bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of the binding of [3H]‐clobenpropit to histamine H3‐receptors in guinea‐pig cerebral cortex membranes
Authors: Harper E A , Shankley N P , Black J W 
Published: January 2005

We have investigated the binding of a novel histamine H3‐receptor antagonist radioligand, [3H]‐ clobenpropit ([3H]‐VUF9153), to guinea‐pig cerebral cortex membranes.
Saturation isotherms for [3H]‐clobenpropit appeared biphasic. Scatchard plots were curvilinear and Hill plot slopes were significantly less than unity (0.63±0.03; n=12±s.e.mean). The radioligand appeared to label two sites in guinea‐pig cerebral cortex membranes with apparent affinities (pKD′) of 10.91±0.12 (Bmax=5.34±0.85 fmol mg−1 original wet weight) and 9.17±0.16 (Bmax=23.20± 6.70 fmol mg−1).
In the presence of metyrapone (3 mM) or sodium chloride (100 mM), [3H]‐clobenpropit appeared to label a homogeneous receptor population (Bmax=3.41±0.46 fmol mg−1 and 3.49±0.44 fmol mg−1, pKD′ =10.59±0.17 and 10.77±0.02, respectively). Scatchard plots were linear and Hill slopes were not significantly different from unity (0.91±0.04 and 0.99±0.02, respectively). Granisetron (1 μM), rilmenidine (3 μM), idazoxan (0.3 μM), pentazocine (3 μM) and 1,3‐di‐(2‐tolyl)guanidine (0.3 μM) had no effect on the binding of [3H]‐clobenpropit.
The specific binding of [3H]‐clobenpropit appeared to reach equilibrium after 25 min at 21±3°C and remained constant for >180 min. The estimated pKD′ (10.27±0.27; n=3±s.e.mean) was not significantly different from that estimated by saturation analysis in the presence of metyrapone.
A series of histamine H3‐receptor ligands expressed affinity values for sites labelled with [3H]‐clobenpropit which were not significantly different from those estimated when [3H]‐R‐α‐MH was used to label histamine H3‐receptors in guinea‐pig cerebral cortex membranes.

British Journal of Pharmacology (1999) 128, 881–890; doi:10.1038/sj.bjp.0702860
Block of human aorta Kir6.1 by the vascular KATP channel inhibitor U37883A
Authors: Surah‐Narwal S , Xu S Z , McHugh D , McDonald R L , Hough E , Cheong A , Partridge C , Sivaprasadarao A , Beech D J 
Published: January 2005

A human aorta cDNA library was screened at low stringency with a rat pancreatic Kir6.1 cDNA probe and a homologue of Kir6.1 (hKir6.1) was isolated and sequenced.
Metabolic poisoning of Xenopus laevis oocytes with sodium azide and application of the K+ channel opener drug diazoxide induced K+ channel currents in oocytes co‐injected with cRNA for hKir6.1 and hamster sulphonylurea receptor (SUR1), but not in oocytes injected with water or cRNA for hKir6.1 or SUR1 alone.
K+ channel currents due to hKir6.1+SUR1 or mouse Kir6.2+SUR1 were strongly inhibited by 1 μM glibenclamide. K+‐current carried by hKir6.1+SUR1 was inhibited by the putative vascular‐selective KATP channel inhibitor U37883A (IC50 32 μM) whereas current carried by Kir6.2+SUR1 or Shaker K+ channels was unaffected.
The data support the hypothesis that hKir6.1 is a component of the vascular KATP channel, although the lower sensitivity of hKir6.1+SUR1 to U37883A compared with native vascular tissues suggests the need for another factor or subunit. Furthermore, the data suggest that pharmacology of KATP channels can be determined by the pore‐forming subunit as well as the sulphonylurea receptor and point to a molecular basis for the pharmacological distinction between vascular and pancreatic/cardiac KATP channels.

British Journal of Pharmacology (1999) 128, 667–672; doi:10.1038/sj.bjp.0702862
A major role for the Rho‐associated coiled coil forming protein kinase in G‐protein‐mediated Ca2+ sensitization through inhibition of myosin phosphatase in rabbit trachea
Authors: Iizuka Kunihiko , Yoshii Akihiro , Samizo Koichi , Tsukagoshi Hideo , Ishizuka Tamotsu , Dobashi Kunio , Nakazawa Tsugio , Mori Masatomo 
Published: January 2005

G protein‐mediated Ca2+ sensitization of airway smooth muscle contraction was investigated with respect to the relative importance of Rho‐associated coiled coil forming protein kinase (ROCK) and protein kinase C (PKC). We examined the effects of Y‐27632, a ROCK inhibitor, and GF 109203X, a PKC inhibitor, on guanosine 5′‐O‐(3‐thiotriphosphate) (GTPγS)‐induced contraction in α‐toxin‐ or β‐escin‐permeabilized rabbit trachea.
Although pre‐treatment with Y‐27632 dose‐dependently inhibited GTPγS (10 μM)‐induced Ca2+ sensitization of α‐toxin‐permeabilized trachea, a Y‐27632‐insensitive component (approximately 16% of the maximum contraction) was retained during the early phase of the GTPγS response in the presence of Y‐27632 (100 μM).
GF 109203X (5 μM) abolished 1 μM 4β‐phorbol 12, 13‐dibutyrate (PDBu)‐induced, but only partially inhibited the GTPγS‐induced Ca2+ sensitization. A combination of Y‐27632 (100 μM) and GF 109203X (5 μM) totally abolished the GTPγS response.
GTPγS caused only a small contraction in the absence of Ca2+. Wortmannin (30 μM), a myosin light chain kinase (MLCK) inhibitor, completely inhibited Ca2+‐induced contraction. ATP‐triggered contraction of the strip which had been treated with calyculin A (1 μM), a phosphatase inhibitor, in rigor solutions was markedly slowed by worthmannin (30 μM), but not by Y‐27632 (100 μM), in the presence of GTPγS and Ca2+.
GTPγS, but not PDBu, contracted the β‐escin‐permeabilized trachea in the absence of Ca2+, but the presence of Ca2+‐independent MLCK.
We conclude that ROCK plays a primary role in G‐protein‐mediated Ca2+ sensitization, which requires MLCK activity, with minor contribution of PKC to the early phase of contraction, and PDBu utilizes conventional PKC(s) in airway smooth muscle.

British Journal of Pharmacology (1999) 128, 925–933; doi:10.1038/sj.bjp.0702864
Direction‐independent block of bi‐directional Na+/Ca2+ exchange current by KB‐R7943 in guinea‐pig cardiac myocytes
Authors: Kimura Junko , Watano Tomokazu , Kawahara Masanori , Sakai Eiichi , Yatabe Junichi 
Published: January 2005

We investigated the inhibitory effect of KB‐R7943 on ‘bi‐directional’ Na+/Ca2+ exchange current (iNCX) with the reversal potential of iNCX (ENCX) in the middle of the ramp voltage pulse employed.
Bi‐directional iNCX was recorded with ‘full’ ramp pulses given every 10 s from the holding potential of −60 mV over the voltage range between 30 and −150 mV under the ionic conditions of 140 mM [Na]o, 20 mM [Na]i, 1 mM [Ca]o and 433 nM [Ca]i with calculated ENCX at −50 mV.
KB‐R7943 (0.1–100 μM) concentration‐dependently inhibited the current, which reversed near the calculated ENCX, indicating that the blocked current was iNCX.
The inhibition levels were not significantly different between outward and inward iNCX measured at 0 and −120 mV, respectively. IC50 of KB‐R7943 was approximately 1 μM for both directions of iNCX.
Under the bi‐directional ionic conditions, only an outward or inward iNCX was induced by positive or negative ‘half’ ramp pulses, respectively, from the holding potential of −60 mV. KB‐R7943 inhibited both direction of iNCX and the concentration‐inhibition relations were superimposable to the ones obtained by ‘full’ ramp pulses.
These results indicate that KB‐R7943 inhibits iNCX direction‐independently under bi‐directional conditions. This conclusion is different from that of our previous results obtained from iNCX under uni‐directional ionic conditions, where KB‐R7943 inhibited iNCX direction‐dependently. The difference could be attributed to slow dissociation of the drug from the exchanger.

British Journal of Pharmacology (1999) 128, 969–974; doi:10.1038/sj.bjp.0702869
The Pseudomonas aeruginosa quorum‐sensing signal molecule, N‐(3‐oxododecanoyl)‐L‐homoserine lactone, inhibits porcine arterial smooth muscle contraction
Authors: Lawrence R N , Dunn W R , Bycroft B , Camara M , Chhabra S R , Williams P , Wilson V G 
Published: January 2005

The Pseudomonas aeruginosa quorum sensing molecule N‐(3‐oxododecanoyl)‐L‐homoserine lactone (OdDHL) has been shown to suppress cytokine production in macrophages. We have examined the effect of OdDHL and related compounds on constrictor tone of porcine blood vessels. OdDHL (1–30 μM) caused a concentration‐dependent inhibition of U46619‐induced contractions of the coronary artery through a largely endothelium‐independent mechanism, but was markedly less effective in the pulmonary artery. Quantitively similar effects to those produced by OdDHL were observed with N‐(3‐oxododecanoyl)‐L‐homocysteine thiolactone, a thiolactone derivative, while N‐3‐oxododecanamide, a lactone‐free acyl analogue, possessed 1/3rd the potency as a vasorelaxant. Neither N‐butanoyl‐L‐homoserine lactone nor L‐homoserine lactone (up to 30 μM) were active. Our findings indicate that OdDHL inhibits vasoconstrictor tone of both pulmonary and coronary blood vessels from the pig. The vasorelaxant action of OdDHL appears to be primarily determined by the N‐acyl chain length, with a minor contribution by the homoserine lactone moiety.British Journal of Pharmacology (1999) 128, 845–848; doi:10.1038/sj.bjp.0702870
Mechanisms underlying the impairment of endothelium‐dependent relaxation in the pulmonary artery of monocrotaline‐induced pulmonary hypertensive rats
Authors: Nakazawa Hiroshi , Hori Masatoshi , Ozaki Hiroshi , Karaki Hideaki 
Published: January 2005

It has been reported that endothelium‐dependent relaxation is impaired in pulmonary hypertensive vessels. The underlying mechanisms for this phenomenon, however, have not yet been identified. In this study, the mechanisms responsible for decreased endothelium‐dependent relaxation in the pulmonary artery isolated from monocrotaline (MCT)‐induced pulmonary hypertensive rat (MCT rat) were examined. MCT (60 mg kg−1), or its vehicle was administered by a single subcutaneous injection to 6‐week‐old male Sprague Dawley rats.
Endothelium‐dependent relaxation induced by carbachol or ionomycin in the MCT rat artery was significantly smaller than that in vehicle‐treated rat (control rat) artery. Cyclic GMP levels, measured by enzyme‐immunoassay, under resting or stimulation with carbachol or ionomycin were also smaller in the MCT rat artery. However, sodium nitroprusside‐induced cyclic GMP accumulation in the endothelium‐denuded artery was similar in control and MCT rats. These results suggest that MCT treatment decreases endothelial nitric oxide (NO) production.
Resting endothelial Ca2+ levels ([Ca2+]i) in the fura‐PE3‐loaded MCT rat artery, were not different from those in the control rat. However, the increase in endothelial [Ca2+]i elicited by carbachol was attenuated in the MCT rat.
In quantitative RT–PCR analysis, the expression of mRNA encoding endothelial NO synthase was rather increased in the MCT rat artery, suggesting an up‐regulation of eNOS expression.
These results provide evidence that impaired NO‐mediated arterial relaxation in the MCT rat is due to dissociation between eNOS expression and NO production. This dissociation may be derived from an inhibition of receptor‐mediated Ca2+ metabolism and also from the apparent decrease in Ca2+ sensitivity of eNOS.

British Journal of Pharmacology (1999) 128, 1098–1104; doi:10.1038/sj.bjp.0702878
Effects of luteolin and quercetin, inhibitors of tyrosine kinase, on cell growth and metastasis‐associated properties in A431 cells overexpressing epidermal growth factor receptor
Authors: Huang Y ‐T , Hwang J ‐J , Lee P ‐P , Ke F ‐C , Huang J ‐H , Huang C ‐J , Kandaswami C , Middleton E , Lee M ‐T 
Published: January 2005

Flavonoids display a wide range of pharmacological properties including anti‐inflammatory. Anti‐mutagenic, anti‐carcinogenic and anti‐cancer effects. Here, we evaluated the effects of eight flavonoids on the tumour cell proliferation, cellular protein phosphorylation, and matrix metalloproteinase (MMPs) secretion.
Of the flavonoids examined, luteolin (Lu) and quercetin (Qu) were the two most potent agents, and significantly inhibited A431 cell proliferation with IC50 values of 19 and 21 μM, respectively.
The epidermal growth factor (EGF) (10 nM) promoted growth of A431 cells (+25±4.6%) and mediated epidermal growth factor receptor (EGFR) tyrosine kinase activity and autophosphorylation of EGFR were inhibited by Lu and Qu. At concentration of 20 μM, both Lu and Qu markedly decreased the levels of phosphorylation of A431 cellular proteins, including EGFR.
A431 cells treated with Lu or Qu exhibited protuberant cytoplasmic blebs and progressive shrinkage morphology. Lu and Qu also time‐dependently induced the appearance of a ladder pattern of DNA fragmentation, and this effect was abolished by EGF treatment.
The addition of EGF only marginally diminished the inhibitory effect of luteolin and quercetin on the growth rate of A431 cells, treatment of cellular proteins with EGF and luteolin or quercetin greatly reduced protein phosphorylation, indicating Lu and Qu may act effectively to inhibit a wide range of protein kinases, including EGFR tyrosine kinase.
EGF increased the levels of matrix metalloproteinase‐2 (MMP‐2) and matrix metalloproteinase‐9 (MMP‐9), while Lu and Qu appeared to suppress the secretion of these two MMPs in A431 cells.
Examination of the relationship between the chemical structure and inhibitory effects of eight flavonoids reveal that the double bond between C2 and C3 in ring C and the OH groups on C3′ and C4′ in ring B are critical for the biological activities.
This study demonstrates that the inhibitory effects of Lu and Qu, and the stimulatory effects of EGF, on tumour cell proliferation, cellular protein phosphorylation, and MMP secretion may be mediated at least partly through EGFR. This study supports the idea that Lu and Qu may have potential as anti‐cancer and anti‐metastasis agents.

British Journal of Pharmacology (1999) 128, 999–1010; doi:10.1038/sj.bjp.0702879
In vitro mechanism of action on insulin release of S‐22068, a new putative antidiabetic compound
Authors: Le Brigand Laurence , Virsolvy Anne , Manechez Dominique , Godfroid Jean‐Jacques , Guardiola‐Lemaître Beatrice , Gribble Fiona M , Ashcroft Frances M , Bataille Dominique 
Published: January 2005

The MIN6 cell line derived from in vivo immortalized insulin‐secreting pancreatic β cells was used to study the insulin‐releasing capacity and the cellular mode of action of S‐22068, a newly synthesized imidazoline compound known for its antidiabetic effect in vivo.
S‐22068, was able to release insulin from MIN6 cells in a dose‐dependent manner with a half‐maximal stimulation at 100 μM. Its efficacy (8 fold over the basal value), which did not differ whatever the glucose concentration (stimulatory or not), was intermediate between that of sulphonylurea and that of efaroxan.
Similarly to sulphonylureas and classical imidazolines, S‐22068 blocked KATP channels and, in turn, opened nifedipine‐sensitive voltage‐dependent Ca2+ channels, triggering Ca2+ entry.
Similarly to other imidazolines, S‐22068 induced a closure of cloned KATP channels injected to Xenopus oocytes by interacting with the pore‐forming Kir6.2 moiety.
S‐22068 did not interact with the sulphonylurea binding site nor with the non‐I1 and non‐I2 imidazoline site evidenced in the β cells that is recognized by the imidazoline compounds efaroxan, phentolamine and RX821002.
We conclude that S‐22068 is a novel imidazoline compound which stimulates insulin release via interaction with an original site present on the Kir6.2 moiety of the β cell KATP channels.

British Journal of Pharmacology (1999) 128, 1021–1026; doi:10.1038/sj.bjp.0702883
Nociceptin and the ORL‐1 ligand [Phe1ψ (CH2‐NH)Gly2]nociceptin(1‐13)NH2 exert anti‐opioid effects in the Freund's adjuvant‐induced arthritic rat model of chronic pain
Authors: Bertorelli Rosalia , Corradini Laura , Rafiq Kamran , Tupper Joanna , Calò Girolamo , Ongini Ennio 
Published: January 2005

Stimulation of the opioid receptor‐like1 (ORL‐1) receptor by nociceptin (NC) produces hyperalgesia and reverses the antinociceptive effects induced by opioids. Most studies concerning the central effects of NC were conducted using acute pain models. The role NC may play in chronic inflammation remains unelucidated.
The present study was undertaken to assess the action of NC in the Freund's adjuvant‐induced monoarthritic rat model. The effects of drugs known to act as analgesics in this model were evaluated. The effects of NC, NCNH2, and the ORL‐1 ligand, [Phe1ψ(CH2‐NH)Gly2]NC(1‐13)NH2 ([F/G]NC(1‐13)NH2), were also studied alone or in association with morphine.
NC (1–30 nmol, i.c.v.) was inactive, whilst NCNH2 (10 nmol, i.c.v.) exerted hyperalgesic effects (−4.5±0.9 vs −0.7±0.8 s of vehicle‐treated animals). [F/G]NC(1‐13)NH2 (0.01–10 nmol, i.c.v.) induced hyperalgesia in the arthritic paw (−3.3±0.6 vs −0.3±0.5 s of vehicle‐treated animals; 10 nmol).
Both NC (0.01–10 nmol, i.c.v.) and [F/G]NC(1‐13)NH2 (0.01–1 nmol, i.c.v), 30 min after morphine (3 mg kg−1, s.c.) induced an immediate and short‐lived reversal of morphine effects (2.6±0.3 vs 10.4±1.0 and 1.2±1.5 vs 9.3±1.1 s of morphine alone, respectively), therefore displaying anti‐opioid activity.
In the Freund's adjuvant‐induced rat model of arthritis, both NC and [F/G]NC(1‐13)NH2 act as anti‐opioid peptides. Furthermore, NCNH2 and [F/G]NC(1‐13)NH2 induce hyperalgesia when given alone. Further investigations and the identification of a centrally acting ORL‐1 antagonist are necessary to better understand the role of NC in pain mechanisms.

British Journal of Pharmacology (1999) 128, 1252–1258; doi:10.1038/sj.bjp.0702884
Reduction of myocardial infarct size with sCR1sLex, an alternatively glycosylated form of human soluble complement receptor type 1 (sCR1), possessing sialyl Lewis x
Authors: Zacharowski Kai , Otto Mike , Hafner Gerd , Marsh Henry C , Thiemermann Christoph 
Published: January 2005

This study investigated the effects of soluble complement receptor type 1 (sCR1) or sCR1sLex, agents which function as a complement inhibitor or as a combined complement inhibitor and selectin adhesion molecule antagonist, respectively, on the infarct size and cardiac troponin T (cTnT) release caused by regional myocardial ischaemia and reperfusion in the rat.
Eighty‐two, male Wistar rats were subjected to 30 min occlusion of the left anterior descending coronary artery (LAD) followed by 2 h of reperfusion. Haemodynamic parameters were continuously recorded and at the end of the experiments infarct size (with p‐nitro‐blue tetrazolium) and cTnT release were determined.
Infusion of sCR1 (1, 5 or 15 mg kg−1, each n=7) or sCR1sLex (1, 5 or 15 mg kg−1, n=7, 13 or 13, respectively) 5 min prior to LAD‐reperfusion caused a reduction in infarct size from 59±2% (PBS–control, n=12) to 46±6%, 25±9% and 37±6% or 42±6%, 35±6% and 35±4%, respectively.
Infusion of sCR1 (15 mg kg−1, n=5) or sCR1sLex (15 mg kg−1, n=5) also reduces the myocardial TnT release from 80±20 ng ml−1 (control) to 13±7 or 4±1 ng ml−1, respectively.
Thus, sCR1 or sCRsLex significantly reduce infarct size and cardiac TnT release caused by 30 min of regional myocardial ischaemia and 2 h of reperfusion in the rat. The mechanisms of the cardioprotective effects of sCR1 or sCR1sLex are not entirely clear, but may be due complement inhibition and/or prevention of the adhesion and activation of neutrophils.

British Journal of Pharmacology (1999) 128, 945–952; doi:10.1038/sj.bjp.0702889
The involvement of protein kinase C in nitric oxide‐induced damage to rat isolated colonic mucosal cells
Authors: Tepperman B L , Chang Q , Soper B D 
Published: January 2005

The role of protein kinase C (PKC) in colonic cellular injury in response to high concentrations of nitric oxide (NO) released from the donor, S‐nitroso‐N‐acetyl‐DL‐penicillamine (SNAP) was investigated.
Addition of SNAP (0.1–1000 μM) to the cellular suspension resulted in a dose‐dependent increase in the extent of damage to isolated colonic mucosal cells as assessed by Trypan blue dye uptake and release of the lysosmal enzyme, N‐acetyl‐β‐glucosaminidase. SNAP treatment also resulted in an increase in cellular total PKC activity. These increases were reduced or eliminated by pretreatment of the cells with the PKC antagonists staurosporine or GF 109203X or the NO scavenger, phenyl‐4,4,5,5,‐tetramethylimidazoline‐1‐oxyl 3‐oxide (PTIO).
PKC‐α, PKC‐δ, PKC‐ε and PKC‐ζ were detected in colonic cellular lysates by immunoblotting. However, only PKC‐ε protein was increased in response to SNAP treatment. Furthermore, SNAP treatment resulted in activation of PKC‐ε by causing translocation of the enzyme from the cytosolic to membrane fraction of the cell. This effect was eliminated if cells were preincubated with the NO scavenger, PTIO.
The extent of cellular damage in response to addition of SNAP to the incubation medium was enhanced by coincubation with the PKC activator, phorbol 12‐myristate 13‐acetate (PMA; 1 and 10 μM).
PKC activity and the extent of cell damage in response to SNAP were reduced by preincubation of the cells with the peroxyl scavenger, ebselen (0.01–10 μM).
These data suggest that the PKC‐ε isoform of the enzyme mediates NO‐induced damage to colonic mucosal cells. This response may occur, at least in part, due to peroxynitrite formation.

British Journal of Pharmacology (1999) 128, 1268–1274; doi:10.1038/sj.bjp.0702891
Contrasting EEG profiles elicited by antipsychotic agents in the prefrontal cortex of the conscious rat: antagonism of the effects of clozapine by modafinil
Authors: Sebban C , Tesolin‐Decros B , Millan M J , Spedding M 
Published: January 2005

Power spectra (0–30 Hz) were recorded from transcortical electrodes implanted in prefrontal and sensorimotor cortex in conscious rats. For each animal, the spectra in the presence of a drug were divided by the spectra in the presence of vehicle to give a drug‐related differential display of the power spectra, the profile of EEG effects.
The profiles of a range of antipsychotic agents of different classes were compared. Haloperidol (0.5 mg kg−1 and 1 mg kg−1 s.c., peak 8–12 Hz), chlorpromazine (0.5 mg kg−1, i.p., peak 8 Hz), levomepromazine (1 mg kg−1, i.p., peak 8 Hz), quetiapine (2.5 mg kg−1, s.c., peak 9–12 Hz), sertindole (2.5 mg kg−1, s.c., peak 6–14 Hz), risperidone (0.5 and 1 mg kg−1 i.p., peak 9 Hz), clozapine (0.1, 0.2, 0.3 and 5 mg kg−1, s.c., peak 8 Hz) and MDL100907 (0.01 mg kg−1 s.c. peak 2 Hz) synchronized the EEG, increasing the power spectra between 2 and 30 Hz, although there were marked differences between the individual profile of EEG effects for each drug.
In contrast, the benzamides, sulpiride (7.5 and 15 mg kg−1 i.p.), and amisulpiride (1 and 15 mg kg−1 i.p.) caused marked asynchronous changes in the EEG. Raclopride (2.5 mg kg−1 i.p.), caused an initial peak at 9 Hz, but the effects of raclopride desynchronized over a 3 h time period.
Modafinil and apomorphine, administered alone, decreased the power spectra at frequencies higher than 4 Hz. Modafinil (62.4 mg kg−1, i.p.) selectively antagonized the effects of clozapine, but did not antagonize the effects of raclopride.
Different pharmacological classes of antipsychotic show synchronization or desynchronization of the EEG in the prefrontal cortex, with the benzamides showing a distinctive spectrum. There appears to be a specific interaction between modafinil and clozapine. Thus, modulation of prefrontal cortical function, perhaps by thalamic gating, may be important for antipsychotic activity.

British Journal of Pharmacology (1999) 128, 1055–1063; doi:10.1038/sj.bjp.0702893