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An assay for vesicle--vesicle fusion involving resonance energy transfer between N-(7-nitro-2,1,3-benzoxadiazol-4-yl), the energy donor, and rhodamine, the energy acceptor, has been developed. The two fluorophores are coupled to the free amino group of phosphatidylethanolamine to provide analogues which can be incorporated into a lipid vesicle bilayer. When both fluorescent lipids are in phosphatidylserine vesicles at appropriate surface densities (ratio of fluorescent lipid to total lipid), efficient energy transfer is observed. When such vesicles are fused with a population of pure phosphatidylserine vesicles by the addition of calcium, the two probes mix with the other lipids present to form a new membrane. This mixing reduces the surface density of the energy acceptor resulting in a decreased efficiency of resonance energy transfer which is measured experimentally. These changes in transfer efficiency allow kinetic and quantitative measurements of the fusion process. Using this system, we have studied the ability of phosphatidylcholine, phosphatidylserine, and phosphatidylcholine--phosphatidylserine (1:1) vesicles to fuse with cultured fibroblasts. Under the conditions employed, the majority of the cellular uptake of vesicle lipid could be attributed to the adsorption of intact vesicles to the cell surface regardless of the composition of the vesicle bilayer.

Alcohol use disorders are modulated by genetic factors, but the identification of specific genes and their concomitant biological changes that are associated with a higher risk for these disorders has proven difficult. Alterations in the sensitivity to the motivational effects of ethanol may be one way by which genes modulate the initiation and escalation of ethanol intake. Rats and mice have been selectively bred for high and low ethanol consumption during adulthood. However, selective breeding programs for ethanol intake have not focused on adolescence. This phase of development is associated with the initiation and escalation of ethanol intake and characterized by an increase in the sensitivity to ethanol's appetitive effects and a decrease in the sensitivity to ethanol's aversive effects compared with adulthood. The present study performed short-term behavioral selection to select rat lines that diverge in the expression of ethanol drinking during adolescence. A progenitor nucleus of Wistar rats (F0) and filial generation 1 (F1), F2, and F3 adolescent rats were derived from parents that were selected for high (STDRHI) and low (STDRLO) ethanol consumption during adolescence and were tested for ethanol intake and responsivity to ethanol's motivational effects. STDRHI rats exhibited significantly greater ethanol intake and preference than STDRLO rats. Compared with STDRLO rats, STDRHI F2 and F3 rats exhibited a blunted response to ethanol in the conditioned taste aversion test. F2 and F3 STDRHI rats but not STDRLO rats exhibited ethanol-induced motor stimulation. STDRHI rats exhibited avoidance of the white compartment of the light-dark box, a reduction of locomotion, and a reduction of saccharin consumption, suggesting an anxiety-prone phenotype. The results suggest that the genetic risk for enhanced ethanol intake during adolescence is associated with lower sensitivity to the aversive effects of ethanol, heightened reactivity to ethanol's stimulating effects, and enhanced innate anxiety.

AbstractAlcohol (ethanol) use is almost normative by late adolescence, in most western countries. It is important to identify factors that distinguish those who progress from alcohol initiation to sustained use of the drug, from those that keep a controlled pattern of drinking. The factors precipitating this transition may change across development. This study analyzed associations between behavioral endophenotypes and ethanol intake at three developmental periods. Exp. 1 measured ethanol drinking at postnatal day 18, via an intraoral infusion procedure, in male or female pre‐weanling rats screened for anxiety response in the light‐dark box test and for distance traveled in a novel open field. Exp. 2 measured, in juvenile/adolescent or young adult rats, the association between shelter seeking, exploratory/risk‐taking behaviors, anxiety or hedonic responses, and ethanol intake. Ethanol intake in pre‐weanlings was explained by distance traveled in a novel environment, whereas anxiety responses, measured in the multivariate concentric square field apparatus (MSCF), selectively predicted ethanol intake at adolescence, but not at adulthood. Those juvenile/adolescents with lower mean duration of visit to areas of the MSCF that evoke anxiogenic responses exhibited heightened ethanol intake. These findings suggest that the association between anxiety and ethanol intake may be specifically relevant during adolescence.

Previous studies have shown that both 3-amino-1,2,4-triazole (AT), which inhibits metabolism of ethanol (EtOH) to acetaldehyde by inhibiting catalase, and D-penicillamine (D-P), an acetaldehyde-sequestering agent, modulate EtOH-conditioned place preference (CPP) in male albino Swiss (IOPS Orl) mice. These studies followed a reference-dose-like procedure, which involves comparing cues that have both been paired with EtOH. However, the role of EtOH-derived acetaldehyde has not been examined using a standard CPP method, and efficacy of these treatments could be different under the two circumstances. In the present investigation, we manipulated the strength of CPP across five separate studies and evaluated the effect of D-P and AT on EtOH-induced CPP following a standard unbiased CPP procedure. Mice received pairings with vehicle-saline injections with one cue and, alternatively, with AT- and D-P-EtOH with another cue. Our studies indicate that AT and D-P only disrupt CPP induced by EtOH in mice when the number of conditioning sessions and the dose of EtOH are low. These findings suggest that acquisition of EtOH-induced CPP may depend on the levels of acetaldehyde available during memory acquisition and the strength of the memory. Therefore, we propose that, at least when the memory processes are labile, brain acetaldehyde could participate in the formation of Pavlovian learning elicited by EtOH.

AbstractDefects in the ubiquitin‐proteasome system have been implicated in Parkinson's Disease (PD). Recently, a rat model of PD was developed using a synthetic proteasome inhibitor (PSI), (Z‐lle‐Glu(OtBu)‐Ala‐Leu‐al). We attempted to transfer this model to mouse studies, where genetics can be more readily investigated due to the availability of genetically modified mice. We treated C57BL/6 (B6) mice with six intraperitoneal injections of 6 mg/kg PSI in 50 μl of 70% ethanol over a 2‐week‐period. We found significant decreases in nigrostriatal dopamine in PSI‐treated mice compared with saline‐treated mice. However, we observed similar decreases in the ethanol‐treated vehicle control group. Administration of ethanol alone led to significant long‐term alterations in dopamine levels. Ethanol significantly eclipses the effects of PSI in the dopamine system, and therefore is a confounding vehicle for this model. © 2006 Movement Disorder Society

Quantitative aspects of the potentiation of GABA and muscimol by benzodiazepines and barbiturates are reviewed, taking account of both electrophysiological and receptor binding data. It has been a consistent finding that barbiturates cause a greater maximal potentiation than do benzodiazepines. The steroid anaesthetic alphaxalone and some naturally occurring steroids were compared as potentiators of electrophysiological responses to muscimol. From the relative potencies, important structural features of the steroid molecule for this effect have been identified. The possibility of the barbiturates and the steroids having a common mode of action as potentiators of GABA and muscimol is discussed, together with the idea that this action may involve perturbation of membrane lipids rather than a barbiturate/steroid receptor site. The GABA-potentiating effect of ethanol may also be barbiturate-like but potentiations by chlormethiazole and ketamine appear to involve different mechanisms. It is predicted that any endogenous potentiators of GABA would be unlikely to have more than a modest effect.

Alcohol abuse is a substantial and growing health problem in Western societies. In the last years in vivo and in vitro studies have suggested that males and females display a different alcohol drinking behaviour, with swingeing differences not only in the propensity for alcohol use but also in the metabolic and behavioural consequences. In this study we investigated, in adult female rats, ethanol self-administration and preference pattern using a 3-bottle paradigm with water, 10% ethanol solution, and white wine (10%, v/v), along a four-week period. The influence of alcohol free-access on explorative behaviour in the open field (OF), and on spatial learning and reference memory in the Morris water maze (MWM) were also evaluated. Our results indicate that: (i) female rats show a higher preference for alcohol, in the first two weeks of the paradigm, displaying a higher consumption of 10% ethanol solution than white wine; in the last two weeks, they reduce their alcoholic preference, drinking the same moderate amounts of the two alcoholic beverages; (ii) at the fourth week of the free-access paradigm rats show a lower explorative behaviour in the open field and a worsening in spatial memory retention in the Morris water maze. In conclusion our data suggest that, despite the ability to self-regulate alcohol intake, female rats suffer from relevant impairments in spatial memory retention and cognitive flexibility, displaying a sexually dimorphic modification in the adaptive strategies.

Comfortable walking speed and energy cost of walking are physiological markers of metabolic activity during gait. People with multiple sclerosis are characterized by altered gait biomechanics and energetics, related to the degree of disability and spasticity, which lead to an increased energy cost of walking. Several studies concerning the energy cost of walking in multiple sclerosis have been published. Nevertheless, differences in protocols and characteristics of the sample have led to different outcomes. The aim of the present meta-analysis is to summarize results from studies with specific inclusion characteristics, and to present data about the comfortable walking speed and the energy cost of walking at that speed. Moreover, a detailed discussion of the potential mechanisms involved in the altered metabolic activity during exercise was included. A total of 19 studies were considered, 12 of which were also part of the quantitative analysis. Despite the strict selection process, high between-group heterogeneity was found for both outcomes. Nevertheless, the overall results suggest a pooled mean comfortable walking speed of 1.12 m/s (95% CI 1.05-1.18) and energy cost of 0.19 mLO2/kg/m (95% CI 0.17-0.21). These findings support the results of previous studies suggesting that energy cost of walking may be increased by 2-3 times compared to healthy controls (HC), and encourage the use of this marker in association with other parameters of the disease.