Prof Susanna Hourani

Susanna Hourani


Emeritus Professor of Pharmacology

Biography

Research interests

My research is in the field of adenosine and adenine nucleotides: their receptors, their effects and their physiological and pathological roles. They are important in platelet function, the control of the cardiovascular and gastrointestinal systems and in the brain. My research has been funded by The Wellcome Trust, The British Heart Foundation and GlaxoSmithKline.

Teaching

I teach pharmacology to both undergraduate and postgraduate students, focussing mainly on the effects of drugs outside the central nervous system.

Affiliations

Fellow of the British Pharmacological Society

Fellow of the Society of Biology

Member of the Biochemical Society

My publications

Publications

Hourani SMO (2001) Discovery and recognition of purine receptor subtypes on platelets, DRUG DEVELOPMENT RESEARCH 52 (1-2) pp. 140-149 WILEY-LISS
COLLIS MG, HOURANI SMO (1993) ADENOSINE RECEPTOR SUBTYPES, TRENDS IN PHARMACOLOGICAL SCIENCES 14 (10) pp. 360-366 ELSEVIER SCI LTD
CUSACK NJ, HOURANI SMO, LOIZOU GD, WELFORD LA (1987) PHARMACOLOGICAL EFFECTS OF ISOPOLAR PHOSPHONATE ANALOGS OF ATP ON P-2-PURINOCEPTORS IN GUINEA-PIG TAENIA-COLI AND URINARY-BLADDER, BRITISH JOURNAL OF PHARMACOLOGY 90 (4) pp. 791-795 STOCKTON PRESS
Brownhill VR, Hourani SMO, Kitchen I (1997) Ontogeny of P2-purinoceptors in the longitudinal muscle and muscularis mucosae of the rat isolated duodenum, BRITISH JOURNAL OF PHARMACOLOGY 122 (2) pp. 225-232 STOCKTON PRESS
Park HS, Hourani SMO (1999) Different effects of adenine nucleotide analogues on the responses mediated by adenosine 5 ' diphosphate (ADP) receptors on human platelets, BRITISH JOURNAL OF PHARMACOLOGY 126 pp. U103-U103 STOCKTON PRESS
Peachey JA, Brownhill VR, Hourani SMO, Kitchen I (1996) The ontogenetic profiles of the pre- and postjunctional adenosine receptors in the rat vas deferens, BRITISH JOURNAL OF PHARMACOLOGY 117 (6) pp. 1105-1110 STOCKTON PRESS
Hourani SM (2004) Pharmacological approaches to studying platelet function: an overview., Methods Mol Biol 273 pp. 73-86
JOHNSON CR, HOURANI SMO (1994) CONTRACTILE EFFECTS OF URIDINE 5'-TRIPHOSPHATE IN THE RAT DUODENUM, BRITISH JOURNAL OF PHARMACOLOGY 113 (4) pp. 1191-1196 STOCKTON PRESS
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.
Tennant JP, Hourani SMO (2000) Breakdown of extracellular ATP by the prostatic and epididymal ends of the guinea pig vas deferens, EUROPEAN JOURNAL OF PHARMACOLOGY 387 (1) pp. 107-109 ELSEVIER SCIENCE BV
Thakur S, Hourani S, Li JM (2009) REGULATION OF ANGIOTENSIN II-INDUCED ROS PRODUCTION AND REDOX-SIGNALLING BY THE ADENOSINE A2A RECEPTOR IN ENDOTHELIAL CELLS, HYPERTENSION 54 (5) pp. 1165-1165 LIPPINCOTT WILLIAMS & WILKINS
Peachey JA, Hourani SMO, Kitchen I (1996) Differential development of adenosine A(1) and A(2b) receptors in the rat duodenum, BRITISH JOURNAL OF PHARMACOLOGY 119 (5) pp. 949-958 STOCKTON PRESS
BAILEY SJ, HOURANI SMO (1992) EFFECTS OF PURINES ON THE LONGITUDINAL MUSCLE OF THE RAT COLON, BRITISH JOURNAL OF PHARMACOLOGY 105 (4) pp. 885-892 STOCKTON PRESS
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.
Bailey A, Lesscher HMB, Kelly MDW, Davis L, Ledent C, Hourani SMO, Kitchen I (2003) Morphine withdrawal in A(2A) adenosine receptor knockout mice, BRITISH JOURNAL OF PHARMACOLOGY 140 NATURE PUBLISHING GROUP
Kelly M, Bailey A, Ledent C, Kitchen I, Hourani S (2004) Characterization of [H-3]ZM 241385 binding in wild-type and adenosine A(2A) receptor knockout mice, EUROPEAN JOURNAL OF PHARMACOLOGY 504 (1-2) pp. 55-59 ELSEVIER SCIENCE BV
Prentice D, Boon K, Hourani S (2001) Relaxation of mouse isolated aorta to adenosine and its analogues does not involve adenosine A(1), A(2) or A(3) receptors, EUROPEAN JOURNAL OF PHARMACOLOGY 415 (2-3) pp. 251-255 ELSEVIER SCIENCE BV
Lamb D, Tickner M, El-Sankary W, Hourani S, Reynolds LJ, Ferns G (2002) Immunisation with bacillus Calmette-Guerin enhances aortic atherosclerosis in chronic low level hypercholesterolaemic rabbits, ATHEROSCLEROSIS: RISK FACTORS, DIAGNOSIS, AND TREATMENT pp. 463-466 MEDIMOND S R L
HALL DA, HOURANI SMO (1993) EFFECTS OF ANALOGS OF ADENINE-NUCLEOTIDES ON INCREASES IN INTRACELLULAR CALCIUM MEDIATED BY P2T-PURINOCEPTORS ON HUMAN BLOOD-PLATELETS, BRITISH JOURNAL OF PHARMACOLOGY 108 (3) pp. 728-733 STOCKTON PRESS
Bailey A, Ledent C, Kelly M, Hourani SMO, Kitchen I (2002) Changes in spinal delta and kappa opioid systems in mice deficient in the A(2A) receptor gene, JOURNAL OF NEUROSCIENCE 22 (21) pp. 9210-9220 SOC NEUROSCIENCE
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
Brownhill VR, Hourani SMO, Kitchen I (1996) Selective enhancement by an adenosine A(1) receptor agonist of agents inducing contraction of the rat vas deferens, NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY 353 (5) pp. 499-504 SPRINGER VERLAG
Nicholls J, Hourani SMO, Hall JM (1999) Characterisation of receptors mediating vasomotor effects of adenosine analogues in hamster cheek pouch, BRITISH JOURNAL OF PHARMACOLOGY 126 pp. U103-U103 STOCKTON PRESS
Prentice DJ, Hourani SMO (1999) Characterisation of adenosine receptors mediating relaxation in hamster isolated aorta, BRITISH JOURNAL OF PHARMACOLOGY 126 pp. U104-U104 STOCKTON PRESS
Godfrey L, Morselli A, Bennion P, Clarke GD, Hourani SMO, Kitchen I (2005) An investigation of binding sites for paracetamol in the mouse brain and spinal cord, EUROPEAN JOURNAL OF PHARMACOLOGY 508 (1-3) pp. 99-106 ELSEVIER SCIENCE BV
Hourani SMO, Mackins CJ, Kelly MDW, Ledent C, Prentice DJ (2001) Effect of A(2A) adenosine receptor knock-out on inhibition by NECA and CGS21680 of KCl-induced contractions in murine vas deferens, BRITISH JOURNAL OF PHARMACOLOGY 134 NATURE PUBLISHING GROUP
HOURANI SMO, HALL DA, NIEMAN CJ (1992) EFFECTS OF THE P(2)-PURINOCEPTOR ANTAGONIST, SURAMIN, ON HUMAN PLATELET-AGGREGATION INDUCED BY ADENOSINE 5'-DIPHOSPHATE, BRITISH JOURNAL OF PHARMACOLOGY 105 (2) pp. 453-457 STOCKTON PRESS
NICHOLLS J, HOURANI SMO, KITCHEN I (1990) THE ONTOGENY OF PURINOCEPTORS IN RAT URINARY-BLADDER AND DUODENUM, BRITISH JOURNAL OF PHARMACOLOGY 100 (4) pp. 874-878 STOCKTON PRESS
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, BRIT J PHARMACOL 155 (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.
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.
Lamb D, Tickner M, Dreux A, El-Sankary W, Hourani S, Eales-Reynolds LJ, Ferns G (2003) BCG immunization is atherogenic in the chronically hypercholesterolaemic rabbit: Immune and vascular endothelial effects, ATHEROSCLEROSIS SUPPLEMENTS 4 (2) pp. 310-310 ELSEVIER SCI IRELAND LTD
Bailey A, Ledent C, Kelly MDW, Kitchen I, Hourani SMO (2002) Changes in opioid systems in A(2A) receptor knockout mice, DRUG DEVELOPMENT RESEARCH 56 (4) pp. 562-562 WILEY-LISS
Nicholls J, Hourani SM, Hall JM (2002) Characterization of adenosine receptors mediating the vasodilator effects of adenosine receptor agonists in the microvasculature of the hamster cheek pouch in vivo., Auton Autacoid Pharmacol 22 (4) pp. 209-214
1 The aim of this study was to characterize the adenosine receptor mediating vasodilation in the microvasculature of the hamster cheek pouch in vivo. A range of adenosine agonists was used including N6-cyclopentyladenosine (CPA) (A1 agonist), 5'-N-ethylcarboxamidoadenosine (NECA) (non-selective), 2-chloroadenosine (2CADO) (non-selective), 2-p-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680) (A2A agonist), N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IBMECA) (A3 agonist) and adenosine, as well as the adenosine antagonists 8-sulphophenyltheophylline (8-SPT) (A1/A2 antagonist), 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) (A1 antagonist) and 4-(2-[7-amino-2-(2-furyl)[1,2,4]-triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) (A2A antagonist). 2 All the adenosine analogues used induced vasodilation at concentrations between 10 nm and 1 microm, and the potency order was NECA > CGS 21680 > 2CADO > CPA=IBMECA > adenosine, indicating an action at A2A receptors. 8-SPT (50 microm) antagonized vasodilator responses to NECA with an apparent pKB of 5.4, consistent with an action at A1 or A2 receptors and confirming that A3 receptors are not involved in this response. 3 DPCPX (10 nm) had no effect on vasodilation evoked by NECA, suggesting that this response was not mediated via A1 receptors, while ZM 241385 (10 nm) antagonized dilator responses to NECA with an apparent pKB of 8.9 consistent with an action via A2A receptors. 4 Overall these results suggest that adenosine A2A receptors mediate vasodilation in the hamster cheek pouch in vivo.
Lamb DJ, Tickner ML, Hourani SMO, Ferns GAA (2005) Dietary copper supplements modulate aortic superoxide dismutase, nitric oxide and atherosclerosis, INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY 86 (4) pp. 247-255 BLACKWELL PUBLISHING
Cusack NJ, Hourani SMO (2000) Platelet P2 receptors: from curiosity to clinical targets, JOURNAL OF THE AUTONOMIC NERVOUS SYSTEM 81 (1-3) pp. 37-43 ELSEVIER SCIENCE BV
Godfrey L, Bailey I, Toms NJ, Clarke GD, Kitchen I, Hourani SMO (2007) Paracetamol inhibits nitric oxide synthesis in murine spinal cord slices, EUR J PHARMACOL 562 (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 ¼M) had no effect on NO synthase activity in cerebellum, but in the spinal cord both paracetamol (100 ¼M) and caffeine (30 ¼M) 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.
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
Boarder MR, Hourani SMO (1998) The regulation of vascular function by P2 receptors: multiple sites and multiple receptors, TRENDS IN PHARMACOLOGICAL SCIENCES 19 (3) pp. 99-107 ELSEVIER SCI LTD
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.
Prentice DJ, Kelly MDW, Ledent C, Hourani SMO (2001) Effect of A(2A) adenosine receptor knockout on relaxant effects of adenosine and analogues in mouse isolated aorta., BRITISH JOURNAL OF PHARMACOLOGY 134 NATURE PUBLISHING GROUP
HOURANI SMO, NICHOLLS J, LEE BSS, HALFHIDE EJ, KITCHEN I (1993) CHARACTERIZATION AND ONTOGENY OF P-1-PURINOCEPTORS ON RAT VAS-DEFERENS, BRITISH JOURNAL OF PHARMACOLOGY 108 (3) pp. 754-758 STOCKTON PRESS
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.
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 mGlu5 Receptor following Morphine Abstinence: Implications of an mGlu5-MOPr Interaction., The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP) 19 (7)
A difficult problem in treating opioid addicts is the maintenance of a drug-free state because of the negative emotional symptoms associated with withdrawal, which may trigger relapse. Several lines of evidence suggest a role for the metabotropic glutamate receptor 5 in opioid addiction; however, its involvement during opioid withdrawal is not clear.Mice were treated with a 7-day escalating-dose morphine administration paradigm. Following withdrawal, the development of affective behaviors was assessed using the 3-chambered box, open-field, elevated plus-maze and forced-swim tests. Metabotropic glutamate receptor 5 autoradiographic binding was performed in mouse brains undergoing chronic morphine treatment and 7 days withdrawal. Moreover, since there is evidence showing direct effects of opioid drugs on the metabotropic glutamate receptor 5 system, the presence of an metabotropic glutamate receptor 5/¼-opioid receptor interaction was assessed by performing metabotropic glutamate receptor 5 autoradiographic binding in brains of mice lacking the ¼-opioid receptor gene.Withdrawal from chronic morphine administration induced anxiety-like, depressive-like, and impaired sociability behaviors concomitant with a marked upregulation of metabotropic glutamate receptor 5 binding. Administration of the metabotropic glutamate receptor 5 antagonist, 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine, reversed morphine abstinence-induced depressive-like behaviors. A brain region-specific increase in metabotropic glutamate receptor 5 binding was observed in the nucleus accumbens shell, thalamus, hypothalamus, and amygdala of ¼-opioid receptor knockout mice compared with controls.These results suggest an association between metabotropic glutamate receptor 5 alterations and the emergence of opioid withdrawal-related affective behaviors. This study supports metabotropic glutamate receptor 5 system as a target for the development of pharmacotherapies for the treatment of opioid addiction. Moreover, our data show direct effects of ¼-opioid receptor system manipulation on metabotropic glutamate receptor 5 binding in the brain.
Prentice DJ, Hourani SMO (1997) Adenosine analogues relax guinea-pig taenia caeci via an adenosine A(2B) receptor and a xanthine-resistant site, EUROPEAN JOURNAL OF PHARMACOLOGY 323 (1) pp. 103-106 ELSEVIER SCIENCE BV
Peachey JA, Hourani SMO, Kitchen I (1999) Ontogeny of adenosine receptors in the longitudinal muscle and muscularis mucosae of the rat distal colon, NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY 359 (2) pp. 140-146 SPRINGER VERLAG
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, EUR J PHARMACOL 531 (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
BAILEY SJ, HICKMAN D, HOURANI SMO (1992) CHARACTERIZATION OF THE P(1)-PURINOCEPTORS MEDIATING CONTRACTION OF THE RAT COLON MUSCULARIS MUCOSAE, BRITISH JOURNAL OF PHARMACOLOGY 105 (2) pp. 400-404 STOCKTON PRESS
PRENTICE DJ, HOURANI SMO (1995) NECA AND R-PIA ACTIVATE DISTINCT SITES TO CAUSE RELAXATION OF THE ISOLATED RAT AORTA, BRITISH JOURNAL OF PHARMACOLOGY 115 pp. P64-P64 STOCKTON PRESS
HOURANI SMO, CHOWN JA (1989) THE EFFECTS OF SOME POSSIBLE INHIBITORS OF ECTONUCLEOTIDASES ON THE BREAKDOWN AND PHARMACOLOGICAL EFFECTS OF ATP IN THE GUINEA-PIG URINARY-BLADDER, GENERAL PHARMACOLOGY 20 (4) pp. 413-416 PERGAMON-ELSEVIER SCIENCE LTD
Nicholls J, Brownhill VR, Hourani SMO (1996) Characterization of P-1-purinoceptors on rat isolated duodenum longitudinal muscle and muscularis mucosae, BRITISH JOURNAL OF PHARMACOLOGY 117 (1) pp. 170-174 STOCKTON PRESS
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.
Bailey A, Ledent C, Kelly MDW, Kitchen I, Hourani SMO (2004) Interactions between opioid receptors and the adenosine system, FUNDAMENTAL & CLINICAL PHARMACOLOGY 18 pp. 15-15 WILEY-BLACKWELL
HOURANI SMO, CUSACK NJ (1991) PHARMACOLOGICAL RECEPTORS ON BLOOD-PLATELETS, PHARMACOLOGICAL REVIEWS 43 (3) pp. 243-298 WILLIAMS & WILKINS
HALL DA, FROST V, HOURANI SMO (1994) EFFECTS OF EXTRACELLULAR DIVALENT-CATIONS ON RESPONSES OF HUMAN BLOOD-PLATELETS TO ADENOSINE 5'-DIPHOSPHATE, BIOCHEMICAL PHARMACOLOGY 48 (7) pp. 1319-1326 PERGAMON-ELSEVIER SCIENCE LTD
Brownhill VR, Hourani SMO, Kitchen I (1996) Differential ontogeny of adenosine receptors in the longitudinal muscle and muscularis mucosae of the rat isolated duodenum, EUROPEAN JOURNAL OF PHARMACOLOGY 317 (2-3) pp. 321-328 ELSEVIER SCIENCE BV
CUSACK NJ, HOURANI SMO (1991) DESIGN, SYNTHESES AND PHARMACOLOGY OF ATP ANALOGS SELECTIVE FOR SUBTYPES OF P2-PURINOCEPTORS, NUCLEOSIDES & NUCLEOTIDES 10 (5) pp. 1019-1028 MARCEL DEKKER INC
Bailey A, Weber D, Zimmer A, Zimmer AM, Hourani SMO, Kitchen I (2004) Quantitative autoradiography of adenosine receptors and NBTI-sensitive adenosine transporters in the brains of mice deficient in the preproenkephalin gene, BRAIN RESEARCH 1025 (1-2) pp. 1-9 ELSEVIER SCIENCE BV
Brownhill VR, Hourani SMO, Kitchen I (1996) Differential distribution of adenosine A(2) receptors in the epididymal and prostatic portions of the rat vas deferens, EUROPEAN JOURNAL OF PHARMACOLOGY 303 (1-2) pp. 87-90 ELSEVIER SCIENCE BV
HOURANI SMO, WELFORD LA, LOIZOU GD, CUSAK NJ (1988) ADENOSINE 5'-(2-FLUORODIPHOSPHATE) IS A SELECTIVE AGONIST AT P2-PURINOCEPTORS MEDIATING RELAXATION OF SMOOTH-MUSCLE, EUROPEAN JOURNAL OF PHARMACOLOGY 147 (1) pp. 131-136 ELSEVIER SCIENCE BV
Prentice DJ, Kelly MDW, Ledent C, Hourani SMO (2002) Relaxation of the mouse isolated aorta and carotid artery in response to adenosine analogues in genetically-modified mice lacking the adenosine A(2A) receptor, NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY 366 (2) pp. 127-133 SPRINGER-VERLAG
NICHOLLS J, HOURANI SMO, KITCHEN I (1992) CHARACTERIZATION OF P1-PURINOCEPTORS ON RAT DUODENUM AND URINARY-BLADDER, BRITISH JOURNAL OF PHARMACOLOGY 105 (3) pp. 639-642 STOCKTON PRESS
LEWIS CD, HOURANI SMO, LONG CJ, COLLIS MG (1994) CHARACTERIZATION OF ADENOSINE RECEPTORS IN THE RAT ISOLATED AORTA, GENERAL PHARMACOLOGY 25 (7) pp. 1381-1387 PERGAMON-ELSEVIER SCIENCE LTD
PEACHEY JA, BROWNHILL VR, HOURANI SMO, KITCHEN I (1995) THE ONTOGENY OF ADENOSINE RECEPTOR SUBTYPES IN THE RAT VAS-DEFERENS, BRITISH JOURNAL OF PHARMACOLOGY 115 pp. P143-P143 STOCKTON PRESS
HOURANI SMO, HALL DA (1994) RECEPTORS FOR ADP ON HUMAN BLOOD-PLATELETS, TRENDS IN PHARMACOLOGICAL SCIENCES 15 (4) pp. 103-108 ELSEVIER SCI LTD
Prentice DJ, Hourani SMO (1997) Information in agonist curve shape for receptor classification, RECEPTOR CLASSIFICATION 812 pp. 234-235 NEW YORK ACAD SCIENCES
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
HALL DA, HOURANI SMO (1994) EFFECTS OF SURAMIN ON INCREASES IN CYTOSOLIC CALCIUM AND ON INHIBITION OF ADENYLATE-CYCLASE INDUCED BY ADENOSINE 5'-DIPHOSPHATE IN HUMAN PLATELETS, BIOCHEMICAL PHARMACOLOGY 47 (6) pp. 1013-1018 PERGAMON-ELSEVIER SCIENCE LTD
HOURANI SMO, BAILEY SJ, NICHOLLS J, KITCHEN I (1991) DIRECT EFFECTS OF ADENYLYL 5'-(BETA,GAMMA-METHYLENE)DIPHOSPHONATE, A STABLE ATP ANALOG, ON RELAXANT P1-PURINOCEPTORS IN SMOOTH-MUSCLE, BRITISH JOURNAL OF PHARMACOLOGY 104 (3) pp. 685-690 STOCKTON PRESS
WELFORD LA, CUSACK NJ, HOURANI SMO (1986) ATP ANALOGS AND THE GUINEA-PIG TAENIA-COLI - A COMPARISON OF THE STRUCTURE-ACTIVITY-RELATIONSHIPS OF ECTONUCLEOTIDASES WITH THOSE OF THE P-2-PURINOCEPTOR, EUROPEAN JOURNAL OF PHARMACOLOGY 129 (3) pp. 217-224 ELSEVIER SCIENCE BV
Hourani SMO, Boon K, Fooks HM, Prentice DJ (2001) Role of cyclic nucleotides in vasodilations of the rat thoracic aorta induced by adenosine analogues, BRITISH JOURNAL OF PHARMACOLOGY 133 (6) pp. 833-840 NATURE PUBLISHING GROUP
Park HS, Hourani SMO (1999) Differential effects of adenine nucleotide analogues on shape change and aggregation induced by adenosine 5 '-diphospbate (ADP) in human platelets, BRITISH JOURNAL OF PHARMACOLOGY 127 (6) pp. 1359-1366 STOCKTON PRESS
WELFORD LA, CUSACK NJ, HOURANI SMO (1987) THE STRUCTURE-ACTIVITY-RELATIONSHIPS OF ECTONUCLEOTIDASES AND OF EXCITATORY P2-PURINOCEPTORS - EVIDENCE THAT DEPHOSPHORYLATION OF ATP ANALOGS REDUCES PHARMACOLOGICAL POTENCY, EUROPEAN JOURNAL OF PHARMACOLOGY 141 (1) pp. 123-130 ELSEVIER SCIENCE BV
Hourani SMO, Bailey SJ, Johnson CR, Tennant JP (1998) Effects of adenosine 5 '-triphosphate, uridine 5 '-triphosphate, adenosine 5 '-tetraphosphate and diadenosine polyphosphates in guinea-pig taenia caeci and rat colon muscularis mucosae, NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY 358 (4) pp. 464-473 SPRINGER VERLAG
Bailey A, Mathes H, Kieffer B, Slowe S, Hourani SMO, Kitchen I (2002) Quantitative autoradiography of adenosine receptors and NBTI-sensitive adenosine transporters in the brains and spinal cords of mice deficient in the mu-opioid receptor gene, BRAIN RESEARCH 943 (1) PII S0006-8993(02)02536-2 pp. 68-79 ELSEVIER SCIENCE BV
Lamb DJ, Tickner ML, Dreux AC, El-Sankary W, Hourani SMO, Eales-Reynolds LJ, Ferns GAA (2004) Impairment of vascular function following BCG immunisation is associated with immune responses to HSP-60 in the cholesterol-fed rabbit, ATHEROSCLEROSIS 172 (1) pp. 13-20 ELSEVIER SCI IRELAND LTD
Johnson CR, Charlton SJ, Hourani SMO (1996) Responses of the longitudinal muscle and the muscularis mucosae of the rat duodenum to adenine and uracil nucleotides, BRITISH JOURNAL OF PHARMACOLOGY 117 (5) pp. 823-830 STOCKTON PRESS
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
HOURANI SMO, LOIZOU GD, CUSACK NJ (1986) PHARMACOLOGICAL EFFECTS OF L-AMP-PCP ON ATP RECEPTORS IN SMOOTH-MUSCLE, EUROPEAN JOURNAL OF PHARMACOLOGY 131 (1) pp. 99-103 ELSEVIER SCIENCE BV
PEACHEY JA, HOURANI SMO, KITCHEN I (1994) THE BINDING OF 1,3-[H-3]-DIPROPYL-8-CYCLOPENTYLXANTHINE TO ADENOSINE A(1) RECEPTORS IN RAT SMOOTH-MUSCLE PREPARATIONS, BRITISH JOURNAL OF PHARMACOLOGY 113 (4) pp. 1249-1256 STOCKTON PRESS
HOURANI SMO, JONES DAD (1994) POSTJUNCTIONAL EXCITATORY ADENOSINE A(1) RECEPTORS IN THE RAT VAS-DEFERENS, GENERAL PHARMACOLOGY 25 (3) pp. 417-420 PERGAMON-ELSEVIER SCIENCE LTD
BAILEY SJ, HOURANI SMO (1995) EFFECTS OF SURAMIN ON CONTRACTIONS OF THE GUINEA-PIG VAS-DEFERENS INDUCED BY ANALOGS OF ADENOSINE 5'-TRIPHOSPHATE, BRITISH JOURNAL OF PHARMACOLOGY 114 (6) pp. 1125-1132 STOCKTON PRESS
HOURANI SMO, JOHNSON CR, BAILEY SJ (1993) DESENSITIZATION OF THE P(2)-PURINOCEPTORS ON THE RAT COLON MUSCULARIS MUCOSAE, BRITISH JOURNAL OF PHARMACOLOGY 110 (1) pp. 501-505 STOCKTON 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
Lewis CD, Hourani SMO (1997) Involvement of functional antagonism in the effects of adenosine antagonists and L-NAME in the rat isolated heart, GENERAL PHARMACOLOGY 29 (3) pp. 421-427 PERGAMON-ELSEVIER SCIENCE LTD
Hourani SMO (1999) Postnatal development of purinoceptors in rat visceral smooth muscle preparations, GENERAL PHARMACOLOGY 32 (1) pp. 3-7 PERGAMON-ELSEVIER SCIENCE LTD
BAILEY SJ, HOURANI SMO (1994) DIFFERENTIAL-EFFECTS OF SURAMIN ON P-2-PURINOCEPTORS MEDIATING CONTRACTION OF THE GUINEA-PIG VAS-DEFERENS AND URINARY-BLADDER, BRITISH JOURNAL OF PHARMACOLOGY 112 (1) pp. 219-225 STOCKTON PRESS
Hourani SMO, Welford LA, Cusack NJ (1996) Effects of 2-methylthioadenosine 5'-beta,gamma-methylenetriphosphonate and 2-ethyithioadenosine 5'-monophosphate on human platelet activation induced by adenosine 5'-diphosphate, DRUG DEVELOPMENT RESEARCH 38 (1) pp. 12-23 WILEY-LISS
Prentice DJ, Hourani SMO (2000) Characterisation of adenosine receptors mediating relaxation in hamster isolated aorta, NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY 362 (4-5) pp. 427-434 SPRINGER-VERLAG
PEACHEY JA, HOURANI SMO, KITCHEN I (1994) ADENOSINE-A(1) BINDING-SITES IN RAT SMOOTH-MUSCLE PREPARATIONS, BRITISH JOURNAL OF PHARMACOLOGY 111 pp. P323-P323 STOCKTON PRESS
Tennant JP, Callaghan F, Turner C, Hourani SMO (1999) Effects of allopurinol, erythro-9-(2-hydroxy-3-nonyl)adenine and S-(4-nitrobenzyl)-6-thioinosine on the degradation of adenosine 5 '-triphosphate in the rat colon muscularis mucosae, JOURNAL OF AUTONOMIC PHARMACOLOGY 19 (4) pp. 229-232 BLACKWELL SCIENCE LTD
Godfrey L, Hourani SMO, Kitchen I (2003) Quantitative autoradiography of [H-3]paracetamol binding in the mouse brain, BRITISH JOURNAL OF PHARMACOLOGY 140 NATURE PUBLISHING GROUP
Nicholls J, Hourani SMO (1997) Characterization of adenosine receptors on rat ileum, ileal longitudinal muscle and muscularis mucosae, EUROPEAN JOURNAL OF PHARMACOLOGY 338 (2) pp. 143-150 ELSEVIER SCIENCE BV
Prentice DJ, Hourani SMO (1996) Activation of multiple sites by adenosine analogues in the rat isolated aorta, BRITISH JOURNAL OF PHARMACOLOGY 118 (6) pp. 1509-1517 STOCKTON PRESS
HOURANI SMO, BAILEY SJ, NICHOLLS J, KITCHEN I (1991) AMPPCP ACTS VIA P1-RECEPTORS AND NOT P2-RECEPTORS IN SOME ISOLATED SMOOTH-MUSCLE PREPARATIONS, NUCLEOSIDES & NUCLEOTIDES 10 (5) pp. 1203-1205 MARCEL DEKKER INC
Prentice DJ, Payne SL, Hourani SMO (1997) Activation of two sites by adenosine receptor agonists to cause relaxation in rat isolated mesenteric artery, BRITISH JOURNAL OF PHARMACOLOGY 122 (7) pp. 1509-1515 STOCKTON PRESS
Bailey A, Hawkins RM, Hourani SMO, Kitchen I (2003) Quantitative autoradiography of adenosine receptors in brains of chronic naltrexone-treated mice, BRITISH JOURNAL OF PHARMACOLOGY 139 (6) pp. 1187-1195 NATURE PUBLISHING GROUP
Bailey A, Davis L, Lesscher HMB, Kelly MDW, Ledent C, Hourani SMO, Kitchen I (2004) Enhanced morphine withdrawal and mu-opioid receptor G-protein coupling in A(2A) adenosine receptor knockout ti ice, JOURNAL OF NEUROCHEMISTRY 88 (4) pp. 827-834 BLACKWELL PUBLISHING LTD
Tickner ML, Lamb DJ, Dreux AC, El-Sankary W, Hourani S, Eales-Reynolds LJ, Ferns GAA (2003) BCG immunisation impairs vascular relaxation and enhances atherosclerosis in the chronically hypercholesterolaemic rabbit, BRITISH JOURNAL OF PHARMACOLOGY 140 NATURE PUBLISHING GROUP
BAILEY SJ, HOURANI SMO (1990) A STUDY OF THE PURINOCEPTORS MEDIATING CONTRACTION IN THE RAT COLON, BRITISH JOURNAL OF PHARMACOLOGY 100 (4) pp. 753-756 STOCKTON PRESS
Belchamber K, Hall DA, Hourani SM (2014) Smoking enhances the proinflammatory effects of nucleotides on cytokine release from human lung., PLoS One 9 (6)
Nucleotides have effects on immune cells which are complex but generally proinflammatory, and have been suggested to play a role in smoking-related lung diseases. However, there have been no studies directly measuring functional responses to nucleotides in human lungs taken from smokers. We used fragments of post mortem human lung from smokers and non-smokers, incubated them with a range of nucleotides (4-1000 µM) in the presence of lipopolysaccharide (LPS; 10 µg/ml) for 24 hours and measured cytokines (IL-1², IFN³, IL-17, TNF±, IL-6, IL-8, IL-2 and IL-10) in the supernatants using multiplex immunoassays. Although the basal cytokine levels in the smokers were generally higher in the smokers than the non-smokers, there were no significant differences in either the basal release or the LPS-stimulated release of any of the cytokines when lungs from smokers and non-smokers were compared. There were no significant effects of ATP, ADP, AMP, UTP, ±,²-methylene-ATP, P1, P4-diATP, 2-methylthio-ATP or Bz-ATP on the release of cytokines from the lungs. However, the stable ATP analogue ATP³S increased the release of IL-1² and IFN³, and the effect was greatly increased in lungs from smokers. In non-smokers but not in smokers ATP³S increased the release of IL-17. Overall these results clearly demonstrate for the first time that in normal human lung a stable ATP analogue can enhance LPS-induced pro-inflammatory cytokine release, and that these effects are greatly altered by a prior history of smoking. This provides strong support for the suggestion that nucleotides are involved in the pathogenesis of smoking-related diseases.
Tennant JP, Samuel EJ, Hourani SMO (1997) Ectonucleotidase activity in the prostatic and epididymal portions of the guinea-pig vasdeferens, BRITISH JOURNAL OF PHARMACOLOGY 122 pp. P146-P146 STOCKTON PRESS
Kelly MDW, Ledent C, Kitchen I, Hourani SMO (2003) Characterization of [H-3]-ZM 241385 binding in wildtype and A(2A) knockout mouse brain, BRITISH JOURNAL OF PHARMACOLOGY 140 NATURE PUBLISHING GROUP
Georgiou P, Zanos P, Garcia-Carmona JA, Hourani S, Kitchen I, Laorden ML, Bailey A (2016) Methamphetamine abstinence induces changes in ¼-opioid receptor, oxytocin and CRF systems: Association with an anxiogenic phenotype., Neuropharmacology 105 pp. 520-532
The major challenge in treating methamphetamine addicts is the maintenance of a drug free-state since they experience negative emotional symptoms during abstinence, which may trigger relapse. The neuronal mechanisms underlying long-term withdrawal and relapse are currently not well-understood. There is evidence suggesting a role of the oxytocin (OTR), ¼-opioid receptor (MOPr), dopamine D2 receptor (D2R), corticotropin-releasing factor (CRF) systems and the hypothalamic-pituitary-adrenal (HPA)-axis in the different stages of methamphetamine addiction. In this study, we aimed to characterize the behavioral effects of methamphetamine withdrawal in mice and to assess the modulation of the OTR, MOPr, D2R, CRF and HPA-axis following chronic methamphetamine administration and withdrawal. Ten-day methamphetamine administration (2 mg/kg) increased OTR binding in the amygdala, whilst 7 days of withdrawal induced an upregulation of this receptor in the lateral septum. Chronic methamphetamine treatment increased plasma OT levels that returned to control levels following withdrawal. In addition, methamphetamine administration and withdrawal increased striatal MOPr binding, as well as c-Fos(+)/CRF(+) neuronal expression in the amygdala, whereas an increase in plasma corticosterone levels was observed following METH administration, but not withdrawal. No differences were observed in the D2R binding following METH administration and withdrawal. The alterations in the OTR, MOPr and CRF systems occurred concomitantly with the emergence of anxiety-related symptoms and the development of psychomotor sensitization during withdrawal. Collectively, our findings indicate that chronic methamphetamine use and abstinence can induce brain-region specific neuroadaptations of the OTR, MOPr and CRF systems, which may, at least, partly explain the withdrawal-related anxiogenic effects.
Park HS, Tennant JP, Waktolla GF, Sarkardei S, Kass GEN, Hourani SMO (1998) Effects of adenosine 3 '-phosphate 5 '-phosphosulfate on P2 receptors in platelets and smooth muscle preparations, DRUG DEVELOPMENT RESEARCH 45 (2) pp. 67-73 WILEY-LISS
Thakur S, Du J, Hourani S, Ledent C, Li J-M (2010) Inactivation of Adenosine A(2A) Receptor Attenuates Basal and Angiotensin II-induced ROS Production by Nox2 in Endothelial Cells, JOURNAL OF BIOLOGICAL CHEMISTRY 285 (51) pp. 40104-40113 AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Hourani SMO, Hall DA (1996) P2T purinoceptors: ADP receptors on platelets, P2 PURINOCEPTORS: LOCALIZATION, FUNCTION AND TRANSDUCTION MECHANISMS 198 pp. 53-70 JOHN WILEY & SONS LTD
Hourani SMO (1996) Purinoceptors and platelet aggregation, JOURNAL OF AUTONOMIC PHARMACOLOGY 16 (6) pp. 349-352 BLACKWELL SCIENCE LTD
Hourani SMO, Smith NC, Nettell JJ, Hall JM (1997) Relaxation of the ovine isolated iris sphincter by adenosine receptor agonists: Lack of effect of adenosine A(1) and A(2) receptor antagonists, EUROPEAN JOURNAL OF PHARMACOLOGY 334 (1) pp. 95-98 ELSEVIER SCIENCE BV
Nicholls J, Skene DJ, Hourani SMO (1997) Use of a newly developed technique to isolate rat pinealocytes and study the effects of adenosine agonists on melatonin production, JOURNAL OF PINEAL RESEARCH 23 (3) pp. 164-168 WILEY-BLACKWELL
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, 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.
Tennant JP, Pearson A, Hourani SMO (1999) Effects of noradrenaline, the calcium ionophore A23 187, forskolin, sodium nitroprusside and glibenclamide on the degradation of extracellular adenosine 5 '-triphosphate by the rat isolated vas deferens, JOURNAL OF AUTONOMIC PHARMACOLOGY 19 (3) pp. 167-171 BLACKWELL SCIENCE LTD
Geeson J, Larsson K, Hourani SM, Toms NJ (2002) Sodium nitroprusside-induced rat fundus relaxation is ryanodine-sensitive and involves L-type Ca2+ channel and small conductance Ca(2+)-sensitive K+ channel components., Auton Autacoid Pharmacol 22 (5-6) pp. 297-301
1 The aim of this study was to examine whether sodium nitroprusside (SNP)-induced relaxation of rat fundus longitudinal smooth muscle involves ryanodine-sensitive Ca2+ release. 2 SNP (300 nM-30 microM) elicited concentration-dependent relaxation of precontracted (1 microM carbachol) rat fundus, an effect almost abolished by the selective guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ, 10 microM). 3 SNP-mediated relaxations were almost abolished by 10 microM ryanodine. 4 SNP-mediated relaxations were also reduced by either 1 microM apamin (a selective small conductance Ca(2+)-sensitive K+ channel, SKCa, inhibitor) or the selective L-type Ca2+ channel inhibitor, nicardipine (3 microM). 5 SNP-induced relaxations were insensitive to 1 mM tetraethylammonium chloride (an inhibitor of large-conductance Ca(2+)-sensitive K+ channels) and 1 microM glibenclamide (an ATP-sensitive K+ channel inhibitor). 6 These data suggest that SNP-mediated fundus relaxation occurs via a cGMP-mediated and ryanodine-sensitive mechanism which requires, at least in part, SKCa and L-type Ca2+ channel activity.
Oxidative stress attributable to the activation of a Nox2-containing NADPH oxidase is involved in dietary obesity-associated cardiovascular diseases. However, the mechanism of Nox2 activation in dietary obesity remains unclear. In this project age-matched apolipoprotein E knockout (ApoEKO) and Nox2/ApoE double knockout (D-KO) mice were used to investigate high-fat diet (HFD)-induced obesity-related metabolic disorders, Nox2 activation, endothelial and adipose tissue dysfunction.

Compared to NCD, HFD ApoEKO mice developed insulin resistance, increased systemic oxidative stress and vascular dysfunction which was accompanied by increased Nox2 expression, activated mitogen-activated protein kinase (MAPK) and attenuated Akt/endothelial nitric oxide synthesis (eNOS) pathways. Akt was decreased, vascular cell adhesion molecule-1 was increased and macrophages were recruited indicating endothelial cell activation and inflammation, attenuating the phosphatidylinositol-3-kinase/Akt/eNOS branch in favour of the MAPK. In vitro experiments showed that in response to high glucose/insulin challenge, ApoEKO aortas increased significantly the levels of Nox2 expression, activation of stress signalling pathways and the cells were senescent. Finally, the relationship of Nox2-derived reactive oxygen species due to obesity and adipose tissue dysfunction was examined for the first time in ApoEKO mice. It was found that adipose tissue in obesity is infiltrated by macrophages and intercellular adhesion molecule-1 is increased. Insulin receptor is decreased whereas ERK phosphorylation is increased and eNOS phosphorylation is decreased suggesting impaired insulin signalling. Uncoupled protein-1 levels also decreased. Nox2/ApoE D-KO mice did not exhibit any of the delirious effects of HFD/ insulin resistance and were protected from adipose tissue inflammation.

In conclusion, this project demonstrated a crucial role for metabolic disorders in systemic Nox2 activation, inflammation, endothelial dysfunction and insulin receptor function in HFD ApoEKO mice. Also, it provides novel insights into mechanisms underlying adipose tissue dysfunction. Therefore, Nox2 targeting may represent an effective therapy to preserve endothelial and adipose tissue function and improve global metabolism in dietary obesity.