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Some of the behavioral consequences of deficits in N-methyl-D-aspartate (NMDA) glutamate receptor function are thought to arise from the disinhibition of cortical glutamatergic circuitry. This study evaluated whether pretreatment with a drug that reduces glutamatergic activation, the group II metabotropic glutamate receptor (mGluR) agonist, LY354740, reduced the cognitive effects of the NMDA glutamate receptor antagonist, ketamine, in healthy human subjects. Nineteen healthy human subjects completed 3 test days during which LY354740 (matched placebo, 100 mg, 400 mg) was administered under double-blind conditions 4 h prior to the single-blind intravenous administration of saline and 5.7 h prior to ketamine administration (bolus of 0.26 mg/kg over 1 min, infusion of 0.65 mg/kg per hour for 100 min). Thus on each test day each subject received a single dose of LY354740 (or its matched placebo) and both saline and ketamine infusions. Ketamine impaired attention, working memory, and delayed recall. It also produced positive and negative symptoms, perceptual changes, and dysphoric mood. LY354740 did not have a significant effect on working memory on the placebo day; however, it produced a significant dose-related improvement in working memory during ketamine infusion. These data provide preliminary and suggestive evidence that LY354740 or other group II mGluR agonists might play a role in treating working memory impairment related to deficits in NMDA receptor function.

Sleep has a pivotal role in the consolidation of declarative memory. The coordinated neuronal replay of information encoded before sleep has been identified as a key process. It is assumed that the repeated reactivation of firing patterns in glutamatergic neuron assemblies translates into plastic synaptic changes underlying the formation of longer-term neuronal representations. Here, we tested the effects of blocking and enhancing glutamatergic neurotransmission during sleep on declarative memory consolidation in humans. We conducted three placebo-controlled, crossover, double-blind studies in which participants learned a word-pair association task. Afterwards, they slept in a sleep laboratory and received glutamatergic modulators. Our first two studies aimed at impairing consolidation by administering the NMDA receptor blocker ketamine and the AMPA receptor blocker caroverine during retention sleep, which, paradoxically, remained unsuccessful, inasmuch as declarative memory performance was unaffected by the treatment. However, in the third study, administration of the NMDA receptor coagonist D-cycloserine (DCS) during retention sleep facilitated consolidation of declarative memory (word pairs) but not consolidation of a procedural control task (finger sequence tapping). Administration of DCS during a wake interval remained without effect on retention of word pairs but improved encoding of numbers. From the overall pattern, we conclude that the consolidation of hippocampus-dependent declarative memory during sleep relies on NMDA-related plastic processes that differ from those processes leading to wake encoding. We speculate that glutamatergic activation during sleep is not only involved in consolidation but also in forgetting of hippocampal memory with both processes being differentially sensitive to DCS and unselective blockade of NMDA and AMPA receptors.

A meta-analysis was conducted to evaluate the effects of branched-chain amino acids (BCAA), their interactions, and interactions with large neutral amino acids (LNAA) to develop prediction equations for growth performance of pigs. Data from 25 papers, published from 1995 to 2018, for a total of 44 trials and 210 observations were recorded in a database. Diets were reformulated using the NRC (2012) loading values to estimate nutrient concentrations. The response variables were average daily gain (ADG), average daily feed intake (ADFI), and gain-to-feed ratio (G:F). The predictor variables tested included average body weight (BW), crude protein, neutral detergent fiber, Ile:Lys, Leu:Lys, Val:Lys, BCAA:Lys, Ile:Leu, Val:Leu, Ile:Val, (Ile+Val):Leu, Trp:Lys, Leu:Trp, Ile:Trp, Val:Trp, BCAA:Trp, Met:Lys, Leu:Met, Ile:Met, Val:Met, BCAA:Met, His:Lys, Leu:His, Ile:His, Val:His, BCAA:His, Thr:Lys, Leu:Thr, Ile:Thr, Val:Thr, BCAA:Thr, (Phe+Tyr):Lys, Leu:(Phe+Tyr), Ile:(Phe+Tyr), Val:(Phe+Tyr), BCAA:(Phe+Tyr), LNAA:Lys, Leu:LNAA, Ile:LNAA, Val:LNAA, and BCAA:LNAA. Amino acids were expressed on standardized ileal digestible basis. The MIXED procedure of SAS (SAS Institute Inc., Cary, NC) was used to develop the equations. The inverse of squared SEM was used to account for heterogeneous errors using the WEIGHT statement. Models were selected with a step-wise manual forward selection. In order to be included in the final model, predictor variables had to be statistically significant (P < 0.05) and provide an improvement of at least 2 points in Bayesian information criterion. The optimum equations were: ADG, g = - 985.94 + (15.2499 × average BW (kg)) - (0.08885 × average BW × average BW) + (1.063 × Leu:Lys) + (20.2659 × Ile:Lys) - (0.1479 × Ile:Lys × Ile:Lys) + (9.2243 × (Ile+Val):Leu) - (0.03321 × (Ile+Val):Leu × (Ile+Val):Leu) - (0.4413 × Ile:Trp); G:F, g/kg = 648.3 - (6.2974 × average BW (kg)) + (0.02051 × average BW × average BW) + (0.5396 × Ile:Lys) + (1.7284 × Val:Lys) - (0.00795 × Val:Lys × Val:Lys) - (1.7594 × Met:Lys); and ADFI, kg = predicted ADG/predicted G:F. Overall, the prediction equations suggest that increasing Leu:Lys negatively impacts ADG due to a reduction in G:F and ADFI caused by insufficient levels of other BCAA and LNAA relative to Leu. According to the model, the addition of Val, Ile, and Trp, alone or in combination, has the potential to counteract the negative effects of high dietary Leu concentrations on growth performance.

Owing to the great demand for healthy ageing promotion, and the anti-ageing reputation of anthocyanins and amino acids, we aimed to assess the effect of anthocyanin- and anti-ageing amino acids-enriched pigmented rice innovation on age-related cognitive decline, facial wrinkles, and a cardiovascular risk, and explored its mechanisms and safety. A total of 90 male and female volunteers (45–65 years old) participated in a 3-arm randomized, double blinded, placebo-controlled parallel study for 12 weeks. They were randomly allocated to one of the following groups: placebo, “Zuper rice” (Zup) 2 g/day and “Zuper Rice” 4 g/day. Cognition, facial wrinkles, atherogenic index in plasma (AIP), telomere length, telomerase, oxidative stress and inflammatory markers, together with safety parameters, were assessed every 6 weeks until the end of the study and compared to the baseline data. A high dose of “Zup” improved cognition, facial wrinkles, AIP and oxidative stress, while a low dose of “Zup” improved cognition, telomere length, telomerase and inflammation. No toxicity signs were observed. Therefore, “Zup” is a potential healthy ageing promotion innovation which improves telomere length, telomerase activity and inflammation at a low dose, resulting in an improvement in cognitive decline and the suppression of oxidative stress. At a high dose, it gives rise to improvements in cognition, facial wrinkles and cardiovascular risk.

Background and Objectives: Many patients develop a prolonged decrease of muscle strength after total hip arthroplasty (THA) despite their reconstructed hip joint. Physical exercise combined with branched-chain amino acid (BCAA) supplementation has been reported to improve muscle strength in elderly persons with sarcopenia. However, the effect of BCAA supplementation in patients after THA is unknown. This study examined the effects of BCAA supplementation combined with exercise therapy on the improvement of physical function in elderly patients after THA. Methods and Study Design: The subjects were 31 elderly women who underwent THA. The participants were randomly assigned to two groups: BCAA (n=18) and control (n=13). The combined therapy was carried out for one month after THA. For the exercise intervention, a 3-set physical exercise program was conducted. For the nutritional intervention, the participants consumed 3.4 g of BCAA supplement or 1.2 g of starch immediately after the exercise intervention. Results: BCAA supplementation combined with muscle strengthening exercises had a significant effect on knee extension strength of the contralateral side and on upper arm cross-sectional area. The improvement ratio of knee extension strength before and after intervention on the operated side was also significantly higher in the BCAA group. Conclusions: BCAA supplementation is effective for patients to improve the strength of some muscles when combined with physical exercises, but hip abductor muscle strength of the operated leg did not improve. A future study is needed to determine the efficacy of this combined therapy for hip abductor muscle strength.

ObjectiveTo evaluate the safety and efficacy of Cerebrolysin as an add-on therapy to local standard treatment protocol in patients after moderate-to-severe traumatic brain injury.MethodsThe patients received the study medication in addition to standard care (50 mL of Cerebrolysin or physiological saline solution daily for 10 days, followed by two additional treatment cycles with 10 mL daily for 10 days) in a prospective, randomized, double-blind, placebo-controlled, parallel-group, multi-centre phase IIIb/IV trial. The primary endpoint was a multidimensional ensemble of 14 outcome scales pooled to be analyzed by means of the multivariate, correlation-sensitive Wei-Lachin procedure.ResultsIn 46 enrolled TBI patients (Cerebrolysin 22, placebo 24), three single outcomes showed stand-alone statistically significant superiority of Cerebrolysin [Stroop Word/Dots Interference (p = 0.0415, Mann–Whitney(MW) = 0.6816, 95% CI 0.51–0.86); Color Trails Tests 1 and 2 (p = 0.0223/0.0170, MW = 0.72/0.73, 95% CI 0.53–0.90/0.54–0.91), both effect sizes lying above the benchmark for “large” superiority (MW > 0.71)]. While for the primary multivariate ensemble, statistical significance was just missed in the intention-to-treat population (pWei-Lachin < 0.1, MWcombined = 0.63, 95% CI 0.48–0.77, derived standardized mean difference (SMD) 0.45, 95% CI −0.07 to 1.04, derived OR 2.1, 95% CI 0.89–5.95), the per-protocol analysis showed a statistical significant superiority of Cerebrolysin (pWei-Lachin = 0.0240, MWcombined = 0.69, 95% CI 0.53 to 0.85, derived SMD 0.69, 95% CI 0.09 to 1.47, derived OR 3.2, 95% CI 1.16 to 12.8), with effect sizes of six single outcomes lying above the benchmark for “large” superiority. Safety aspects were comparable to placebo.ConclusionOur trial suggests beneficial effects of Cerebrolysin on outcome after TBI. Results should be confirmed by a larger RCT with a comparable multidimensional approach.

Emerging literature implicates abnormalities in gamma frequency oscillations in the pathophysiology of schizophrenia, with hypofunction of N-methyl-D-aspartate (NMDA) receptors implicated as a key factor. Prepulse inhibition (PPI) is a behavioural measure of sensorimotor gating, which is disrupted in schizophrenia. We studied relationships between ongoing and sensory-evoked gamma oscillations and PPI using pharmacological interventions designed to increase gamma oscillations (ketamine, MK-801); reduce gamma oscillations (LY379268); or disrupt PPI (amphetamine). We predicted that elevating ongoing gamma power would lead to increased ‘neural noise’ in cortical circuits, dampened sensory-evoked gamma responses and disrupted behaviour. Wistar rats were implanted with EEG recording electrodes. They received ketamine (5 mg/kg), MK-801 (0.16 mg/kg), amphetamine (0.5 mg/kg), LY379268 (3 mg/kg) or vehicle and underwent PPI sessions with concurrent EEG recording. Ketamine and MK-801 increased the power of ongoing gamma oscillations and caused time-matched disruptions of PPI, while amphetamine marginally affected ongoing gamma power. In contrast, LY379268 reduced ongoing gamma power, but had no effect on PPI. The sensory gamma response evoked by the prepulse was reduced following treatment with all psychotomimetics, associating with disruptions in PPI. This was most noticeable following treatment with NMDA receptor antagonists. We found that ketamine and MK-801 increase ongoing gamma power and reduce evoked gamma power, both of which are related to disruptions in sensorimotor gating. This appears to be due to antagonism of NMDA receptors, since amphetamine and LY379268 differentially impacted these outcomes and possess different neuropharmacological substrates. Aberrant gamma frequency oscillations caused by NMDA receptor hypofunction may mediate the sensory processing deficits observed in schizophrenia.

Huntington’s disease (HD) is a neurodegenerative disease for which there is no curative treatment available. Given that the endocannabinoid system is involved in the pathogenesis of HD mouse models, stimulation of specific targets within this signaling system has been investigated as a promising therapeutic agent in HD. We conducted a double-blind, randomized, placebo-controlled, cross-over pilot clinical trial with Sativex ® , a botanical extract with an equimolecular combination of delta-9-tetrahydrocannabinol and cannabidiol. Both Sativex ® and placebo were dispensed as an oral spray, to be administered up to 12 sprays/day for 12 weeks. The primary objective was safety, assessed by the absence of more severe adverse events (SAE) and no greater deterioration of motor, cognitive, behavioral and functional scales during the phase of active treatment. Secondary objectives were clinical improvement of Unified Huntington Disease Rating Scale scores. Twenty-six patients were randomized and 24 completed the trial. After ruling-out period and sequence effects, safety and tolerability were confirmed. No differences on motor ( p  = 0.286), cognitive ( p  = 0.824), behavioral ( p  = 1.0) and functional ( p  = 0.581) scores were detected during treatment with Sativex ® as compared to placebo. No significant molecular effects were detected on the biomarker analysis. Sativex ® is safe and well tolerated in patients with HD, with no SAE or clinical worsening. No significant symptomatic effects were detected at the prescribed dosage and for a 12-week period. Also, no significant molecular changes were observed on the biomarkers. Future study designs should consider higher doses, longer treatment periods and/or alternative cannabinoid combinations. Clincaltrals.gov identifier: NCT01502046

Rationale Alcohol use disorders are associated with deficits in adaptive behavior. While some behavioral impairments that are associated with alcohol use disorders may predate exposure to drugs of abuse, others may result directly from exposure to drugs of abuse, including alcohol. Identifying a causal role for how alcohol exposure leads to these impairments will enable further investigation of the neurobiological mechanisms by which it acts to dysregulate adaptive behavior. Objectives In the present study, we examined the effects of chronic intermittent ethanol exposure (CIE) on the use of reward-paired cues to guide consummatory behaviors in a mouse model, and further, how manipulations of mGluR2/3 signaling—known to be dysregulated after chronic alcohol exposure—may alter the expression of this behavior. Methods Adult male C57B/6J mice were trained to self-administer 10 % ethanol and exposed to CIE via vapor inhalation. After CIE exposure, mice were trained in a Pavlovian task wherein a cue (tone) was paired with the delivery of a 10 % sucrose unconditioned stimulus. The use of the reward-paired cue to guide licking behavior was determined across training. The effect of systemic mGluR2/3 manipulation on discrimination between cue-on and cue-off intervals was assessed by administration of the mGluR2/3 agonist LY379268 or the antagonist LY341495 prior to a testing session. Results Exposure to CIE resulted in reductions in discrimination between cue-on and cue-off intervals, with CIE-exposed mice exhibiting significantly lower consummatory behavior during reward-paired cues than air controls. In addition, systemic administration of an mGluR2/3 agonist restored the use of reward-paired cues in CIE-exposed animals without impacting behavior in air controls. Conversely, administration of an mGluR2/3 antagonist mimicked the effects of CIE on cue-guided licking behavior, indicating that mGluR2/3 signaling can bidirectionally regulate the ability to use reward-paired cues to guide behavior. Conclusions Together, these data suggest that chronic ethanol exposure drives impairments in the ability to use reward-paired cues to adaptively regulate behavior and that mGluR2/3 receptors represent a therapeutic target for restoration of these deficits in behavioral control in the alcoholic.

Reward sensitivity and possible alterations in the dopaminergic-reward system are associated with obesity. We therefore aimed to investigate the influence of dopamine depletion on food-reward processing. We investigated 34 female subjects in a randomized placebo-controlled, within-subject design (body mass index (BMI)=27.0 kg/m(2) ±4.79 SD; age=28 years ±4.97 SD) using an acute phenylalanine/tyrosine depletion drink representing dopamine depletion and a balanced amino acid drink as the control condition. Brain activity was measured with functional magnetic resonance imaging during a 'wanting' and 'liking' rating of food items. Eating behavior-related traits and states were assessed on the basis of questionnaires. Dopamine depletion resulted in reduced activation in the striatum and higher activation in the superior frontal gyrus independent of BMI. Brain activity during the wanting task activated a more distributed network than during the liking task. This network included gustatory, memory, visual, reward, and frontal regions. An interaction effect of dopamine depletion and the wanting/liking task was observed in the hippocampus. The interaction with the covariate BMI was significant in motor and control regions but not in the striatum. Our results support the notion of altered brain activity in the reward and prefrontal network with blunted dopaminergic action during food-reward processing. This effect is, however, independent of BMI, which contradicts the reward-deficiency hypothesis. This hints to the hypothesis suggesting a different or more complex mechanism underlying the dopaminergic reward function in obesity.