The Compact Linear Collider (CLIC) is an option for a future collider operating at centre-of-mass energies up to , providing sensitivity to a wide range of new physics phenomena and precision physics measurements at the energy frontier. This paper is the first comprehensive presentation of the Higgs physics reach of CLIC operating at three energy stages: , 1.4 and . The initial stage of operation allows the study of Higgs boson production in Higgsstrahlung () and -fusion (), resulting in precise measurements of the production cross sections, the Higgs total decay width , and model-independent determinations of the Higgs couplings. Operation at provides high-statistics samples of Higgs bosons produced through -fusion, enabling tight constraints on the Higgs boson couplings. Studies of the rarer processes and allow measurements of the top Yukawa coupling and the Higgs boson self-coupling. This paper presents detailed studies of the precision achievable with Higgs measurements at CLIC and describes the interpretation of these measurements in a global fit.

Open Access, Copyright CERN, for the benefit of the CLICdp Collaboration. Article funded by SCOAP 3 .

Top quark production in the process e + e − → tt at a future linear electron positron collider with polarised beams is a powerful tool to determine indirectly the scale of new physics. The presented study, based on a detailed simulation of the ILD detector concept, assumes a centre-of-mass energy of √ s = 500 GeV and a luminosity of L = 500 fb −1 equally shared between the incoming beam polarisations of P e − , P e + = ±0.8, ∓0.3. Events are selected in which the top pair decays semi-leptonically and the cross sections and the forward-backward asymmetries are determined. Based on these results, the vector, axial vector and tensorial C P conserving couplings are extracted separately for the photon and the Z 0 component. With the expected precision, a large number of models in which the top quark acts as a messenger to new physics can be distinguished with many standard deviations. This will dramatically improve expectations from e.g. the LHC for electro-weak couplings of the top quark.

1 This study was designed to assess the in¯uence of activation and blockade of the endogenous opioid system in the brain on two key proteins involved in the regulation of programmed cell death: the pro-apoptotic Fas receptor and the anti-apoptotic Bcl-2 oncoprotein. 2 The acute treatment of rats with the m-opioid receptor agonist morphine (3 ± 30 mg kg 71 , i.p., 2 h) did not modify the immunodensity of Fas or Bcl-2 proteins in the cerebral cortex. Similarly, the acute treatment with low and high doses of the antagonist naloxone (1 and 100 mg kg 71 , i.p., 2 h) did not alter Fas or Bcl-2 protein expression in brain cortex. These results discounted a tonic regulation through opioid receptors on Fas and Bcl-2 proteins in rat brain.

1 Agmatine, the proposed endogenous ligand for imidazoline receptors, has been shown to attenuate tolerance to morphine-induced antinociception (Kolesnikov et al., 1996). The main aim of this study was to assess if idazoxan, an a 2 -adrenoceptor antagonist that also interacts with imidazoline receptors, could also modulate opioid tolerance in rats and to establish which type of imidazoline receptors (or other receptors) are involved. 2 Antinociceptive responses to opioid drugs were determined by the tail-¯ick test. The acute administration of morphine (10 mg kg 71 , i.p., 30 min) or pentazocine (10 mg kg 71 , i.p., 30 min) resulted in marked increases in tail-¯ick latencies (TFLs). As expected, the initial antinociceptive response to the opiates was lost after chronic (13 days) treatment (tolerance). When idazoxan (10 mg kg 71 , i.p.) was given chronically 30 min before the opiates it completely prevented morphine tolerance and markedly attenuated tolerance to pentazocine (TFLs increased by 71 ± 143% at day 13). Idazoxan alone did not modify TFLs. 3 The concurrent chronic administration (10 mg kg 71 , i.p., 13 days) of 2-BFI, LSL 60101, and LSL 61122 (valldemossine), selective and potent I 2 -imidazoline receptor ligands, and morphine (10 mg kg 71 , i.p.), also prevented or attenuated morphine tolerance (TFLs increased by 64 ± 172% at day 13). This attenuation of morphine tolerance was still apparent six days after discontinuation of the chronic treatment with LSL 60101-morphine. The acute treatment with these drugs did not potentiate morphineinduced antinociception. These drugs alone did not modify TFLs. Together, these results indicated the speci®c involvement of I 2 -imidazoline receptors in the modulation of opioid tolerance. The potencies of the imidazolines idazoxan, RX821002 and moxonidine were similar, indicating a lack of relationship between potency on NMDA receptors and ability to attenuate opioid tolerance. These results suggested that modulation of opioid tolerance by idazoxan is not related to NMDA receptors blockade. 6 Chronic treatment (13 days) with morphine (10 mg kg 71 , i.p.) was associated with a marked decrease (49%) in immunolabelled neuro®lament proteins (NF-L) in the frontal cortex of morphine-tolerant rats, suggesting the induction of neuronal damage. Chronic treatment (13 days) with idazoxan (10 mg kg 71 ) and LSL 60101 (10 mg kg 71 ) did not modify the levels of NF-L proteins in brain. Interestingly, the concurrent chronic treatment (13 days) of idazoxan or LSL 60101 and morphine, completely reversed the morphine-induced decrease in NF-L immunoreactivity, suggesting a neuroprotective role for these drugs. 7 Together, the results indicate that chronic treatment with I 2 -imidazoline ligands attenuates the development of tolerance to opiate drugs and may induce neuroprotective eects on chronic opiate treatment. Moreover, these ®ndings oer the I 2 -imidazoline ligands as promising therapeutic coadjuvants in the management of chronic pain with opiate drugs.

1 This work investigates the receptor acted upon by imidazoline compounds in the modulation of morphine analgesia. The eects of highly selective imidazoline ligands on the supraspinal antinociception induced by morphine in mice were determined. 2 Intracerebroventricular (i.c.v.) or subcutaneous (s.c.) administration of ligands selective for the I 2 -imidazoline receptor, 2-BFI, LSL 60101, LSL 61122 and aganodine, and the non selective ligand agmatine, increased morphine antinociception in a dose-dependent manner. Neither moxonidine, a mixed I 1 -imidazoline and a 2 -adrenoceptor agonist, RX821002, a potent a 2 -adrenoceptor antagonist that displays low anity at I 2 -imidazoline receptors, nor the selective non-imidazoline a 2 -adrenoceptor antagonist RS-15385-197, modi®ed the analgesic responses to morphine. 3 Administration of pertussis toxin (0.25 mg per mouse, i.c.v.) 6 days before the analgesic test blocked the ability of the I 2 -imidazoline ligands to potentiate morphine antinociception. 4 The increased eect of morphine induced by I 2 -imidazoline ligands (agonists) was completely reversed by idazoxan and BU 224. Identical results were obtained with IBI, which alkylates I 2 -imidazoline binding sites. Thus, both agonist and antagonist properties of imidazoline ligands at the I 2 -imidazoline receptors were observed. 5 Pre-treatment (30 min) with deprenyl, an irreversible inhibitor of monoamine oxidase B (IMAO-B), produced an increase of morphine antinociception. Clorgyline, an irreversible IMAO-A, given 30 min before morphine did not alter the eect of the opioid. At longer intervals (24 h) a single dose of either clorgyline or deprenyl reduced the density of I 2 -imidazoline receptors and prevented the I 2 -mediated potentiation of morphine analgesia. 6 These results demonstrate functional interaction between I 2 -imidazoline and opioid receptors. The involvement of G i -G o transducer proteins in this modulatory eect is also suggested.

1 I 2 -Imidazoline sites ([ 3 H]-idazoxan binding) have been identi®ed on monoamine oxidase (MAO) and proposed to modulate the activity of the enzyme through an allosteric inhibitory mechanism (Tesson et al., 1995). The main aim of this study was to assess the inhibitory e ects and nature of the inhibition of imidazol(ine)/guanidine drugs on rat liver MAO-A and MAO-B isoforms and to compare their inhibitory potencies with their a nities for the sites labelled by [ 3 H]-clonidine in the same tissue. 2 Competition for [ 3 H]-clonidine binding in rat liver mitochondrial fractions by imidazol(ine)/guanidine compounds revealed that the pharmacological pro®le of the interaction (2 -styryl -2 -imidazoline, LSL 611124idazoxan42 -benzofuranyl -2 -imidazoline, 2-BFI=cirazoline4guanabenz4oxymetazoline44 clonidine) was typical of that for I 2 -sites. 3 Clonidine inhibited rat liver MAO-A and MAO-B activities with very low potency (IC 50 s: 700 mM and 6 mM, respectively) and displayed the typical pattern of competitive enzyme inhibition (LineweaverBurk plots: increased K m and unchanged V max values). Other imidazol(ine)/guanidine drugs also were weak MAO inhibitors with the exception of guanabenz, 2-BFI and cirazoline on MAO-A (IC 50 s: 4 ± 11 mM) and 2-benzofuranyl-2-imidazol (LSL 60101) on MAO-B (IC 50 : 16 mM). Idazoxan was a full inhibitor, although with rather low potency, on both MAO-A and MAO-B isoenzymes (IC 50 s: 280 mM and 624 mM, respectively). Kinetic analyses of MAO-A inhibition by these drugs revealed that the interactions were competitive. For the same drugs acting on MAO-B the interactions were of the mixed type inhibition (increased K m and decreased V max values), although the greater inhibitory e ects on the apparent value of V max /K m than on the V max value indicated that the competitive element of the MAO-B inhibition predominated. 5 No signi®cant correlations were found when the potencies of imidazol(ine)/guanidine drugs at the high a nity site (pK iH , nanomolar range) or the low-a nity site (pK iL , micromolar range) of I 2 -imidazoline receptors labelled with [ 3 H]-clonidine were correlated with the pIC 50 values of the same drugs for inhibition of MAO-A or MAO-B activity. These discrepancies indicated that I 2 -imidazoline receptors are not directly related to the site of action of these drugs on MAO activity in rat liver mitochondrial fractions. 6 Although these studies cannot exclude the presence of additional binding sites on MAO that do not a ect the activity of the enzyme, they would suggest that I 2 -imidazoline receptors represent molecular species that are distinct from MAO.

1 This study was designed to assess the potential neuroprotective eect of several imidazol(ine) drugs and agmatine on glutamate-induced necrosis and on apoptosis induced by low extracellular K + in cultured cerebellar granule cells. 2 Exposure (30 min) of energy deprived cells to L-glutamate (1 ± 100 mM) caused a concentrationdependent neurotoxicity, as determined 24 h later by a decrease in the ability of the cells to metabolize 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) into a reduced formazan product. L-glutamate-induced neurotoxicity (EC 50 =5 mM) was blocked by the speci®c NMDA receptor antagonist MK-801 (dizocilpine). 3 Imidazol(ine) drugs and agmatine fully prevented neurotoxicity induced by 20 mM (EC 100 ) Lglutamate with the rank order (EC 50 in mM): antazoline (13) 5 In HEK-293 cells transfected to express the NR1-1a and NR2C subunits of the NMDA receptor, antazoline and agmatine produced a voltage-and concentration-dependent block of glutamateinduced currents. Analysis of the voltage dependence of the block was consistent with the presence of a binding site for antazoline located within the NMDA channel pore with an IC 50 of 10 ± 12 mM at 0 mV. 6 It is concluded that imidazol(ine) drugs and agmatine are neuroprotective against glutamateinduced necrotic neuronal cell death in vitro and that this eect is mediated through NMDA receptor blockade by interacting with a site located within the NMDA channel pore.