Different physicochemical interactions between varietal wines and human saliva: Correspondence with astringency.

Astringency corresponds to the sensation of dryness and roughness that is experienced in the oral cavity in association with the interaction between salivary proteins and food polyphenols. In this study, the phenolic composition of seven varietal wines, the intensity of astringency they evoke and the physicochemical reactivity of these wines with whole human saliva were evaluated. Phenolic composition of wines was characterized by spectrophotometry and HPLC chromatography. Intensity of astringency was evaluated by trained sensory panels. Saliva from a single volunteer subject was used to assess wine-saliva interactions. To this end, binary mixtures were produced at different v/v wine/saliva ratios and each of them assayed for the ability of the salivary protein to diffuse on a cellulose membrane (diffusion test) and to remain in solution (precipitation test). Physicochemical reactivities between wine components and the protein fraction of saliva were contrasted against the astringency and the phenolic profile of each varietal wine. The study supports the view that astringency depends on physicochemical interactions between two complex matrices -wine and saliva- and not between some of their particular components.

Exposure to repeated immobilization stress inhibits cocaine-induced increase in dopamine extracellular levels in the rat ventral tegmental area.

A higher vulnerability to drug abuse has been observed in human studies of individuals exposed to chronic or persistent stress, as well as in animal models of drug abuse. Here, we explored the effect of repeated immobilization stress on cocaine-induced increase in dopamine extracellular levels in VTA and its regulation by corticotropin-releasing factor (CRF) and GABA systems. Cocaine (10mg/Kg i.p.) induced an increase of VTA DA extracellular levels in control rats. However, this effect was not observed in repeated stress rats. Considering the evidence relating stress with CRF, we decided to perfuse CRF and CP-154526 (selective antagonist of CRF1 receptor) in the VTA of control and repeated stress rats, respectively. We observed that perfusion of 20µM CRF inhibited the increase of VTA DA extracellular levels induced by cocaine in control rats. Interestingly, we observed that in the presence of 10µM CP-154526, cocaine induced a significant increase of VTA DA extracellular levels in repeated stress rats. Regarding the role of VTA GABA neurotransmission, cocaine administration induced a significant increase in VTA GABA extracellular levels only in repeated stress rats. Consistently, cocaine was able to increase VTA DA extracellular levels in repeated stress rats when 100µM bicuculline, an antagonist of GABAA receptor, was perfused intra VTA. Thus, both CRF and GABA systems are involved in the lack of response to cocaine in the VTA of repeated stress rats. It is tempting to suggest that the loss of response in VTA dopaminergic neurons to cocaine, after repeated stress, is due to an interaction between CRF and GABA systems.

EphA4 activation of c-Abl mediates synaptic loss and LTP blockade caused by amyloid-ß oligomers.

The early stages of Alzheimer's disease are characterised by impaired synaptic plasticity and synapse loss. Here, we show that amyloid-ß oligomers (AßOs) activate the c-Abl kinase in dendritic spines of cultured hippocampal neurons and that c-Abl kinase activity is required for AßOs-induced synaptic loss. We also show that the EphA4 receptor tyrosine kinase is upstream of c-Abl activation by AßOs. EphA4 tyrosine phosphorylation (activation) is increased in cultured neurons and synaptoneurosomes exposed to AßOs, and in Alzheimer-transgenic mice brain. We do not detect c-Abl activation in EphA4-knockout neurons exposed to AßOs. More interestingly, we demonstrate EphA4/c-Abl activation is a key-signalling event that mediates the synaptic damage induced by AßOs. According to this results, the EphA4 antagonistic peptide KYL and c-Abl inhibitor STI prevented i) dendritic spine reduction, ii) the blocking of LTP induction and iii) neuronal apoptosis caused by AßOs. Moreover, EphA4-/- neurons or sh-EphA4-transfected neurons showed reduced synaptotoxicity by AßOs. Our results are consistent with EphA4 being a novel receptor that mediates synaptic damage induced by AßOs. EphA4/c-Abl signalling could be a relevant pathway involved in the early cognitive decline observed in Alzheimer's disease patients.

Long-term loss of dopamine release mediated by CRF-1 receptors in the rat lateral septum after repeated cocaine administration.

The lateral septum (LS) is a brain nucleus associated to stress and drug addiction. Here we show that dopamine extracellular levels in the lateral septum are under the control of corticotrophin releasing factor (CRF). Reverse dialysis of 1µM stressin-1, a type 1 CRF receptor (CRF-R1) agonist, induced a significant increase of LS dopamine extracellular levels in saline-treated rats that was blocked by the co-perfusion of stressin-1 with CP-154526, a specific CRF-R1 antagonist. Repeated cocaine administration (15mg/kg; twice daily for 14 days) suppressed the increase in LS dopamine extracellular levels induced by CRF-R1 activation. This suppression was observed 24h, as well as 21 days after withdrawal from repeated cocaine administration. In addition, depolarization-induced dopamine release in the LS was significantly higher in cocaine-compared to saline-treated rats. Thus, our results show that the activation of CRF-R1 in the LS induces a significant increase in dopamine extracellular levels. Interestingly, repeated cocaine administration induces a long-term suppression of the CRF-R1 mediated dopamine release and a transient increase in dopamine releasability in the LS.

4-Methylthioamphetamine increases dopamine in the rat striatum and has rewarding effects in vivo.

4-Methylthioamphetamine (MTA) is a phenylisopropylamine derivative whose use has been associated with severe intoxications. MTA is usually regarded as a selective serotonin-releasing agent. Nevertheless, previous data have suggested that its mechanism of action probably involves a catecholaminergic component. As little is known about dopaminergic effects of this drug, in this work the actions of MTA upon the dopamine (DA) transporter (DAT) were studied in vitro, in vivo and in silico. Also, the possible abuse liability of MTA was behaviourally assessed. MTA exhibited an in vitro affinity for the rat DAT in the low micromolar range (6.01 µM) and induced a significant, dose-dependent increase in striatal DA. MTA significantly increased c-Fos-positive cells in striatum and nucleus accumbens, induced conditioned place preference and increased locomotor activity. Docking experiments were performed in a homology model of the DAT. In conclusion, our results show that MTA is able to increase extracellular striatal DA levels and that its administration has rewarding properties. These effects were observed at concentrations or doses that can be relevant to its use in human beings.

Activation of GABA-B receptors induced by systemic amphetamine abolishes dopamine release in the rat lateral septum.

The lateral septum is a brain nucleus involved in various mental disorders such as anxiety and drug addiction. In the present study, we investigated whether systemic amphetamine, known to release dopamine (DA) in nucleus accumbens, will also release DA in lateral septum. Our results show that systemic amphetamine administration (2 mg/kg i.p.) induced a significant increase in DA extracellular levels in nucleus accumbens but not in lateral septum. Interestingly, intralateral septum perfusion of amphetamine through the microdialysis probe induced a significant increase in DA extracellular levels. To test if GABAergic neurotransmission in lateral septum was responsible for inhibiting the release of DA when amphetamine was administered systemically, we perfused a GABA-B selective antagonist (CGP-52432) intra lateral septum. Systemic amphetamine administration induced a significant increase in lateral septum DA release when CGP-52432 was concomitantly superfused. Our results indicate that the systemic administration of amphetamine induces an increase in lateral septum GABA release and the consequent activation of GABA-B receptors counteracting the direct effect of amphetamine on lateral septum DA release.

La influencia de los procesos controlados en el razonamiento con Teoría de la Mente (ToM) en niños con y sin discapacidad intelectual / The influence of controlled processes reasoning with Theory of Mind (ToM) in children with and without intellectual disabilities

La capacidad o mecanismo tácito de atribuir estados mentales a los otros y a uno mismo, con el objeto de anticipar, comprender y predecir la conducta, es conocida como Teoría de la Mente (ToM). Parte de la discusión se centra en comprender si este razonamiento es un proceso independiente o subordinado a los procesos ejecutivos de control consciente. En esta investigación se analiza el efecto de las funciones ejecutivas de control consciente en tareas de razonamiento con ToM, en niños con y sin discapacidad intelectual. La muestra la constituyen 30 niños con discapacidad intelectual y 20 niños sin discapacidad intelectual. Se hipotetizó que la habilidad para responderlas preguntas de control, una operacionalización de las funciones ejecutivas de control consciente, se asocia más a las tareas de segundo orden que a las de primer orden, ya que estas requieren mayor carga representacional. Los resultados obtenidos, sugieren que los procesos de control consciente no sólo se asocian a las tareas que requieren una mayor carga representacional, sino a todas las tareas que requieren razonar con estados mentales, sean ellos de primer o segundo orden.

The ability to attribute mental states to others and oneself, to anticipate, understand and predict behavior is known as Theory of Mind (ToM). Part of the current discussion focuses on understanding whether this reasoning is a separate process or subordinate to the executive process of conscious control. We analyze the effect of executive functions of conscious control on reasoning tasks with ToM, in children with and without intellectual disabilities. The sample included 30 children with intellectual disabilities and 20 children without intellectual disabilities. We hypothesize that the ability to answer the questions of control, an operational definition of the executive functions of conscious control, is most often associated with the tasks of second order to first order, because the second order task requiring increased representational capability. The results suggest that the processes of conscious control are not only associated with tasks requiring a higher representational, but to all the tasks that require reasoning with mental states, be they first or second order.

Role of cannabinoid CB1 receptors and Gi/o protein activation in the modulation of synaptosomal Na+,K+-ATPase activity by WIN55,212-2 and delta(9)-THC.

In the present study, we evaluated the effects of the synthetic cannabinoid receptor agonist (R)-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN55,212-2) and the active component of Cannabis delta-9-tetrahydrocannabinol (triangle up(9)-THC) on Na(+),K(+)-ATPase activity in synaptosomal mice brain preparation. Additionally, the potential exogenous cannabinoids and endogenous opioid peptides interaction as well as the role of G(i/o) proteins in mediating Na(+),K(+)-ATPase activation were also explored. The ouabain-sensitive Na(+),K(+)-ATPase activity was measured in whole-brain pure intact synaptosomes (obtained by Percoll gradient method) of female CF-1 mice and was calculated as the difference between the total and the ouabain (1 mM)-insensitive Na(+),K(+)-ATPase activities. Incubation in vitro of the synaptosomes with WIN55,212-2 (0.1 pM-10 microM) or triangle up(9)-THC (0.1 pM-0.1 microM), in a concentration-dependent manner, stimulated ouabain-sensitive Na(+),K(+)-ATPase activity. WIN55,212-2 was less potent but more efficacious than triangle up(9)-THC. N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM-251) (10 nM), a CB(1) cannabinoid receptor selective antagonist, had not effect per se but antagonized the enhancement of Na(+),K(+)-ATPase activity induced by both, WIN55,212-2 and triangle up(9)-THC. AM-251 produced a significant reduction in the E(max) of cannabinoid-induced increase in Na(+),K(+)-ATPase activity, but did not significantly modify their EC(50). On the other hand, co-incubation with naloxone (1 microM), an opioid receptor antagonist, did not significantly modify the effect of WIN55,212-2 and completely failed to modify the effect of triangle up(9)-THC on synaptosomal Na(+),K(+)-ATPase. Finally, pre-incubation with 0.5 microg of pertussis toxin (G(i/o) protein blocker) completely abolished the enhancement of ouabain-sensitive Na(+),K(+)-ATPase activity induced by WIN55,212-2. A lower dose, 0.25 microg, decreased the E(max) of WIN55,212-2 by 70% but did not significantly affect its EC(50). These results suggest that WIN55212-2 and triangle up(9)-THC indirectly enhance Na(+),K(+)-ATPase activity in the brain by activating cannabinoid CB(1) receptors in a naloxone-insensitive manner. In addition, the effect of WIN55,212-2 on neuronal Na(+),K(+)-ATPase is apparently due to activation of G(i/o) proteins.