, Gonzalez LR, Hourani S, Chen Y, Kitchen I, Kieffer BL, Winsky-Sommerer R, Bailey A (2016) Emotional Impairment and Persistent Upregulation of mGlu(5) Receptor following Morphine Abstinence: Implications of an mGlu(5)-MOPr Interaction, INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY 19 (7) OXFORD UNIV PRESS
Wells L, Opacka-Juffry J, Fisher D, Ledent C, Hourani S, Kitchen I (2011) In vivo dopaminergic and behavioural responses to acute cocaine are altered in adenosine A(2A) receptor knockout mice., Synapse 66 pp. 382-390
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
Cabello J, Bailey A, Kitchen I, Prydderch M, Clark A, Turchetta R, Wells K (2007) Digital autoradiography using room temperature CCD and CMOS imaging technology, PHYSICS IN MEDICINE AND BIOLOGY 52 (16) pp. 4993-5011 IOP PUBLISHING LTD
Yoo JH, Bailey A, Borsodi A, Tóth G, Matifas A, Kieffer BL, Kitchen I (2014) Knockout subtraction autoradiography: a novel ex vivo method to detect heteromers finds sparse KOP receptor/DOP receptor heterodimerization in the brain., Eur J Pharmacol 731 pp. 1-7
Several methodological approaches suggest that receptor heteromers exist in cell systems, but their presence in physiological tissue is widely contentious. We describe a novel method to determine if heterodimers exist in brain tissue sections using autoradiographic binding comparisons from single and double gene knockout mice, where tissues either have a full receptor complement and can form heterodimers, or are incapable of making heterodimers. We have tested this model, which we have named Knockout Subtraction Autoradiography, to determine if heterodimerisation of the kappa (KOP) and delta opioid (DOP) receptors occurs, as evidence from binding studies in cell systems suggest they are present in the brain. Using labeling of putative KOP receptor/DOP receptor heterodimers with either [(3)H]bremazocine or with [(3)H]naltrindole, two ligands which were used to provide evidence suggesting that these opioid receptor subtypes heterodimerize, we have applied a subtraction equation model based on the principle that receptor gene double knockout of either MOP receptor/KOP receptor (DOP receptor expression only) or MOP receptor/DOP receptor (KOP receptor expression only) produces tissue incapable of making the KOP receptor/DOP receptor heterodimer. We have shown in most brain regions that the labeling fits a simple additive model of monomer labeling, but that in a few brain regions opioid receptor heterodimerization does occur. The data does not support the conclusion that KOP receptor/DOP receptor heterodimerisation is widespread in the central nervous system, but does indicate that this novel methodology can detect heterodimerisation, when ligands with distinct binding affinities for monomer and heterodimer forms exist.
Yoo JH, Kitchen I, Bailey A (2012) The endogenous opioid system in cocaine addiction: what lessons have opioid peptide and receptor knockout mice taught us?, Br J Pharmacol 166 (7) pp. 1993-2014
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 º-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.
Wright SR, Zanos P, Georgiou P, Yoo JH, Ledent C, Hourani SM, Kitchen I, Winsky-Sommerer R, Bailey A (2015) A critical role of striatal A2A R-mGlu5 R interactions in modulating the psychomotor and drug-seeking effects of methamphetamine., Addict Biol 21 (4) pp. 811-825
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.
Hussey MJ, Clarke GD, Ledent C, Kitchen I, Hourani SM (2012) Deletion of the adenosine A(2A) receptor in mice enhances spinal cord neurochemical responses to an inflammatory nociceptive stimulus., Neurosci Lett 506 (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.
Fan L, Sawbridge D, Bailey A, Kitchen I, Li J-M (2008) The mechanism of chronic cocaine exposure on cardiac reactive oxygen species production and mitogen-activated protein kinase activation, HEART 94 pp. A115-A115 B M J PUBLISHING GROUP
Godfrey L, Yan L, Clarke GD, Ledent C, Kitchen I, Hourani SMO (2006) Modulation of paracetamol antinociception by caffeine and by selective adenosine A(2) receptor antagonists in mice, EUROPEAN JOURNAL OF PHARMACOLOGY 531 (1-3) pp. 80-86 ELSEVIER SCIENCE BV
Fan L, Sawbridge D, George V, Teng L, Bailey A, Kitchen I, Li J-M (2009) Chronic Cocaine-Induced Cardiac Oxidative Stress and Mitogen-Activated Protein Kinase Activation: The Role of Nox2 Oxidase, JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 328 (1) pp. 99-106 AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
Georgiou P, Zanos P, Ehteramyan M, Hourani S, Kitchen I, Maldonado R, Bailey A (2014) Differential regulation of mGlu5 R and œOPr by priming- and cue-induced reinstatement of cocaine-seeking behaviour in mice., Addict Biol 20 (5) pp. 902-912
The key problem for the treatment of drug addiction is relapse to drug use after abstinence that can be triggered by drug-associated cues, re-exposure to the drug itself and stress. Understanding the neurobiological mechanisms underlying relapse is essential in order to develop effective pharmacotherapies for its prevention. Given the evidence implicating the metabotropic glutamate receptor 5 (mGlu5 R), ¼-opioid receptor (MOPr), º-opioid receptor (šOPr) and oxytocin receptor (OTR) systems in cocaine addiction and relapse, our aim was to assess the modulation of these receptors using a mouse model of cue- and priming-induced reinstatement of cocaine seeking. Male mice were trained to self-administer cocaine (1 mg/kg/infusion, i.v.) and were randomized into different groups: (1) cocaine self-administration; (2) cocaine extinction; (3) cocaine-primed (10 mg/kg i.p.); or (4) cue-induced reinstatement of cocaine seeking. Mice undergoing the same protocols but receiving saline instead of cocaine were used as controls. Quantitative autoradiography of mGlu5 R, MOPr, KOPr and OTR showed a persistent cocaine-induced upregulation of the mGlu5 R and OTR in the lateral septum and central amygdala, respectively. Moreover, a downregulation of mGlu5 R and MOPr was observed in the basolateral amygdala and striatum, respectively. Further, we showed that priming- but not cue-induced reinstatement upregulates mGlu5 R and MOPr binding in the nucleus accumbens core and basolateral amygdala, respectively, while cue- but not priming-induced reinstatement downregulates MOPr binding in caudate putamen and nucleus accumbens core. This is the first study to provide direct evidence of reinstatement-induced receptor alterations that are likely to contribute to the neurobiological mechanisms underpinning relapse to cocaine seeking.
Kitchen I (2006) Opioid receptors: What, where and how?, EPILEPSIA 47 pp. 222-223 BLACKWELL PUBLISHING
Foster JD, Kitchen I, Bettler B, Chen Y (2012) GABA(B) Receptor Subtypes Differentially Modulate Synaptic Inhibition in the Dentate Gyrus to Enhance Granule Cell Output., Br J Pharmacol
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.
Godfrey L, Bailey I, Toms NJ, Clarke GD, Kitchen I, Hourani SMO (2007) Paracetamol inhibits nitric oxide synthesis in murine spinal cord slices, EUROPEAN JOURNAL OF PHARMACOLOGY 562 (1-2) pp. 68-71 ELSEVIER SCIENCE BV
Chu Sin Chung P, Keyworth HL, Martin-Garcia E, Charbogne P, Darcq E, Bailey A, Filliol D, Matifas A, Scherrer G, Ouagazzal AM, Gaveriaux-Ruff C, Befort K, Maldonado R, Kitchen I, Kieffer BL (2014) A novel anxiogenic role for the delta opioid receptor expressed in GABAergic forebrain neurons., Biol Psychiatry 77 (4) pp. 404-415
BACKGROUND: The delta opioid receptor (DOR) is broadly expressed throughout the nervous system; it regulates chronic pain, emotional responses, motivation, and memory. Neural circuits underlying DOR activities have been poorly explored by genetic approaches. We used conditional mouse mutagenesis to elucidate receptor function in GABAergic neurons of the forebrain. METHODS: We characterized DOR distribution in the brain of Dlx5/6-CreXOprd1(fl/fl) (Dlx-DOR) mice and tested main central DOR functions through behavioral testing. RESULTS: The DOR proteins were strongly deleted in olfactory bulb and striatum and remained intact in cortex and basolateral amygdala. Olfactory perception, circadian activity, and despair-like behaviors were unchanged. In contrast, locomotor stimulant effects of SNC80 (DOR agonist) and SKF81297 (D1 agonist) were abolished and increased, respectively. The Dlx-DOR mice showed lower levels of anxiety in the elevated plus maze, opposing the known high anxiety in constitutive DOR knockout animals. Also, Dlx-DOR mice reached the food more rapidly in a novelty suppressed feeding task, despite their lower motivation for food reward observed in an operant paradigm. Finally, c-fos protein staining after novelty suppressed feeding was strongly reduced in amygdala, concordant with the low anxiety phenotype of Dlx-DOR mice. CONCLUSIONS: We demonstrate that DORs expressed in the forebrain mediate the described locomotor effect of SNC80 and inhibit D1-stimulated hyperactivity. Our data also reveal an unanticipated anxiogenic role for this particular DOR subpopulation, with a potential novel adaptive role. In emotional responses, DORs exert dual anxiolytic and anxiogenic roles, both of which may have implications in the area of anxiety disorders.
Yoo J-H, Bailey A, Ansonoff M, Pintar JE, Matifas A, Kieffer BL, Kitchen I (2010) Lack of Genotype Effect on D1, D2 Receptors and Dopamine Transporter Binding in Triple MOP-, DOP-, and KOP-Opioid Receptor Knockout Mice of Three Different Genetic Backgrounds, SYNAPSE 64 (7) pp. 520-527 WILEY-LISS
Cabello J, Bailey A, Kitchen I, Clark A, Crooks J, Halsall R, Key-Charriere M, Martin S, Prydderch M, Turchetta R, Wells K (2007) Digital autoradiography using CCD and CMOS imaging technology, IEEE Nuclear Science Symposium Conference Record 4 pp. 2607-2612
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 radiolabeled 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. © 2006 IEEE.
Cabello J, Wells K, Bailey A, Kitchen I (2007) Semi-automatic elastic registration applied to a beta-autoradiography brain atlas, 2007 IEEE NUCLEAR SCIENCE SYMPOSIUM CONFERENCE RECORD, VOLS 1-11 pp. 4303-4307 IEEE
Zanos P, Wright SR, Georgiou P, Yoo JH, Hourani SM, Kitchen I, Winsky-Sommerer R, Bailey A, Ledent C (2013) Chronic methamphetamine treatment induces oxytocin receptor up-regulation in the amygdala and hypothalamus via an adenosine A receptor-independent mechanism, Pharmacology Biochemistry and Behavior
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.
Castane A, Wells L, Soria G, Hourani S, Ledent C, Kitchen I, Opacka-Juffry J, Maldonado R, Valverde O (2008) Behavioural and biochemical responses to morphine associated with its motivational properties are altered in adenosine A(2A) receptor knockout mice, BRITISH JOURNAL OF PHARMACOLOGY 155 (5) pp. 757-766 WILEY-BLACKWELL
Hussey MJ, Clarke GD, Ledent C, Hourani SMO, Kitchen I (2007) Reduced response to the formalin test and lowered spinal NMDA glutamate receptor binding in adenosine A(2A) receptor knockout mice, PAIN 129 (3) pp. 287-294 ELSEVIER SCIENCE BV
Hammers A, Asselin M-C, Hinz R, Kitchen I, Brooks DJ, Duncan JS, Koepp MJ (2007) Upregulation of opioid receptor binding following spontaneous epileptic seizures, BRAIN 130 pp. 1009-1016 OXFORD UNIV PRESS
Ferre S, Diamond I, Goldberg SR, Yao L, Hourani SMO, Huang ZL, Urade Y, Kitchen I (2007) Adenosine A(2A) receptors in ventral striatum, hypothalamus and nociceptive circuitry - Implications for drug addiction, sleep and pain, PROGRESS IN NEUROBIOLOGY 83 (5) pp. 332-347 PERGAMON-ELSEVIER SCIENCE LTD
Keyworth Helen, Georgiou Polymnia, Zanos Panos, Veloso Rueda Andre, Chen Ying, Kitchen Ian, Camarini Rosana, Cropley Mark, Bailey Alexis (2017) Wheel running during chronic nicotine exposure is protective against mecamylamine-precipitated withdrawal and upregulates hippocampal a7 nACh receptors in mice, British Journal of Pharmacology 175 (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 ±4²2*, ±7 nicotinic acetylcholine (nAChR), ¼-opioid (¼ 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 ±4²2*, ±7 nAChRs, ¼ 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 ±7 nAChR binding in the CA2/3 area of the hippocampus of nicotine-treated mice. Neither exercise nor nicotine treatment affected ¼ or D2 receptor binding or BDNF levels. Nicotine withdrawal increased plasma corticosterone levels and ±4²2* nAChR binding, irrespective of exercise regimen.

Conclusions and implications. We demonstrate for the first time a profound effect of exercise on ±7 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.

Farshim P, Walton G, Chakrabarti B, Givens I, Saddy D, Kitchen I, Swann J, Bailey A (2016) Maternal Weaning Modulates Emotional Behavior and Regulates the Gut-Brain Axis, SCIENTIFIC REPORTS 6 ARTN 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.
Cabello J, Bailey A, Kitchen I, Clark A, Crooks J, Halsall R, Key-Charriere M, Martin S, Prydderch M, Turchetta R, Wells K (2006) Digital Autoradiography using CCD and CMOS Imaging Technology, 2006 IEEE Nuclear Science Symposium Conference Record 4 pp. 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.