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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.

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.

BackgroundThecAMP‐dependent protein kinase (PKA) signaling transduction pathway has been shown to play an important role in the modulation of several ethanol (EtOH)‐induced behavioral actions. In vivo, short‐term exposure to EtOH up‐regulates thecAMP‐signaling cascade. Interestingly, differentCa2+‐dependentcAMP–PKAcascade mediators play a critical role in the neurobehavioral response to EtOH, being of special relevance to theCa2+‐dependent adenylyl cyclases 1 and 8. We hypothesize an intracellularPKAactivation elicited by EtOH administration, which may be regulated by aCa2+‐dependent mechanism as an early cellular response. Thus, the present work aims to explore the role ofCa2+(internal and external) on the EtOH‐activatedPKAcascade.MethodsSwiss male mice received an intraperitoneal injection of EtOH (0 or 4 g/kg), and brains were dissected following a temporal pattern (7, 15, 30, 45, 90, or 120 minutes). Either the enzymaticPKAactivity or its fingerprint was analyzed on different brain areas (cortex, hypothalamus, hippocampus, and striatum). To explore the role ofCa2+on the EtOH‐activatedPKAcascade, mice were pretreated with diltiazem (0 or 20 mg/kg), dantrolene (0 or 5 mg/kg), or 3,7‐Dimethyl‐1‐(2‐propynyl)xanthine (0 or 1 mg/kg) 30 minutes before EtOH (4 g/kg) administration. After 45 minutes of EtOH administration, brains were removed and dissected to measure thePKAactivity or its fingerprint.ResultsResults from these experiments showed an EtOH‐dependent activation ofPKAin different brain areas. Manipulations involving a disruption of intracellularCa2+release from the endoplasmic reticulum resulted in a decreased EtOH‐induced activation ofPKA. On the contrary, extracellular‐to‐cytoplasmCa2+manipulations did not prevent thePKAactivation by EtOH.ConclusionsAltogether, these results show the critical role of storedCa2+as an intracellular mediator of different neurobiological actions of EtOH and provide further evidence of a possible new target for EtOH within the central nervous system.

Early ethanol exposure affects respiratory neuroplasticity; a risk factor associated with the Sudden Infant Death Syndrome. High and chronic ethanol doses exert long-lasting effects upon respiratory rates, apneic episodes and ventilatory processes triggered by hypoxia. The present study was performed in 3-9-day-old rat pups. Respiratory processes under normoxic and hypoxic conditions were analyzed in pups intoxicated with different ethanol doses which were pre-exposed or not to the drug. A second major goal was to examine if acute and/or chronic early ethanol exposure affects blood parameters related with hypercapnic or hypoxic states. In Experiment 1, at postnatal day 9, animals previously treated with ethanol (2.0 g/kg) or vehicle (0.0 g/kg) were tested sober or intoxicated with 0.75, 1.37 or 2.00 g/kg ethanol. The test involved sequential air conditions defined as initial normoxia, hypoxia and recovery normoxia. Motor activity was also evaluated. In Experiment 2, blood parameters indicative of possible hypoxic and hypercapnic states were assessed as a function of early chronic or acute experiences with the drug. The main results of Experiment 1 were as follows: i) ethanol's depressant effects upon respiratory rates increased as a function of sequential treatment with the drug (sensitization); ii) ethanol inhibited apneic episodes even when employing the lowest dose at test (0.75 g/kg); iii) the hyperventilatory response caused by hypoxia negatively correlated with the ethanol dose administered at test; iv) ventilatory long-term facilitation (LTF) during recovery normoxia was observed in pups pre-exposed to the drug and in pups that received the different ethanol doses at test; v) self-grooming increased in pups treated with either 1.37 or 2.00 g/kg ethanol. The main result of Experiment 2 indicated that acute as well as chronic ethanol exposure results in acidosis-hypercapnia. The results indicate that early and brief experiences with ethanol are sufficient to affect different respiratory plasticity processes as well as blood biomarkers indicative of acidosis-hypercapnia. An association between the LTF process and the acidosis-hypercapnic state caused by ethanol seems to exist. The mentioned experiences with the drug are sufficient to result in an anomalous programming of respiratory patterns and metabolic conditions.

The present paper aims at providing an objective narrative review of the existing non-pharmacological treatments for spasticity. Whereas pharmacologic and conventional physiotherapy approaches result well effective in managing spasticity due to stroke, multiple sclerosis, traumatic brain injury, cerebral palsy and incomplete spinal cord injury, the real usefulness of the non-pharmacological ones is still debated. We performed a narrative literature review of the contribution of non-pharmacological treatments to spasticity management, focusing on the role of non-invasive neurostimulation protocols (NINM). Spasticity therapeutic options available to the physicians include various pharmacological and non-pharmacological approaches (including NINM and vibration therapy), aimed at achieving functional goals for patients and their caregivers. A successful treatment of spasticity depends on a clear comprehension of the underlying pathophysiology, the natural history, and the impact on patient's performances. Even though further studies aimed at validating non-pharmacological treatments for spasticity should be fostered, there is growing evidence supporting the usefulness of non-pharmacologic approaches in significantly helping conventional treatments (physiotherapy and drugs) to reduce spasticity and improving patient's quality of life. Hence, non-pharmacological treatments should be considered as a crucial part of an effective management of spasticity.

Sardinian ethanol-preferring (sP), non-preferring (sNP), and Wistar rats show similar dopaminergic response to vanilla sugar consumption in nucleus accumbens shell (NAcS) and medial prefrontal cortex (mPFC), and similarly learn a vanilla sugar-sustained appetitive behavior. In this study we investigated whether in satiated sP, sNP, and Wistar rats vanilla sugar would also elicit a serotonergic response in NAcS and mPFC, and whether in these areas voluntary ethanol consumption would elicit dopaminergic and/or serotoninergic responses. In the NAcS, all rats showed similar serotonin increases in response to the two meals and similar development of rapid habituation. In the mPFC, Wistar and sNP rats showed similar serotonin increases after two vanilla sugar meals, while sP rats, which had low serotonin basal levels, did not show a serotonergic response. When presented with a 10% ethanol solution, Wistar and sP rats rapidly consumed it, while sNP rats did not. In the NAcS, Wistar and sP rats presented dopamine and serotonin increases in response to ethanol. However, while Wistar rats showed habituation in their response, sP rats did not. In the mPFC, ethanol induced similar dopamine increases in Wistar and sP rats; serotonin increases were observed only in Wistar rats. In conclusion, all three lines showed increased serotonin release in response to palatable food, but they profoundly differed in their response to ethanol. In fact, only Wistar and sP rats drank ethanol, Wistar rats showed a monoaminergic response similar to that obtained after palatable food, while sP rats did not develop habituation, suggesting that they perceived ethanol as a more relevant stimulus.