Effects of unpredictable chronic mild stress (UCMS) on anhedonic-like behaviour, physical state, body weight, learning and memory were investigated in three strains of mice. These strains were chosen ...among 11 strains that were tested in a first experiment for their sucrose consumption and preference for sucrose solutions of different concentrations. In the second experiment, groups of mice of the CBA/H, C57BL/6 and DBA/2 strains were submitted to 7 weeks of UCMS. Measures of the sucrose consumption, the evaluation of the physical state and the measurement of body weight were weekly assessed. Following 4-week period of UCMS, sub-groups of stressed and non-stressed mice were submitted to the spontaneous alternation test in the Y-maze, and then to the water-maze test for spatial learning and memory. UCMS induced a significant decrease of the sucrose consumption in CBA/H and in C57BL/6 but not in DBA/2 mice. The UCMS effect on sucrose intake in CBA/H mice was associated with a body weight loss and a physical state degradation. Spatial learning in a water maze was not disturbed by UCMS, however, a long-term memory impairment was observed in CBA/H stressed mice during a probe test. In the Y-maze, UCMS did not modify spontaneous alternation. These results show both an anhedonic-like and an amnesic effect of UCMS in CBA/H mice. They also reveal a difference of sensitivity to UCMS according to the strain of mice.
The aim of this study was to evaluate the effects of various drugs which present antidepressant properties: selective serotonin-reuptake inhibitors (SSRIs, fluoxetine), serotonin and ...noradrenaline-reuptake inhibitors (Desipramine) and phosphodiesterase inhibitors (PDE, rolipram and tofisopam) on bone microarchitecture and biomechanical properties.
Twelve female mice were studied per group starting at an age of 10 weeks. During 4 weeks, they received subcutaneously either placebo or 20 mg kg
−
1
day
−
1
of desipramine, fluoxetine or 10 mg kg
−
1
day
−
1
of rolipram or tofisopam. Serum Osteocalcin and CTx were evaluated by ELISA. Bone microarchitecture of the distal femur was characterized by X-ray microCT (Skyscan1072). Mechanical properties were assessed by three-point bending test (Instron 4501) and antidepressant efficacy by forced swimming and open field tests.
Fluoxetine displayed lower TbTh (−
6.1%,
p
<
0.01) and tofisopam higher TbTh (+
5.0%,
p
<
0.05) versus placebo. Rolipram and tofisopam treatments induced higher BV/TV than placebo (+
23.8% and +
18.3% respectively). Desipramine group had significantly higher cortical area (+
4.8%,
p
<
0.01) and fluoxetine lower cortical area (−
6.1%,
p
<
0.01) compared to placebo. The stiffness and Young's modulus were lower in the fluoxetine group (77
±
13 N mm
−
1
, 6431
±
1182 MPa) than in placebo (101
±
9 N mm
−
1
, 8441
±
1180 MPa). Bone markers indicated a significantly higher bone formation in tofisopam (+
8.6%) and a lower in fluoxetine (−
56.1%) compared to placebo.
These data suggest deleterious effects for SSRIs, both on trabecular and cortical bone and a positive effect of PDE inhibitors on trabecular bone. Furthermore tofisopam anabolic effect in terms of bone markers, suggests a potential therapeutic effect of the PDE inhibitors on bone.
Tolerance to delay of gratification, taken to reflect impulsiveness, has been proposed to be under the preferential control of central serotonin (5-HT) processes.
The present study further examined ...the effects of drugs which directly or indirectly alter 5-HT transmission, on behaviour controlled by a delayed positive reinforcer.
Rats were given the choice in a T-maze between two magnitudes of reward: small (two food pellets) and immediate versus large (ten pellets) but delayed. When a 15-s waiting period was imposed in the arm leading to the large reward, rats selected this arm on 65-70% of the trials. This frequency was reduced to less than 40% when the large reward was delayed by 25 s.
In rats whose ascending 5-HT pathways had been lesioned by infusion of 5,7-dihydroxytryptamine (5,7-DHT) into the dorsal raphe, the introduction of the 15-s delay contingency resulted in a transient larger reduction of the frequency of choice of the now-delayed reward, compared to sham operated controls. In contrast, choice behaviour of rats given 5,7-DHT into the substantia nigra did not differ from controls. para-Chlorophenylalanine (pCPA, 150 mg/kg IP, daily for 3 days), a 5-HT synthesis inhibitor, bretazenil (0.5-8 mg/kg IP), a benzodiazepine (BZD) receptor partial agonist, and muscimol (0.25-1 mg/kg IP), a GABA(A) receptor agonist, induced a shift toward immediate reward. In contrast to the other BZDs, alprazolam (1-2 mg/kg IP) enhanced the frequency of choice of the large-but-25 s-delayed reward. Similar increased preference for the large-but-delayed reward was induced by the selective 5-HT reuptake inhibitors, fluoxetine (4-8 mg/kg IP) and fluvoxamine (4 mg/kg IP). The full 5-HT(1A) receptor agonist, 8-OH-DPAT (0.015-0.5 mg/kg IP) enhanced the frequency of choice of the large reward delayed by 25 s, whereas the partial agonists, buspirone (1-4 mg/kg IP), ipsapirone (0.5-1 mg/kg IP) and MDL 73005EF (1-2 mg/kg SC), and the antagonist, WAY 100635 (4 mg/kg SC), reduced the number of choices of the large reward delayed by 15 s. Unexpectedly, WAY 100635 (2 mg/kg), which had no effect on choice whatever the delay, did not counteract the increased tolerance to delay induced by 8-OH-DPAT (0.06 mg/kg) and further reduced the frequency of choice of the large-but- 15 s-delayed reward induced by ipsapirone (0.5 mg/kg).
These effects on tolerance to delay may be accounted for by a subtle balance between the opposing functional consequences of pre- versus post-synaptic 5-HT(1A) receptor activation or blockade. Overall, the present results provide further support to the idea that 5-HT processes participate in the control of impulsive-related behaviour, as assessed from tolerance to delay of reward in this particular T-maze procedure.
Inclusive charm and beauty cross sections are measured in
e
−
p
and
e
+
p
neutral current collisions at HERA in the kinematic region of photon virtuality 5≤
Q
2
≤2000 GeV
2
and Bjorken scaling ...variable 0.0002≤
x
≤0.05. The data were collected with the H1 detector in the years 2006 and 2007 corresponding to an integrated luminosity of 189 pb
−1
. The numbers of charm and beauty events are determined using variables reconstructed by the H1 vertex detector including the impact parameter of tracks to the primary vertex and the position of the secondary vertex. The measurements are combined with previous data and compared to QCD predictions.
A measurement is presented of the inclusive neutral current e±p scattering cross section using data collected by the H1 experiment at HERA during the years 2003 to 2007 with proton beam energies Ep ...of 920, 575, and 460 GeV. The kinematic range of the measurement covers low absolute four-momentum transfers squared, 1.5 GeV2<Q2<120 GeV2, small values of Bjorken x, 2.9⋅10−5<x<0.01, and extends to high inelasticity up to y=0.85. The structure function FL is measured by combining the new results with previously published H1 data at Ep=920 GeV and Ep=820 GeV. The new measurements are used to test several phenomenological and QCD models applicable in this low Q2 and low x kinematic domain.
Diffractive electroproduction of ρ and ϕ mesons is measured at HERA with the H1 detector in the elastic and proton dissociative channels. The data correspond to an integrated luminosity of 51 pb
−1
. ...About 10500 ρ and 2000 φ events are analysed in the kinematic range of squared photon virtuality 2.5 ≤
Q
2
≤ 60 GeV
2
, photon-proton centre of mass energy 35 ≤
W
≤ 180 GeV and squared four-momentum transfer to the proton |
t
| ≤ 3 GeV
2
. The total, longitudinal and transverse cross sections are measured as a function of
Q
2
,
W
and |
t
|. The measurements show a transition to a dominantly “hard” behaviour, typical of high gluon densities and small
dipoles, for
Q
2
larger than 10 to 20 GeV
2
. They support flavour independence of the diffractive exchange, expressed in terms of the scaling variable (
Q
2
+
M
2
V
)/4, and proton vertex factorisation. The spin density matrix elements are measured as a function of kinematic variables. The ratio of the longitudinal to transverse cross sections, the ratio of the helicity amplitudes and their relative phases are extracted. Several of these measurements have not been performed before and bring new information on the dynamics of diffraction in a QCD framework. The measurements are discussed in the context of models using generalised parton distributions or universal dipole cross sections.
The diffractive process
ep
→
eXY
, where
Y
denotes a proton or its low mass excitation with
M
Y
<1.6 GeV, is studied with the H1 experiment at HERA. The analysis is restricted to the phase space ...region of the photon virtuality 3 ≤
Q
2
≤ 1600 GeV
2
, the square of the four-momentum transfer at the proton vertex |
t
|< 1.0 GeV
2
and the longitudinal momentum fraction of the incident proton carried by the colourless exchange
x
ℙ
<0.05.
\printthanks
Triple differential cross sections are measured as a function of
x
ℙ
,
Q
2
and
β
=
x
/
x
ℙ
where
x
is the Bjorken scaling variable. These measurements are made after selecting diffractive events by demanding a large empty rapidity interval separating the final state hadronic systems
X
and
Y
. High statistics measurements covering the data taking periods 1999–2000 and 2004–2007 are combined with previously published results in order to provide a single set of diffractive cross sections from the H1 experiment using the large rapidity gap selection method. The combined data represent a factor between three and thirty increase in statistics with respect to the previously published results. The measurements are compared with predictions from NLO QCD calculations based on diffractive parton densities and from a dipole model. The proton vertex factorisation hypothesis is tested.
The effect of apamin on learning was examined using two behavioral tasks where the animals were subjected to two trials separated by a 24
h interval. In the Y maze task, apamin administered before ...the acquisition session did not enhance performance on both the acquisition session and the restitution session. In the second behavioral task, animals were trained to press a lever to obtain a food pellet (fixed ratio 1). Then, to study the effect of apamin on extinction, animals were submitted to two sessions where a press on the lever was not reinforced. Apamin administered before the acquisition session reduced the number of lever presses during the first 3-min period of the restitution session. These results suggest that the blockade of SK channels could improve the acquisition but not when the task requires the processing of spatial information.
Abstract A novel pyridine derivative, 8-{4-(6-methoxy-2,3-dihydro-1,4dioxino2,3-bpyridine-3-ylmethyl)-amino-butyl}-8-aza-spiro4.5decane-7,9-dione hydrochloride, termed JB-788, was designed to ...selectively target 5-HT1A receptors. In the present study, the pharmacological profile of JB-788 was characterized in vitro using radioligands binding tests and in vivo using neurochemical and behavioural experiments. JB-788 bound tightly to human 5-HT1A receptor expressed in human embryonic kidney 293 (HEK-293) cells with a Ki value of 0.8 nM. Its binding affinity is in the same range as that observed for the (±)8-OH-DPAT, a reference 5HT1A agonist compound. Notably, JB-788 only bound weakly to 5-HT1B or 5-HT2A receptors and moreover the drug displayed only weak or indetectable binding to muscarinic, α2 , β1 and β2 adrenergic receptors, or dopaminergic D1 receptors. JB-788 was found to display substantial binding affinity for dopaminergic D2 receptors and, to a lesser extend to α1 adrenoreceptors. JB-788 dose-dependently decreased forskolin-induced cAMP accumulation in HEK cells expressing human 5-HT1A , thus acting as a potent 5-HT1A receptor agonist (Emax. 75%, EC50 3.5 nM). JB-788 did not exhibit any D2 receptor agonism but progressively inhibited the effects of quinpirole, a D2 receptor agonist, in the cAMP accumulation test with a Ki value of 250 nM. JB-788 induced a weak change in cAMP levels in mouse brain but, like some antipsychotics, transiently increased glycogen contents in various brain regions. Behavioral effects were investigated in mice using the elevated plus-maze. JB-788 was found to increase the time duration spent by animals in anxiogenic situations. Locomotor hyperactivity induced by methamphetamine in mouse, a model of antipsychotic activity, was dose-dependently inhibited by JB-788. Altogether, these results suggest that JB-788 displays pharmacological properties, which could be of interest in the area of anxiolytic and antipsychotic drugs.
The cross section of diffractive deep-inelastic scattering
ep
→
eXp
is measured, where the system
X
contains at least two jets and the leading final state proton is detected in the H1 Forward Proton ...Spectrometer. The measurement is performed for fractional proton longitudinal momentum loss
x
ℙ
<0.1 and covers the range 0.1<|
t
|<0.7 GeV
2
in squared four-momentum transfer at the proton vertex and 4<
Q
2
<110 GeV
2
in photon virtuality. The differential cross sections extrapolated to |
t
|<1 GeV
2
are in agreement with next-to-leading order QCD predictions based on diffractive parton distribution functions extracted from measurements of inclusive and dijet cross sections in diffractive deep-inelastic scattering. The data are also compared with leading order Monte Carlo models.
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