Intradermal Glycine Detection with a Wearable Microneedle Biosensor: The First In Vivo Assay.

Glycine (GLY) is gaining importance in medical diagnoses due to its relationship with multiple physiological functions. Today, GLY is exclusively analyzed using instrumentation centralized in clinical labs, and a tangible point-of-care tool that gathers real-time data from the patient for effective and fast evaluations is lacking. Relevant clinical advances are expected as soon as the rapid provision of both punctual and continuous measurements is possible. In that context, this work presents a microneedle (MN)-based biosensor for intradermal GLY detection in interstitial fluid (ISF). The MN tip is externally tailored to detect GLY levels through the hydrogen peroxide formed in its reaction with a quinoprotein-based GLY oxidase enzyme. The analytical performance of the MN biosensor indicates a fast response time (<7 s); acceptable reversibility, reproducibility, and stability; as well as a wide linear range of response (25-600 µM) that covers the physiological levels of GLY in ISF. The MN biosensor conveniently exhibits high selectivity for GLY over other compounds commonly found in ISF, and the response is not influenced by temperature, pH, or skin insertions. Validated intradermal measurements of GLY were obtained at the in vitro (with pieces of rat skin), ex vivo (on-body tests of euthanized rats) and in vivo (on-body tests of anesthetized rats) levels, demonstrating its ability to produce accurate physiological data. The developed GLY MN biosensor is skin-wearable and provides reliable, real-time intradermal GLY measurements in ISF by means of a minimally invasive approach.

The effects of alcohol mixed with energy drink (AMED) on subjective intoxication and alertness: results from a double-blind placebo-controlled clinical trial.

OBJECTIVE: The purpose of this double blind placebo controlled study was to examine if specific effects on subjective intoxication and alertness-sleepiness ratings could be demonstrated after consuming alcohol mixed with energy drink (AMED) when compared to consuming alcohol only (AO). METHODS: 56 healthy volunteers rated their subjective intoxication on a scale ranging from 0 (sober) to 10 (highly intoxicated) at baseline, breath alcohol concentration (BAC) of 0%, and at BAC 0.08%, 0.05%, and 0.02%. Alertness-sleepiness was assessed with the Karolinska sleepiness scale. Scores of the AMED and AO condition, at each BAC level, were compared. RESULTS: Subjective intoxication for AMED and AO did not differ significantly from each other at any BAC level, except for BAC 0.02%. A significant increase in sleepiness scores was found in the AO condition, whereas scores remained stable in the AMED condition. Sleepiness scores at BAC0.08% and 0.05% were significantly lower after AMED when compared to AO. However, the observed differences between AMED and AO were small and have no clinical relevance. CONCLUSION: Mixing alcohol with energy drink had no overall masking effect on subjective intoxication caused by alcohol, nor had a relevant effect on subjective alertness-sleepiness ratings. Copyright © 2016 John Wiley & Sons, Ltd.

Sex-specific differences and similarities of olanzapine and risperidone on avoidance suppression in rats in the conditioned avoidance response test.

It is well known that antipsychotic drugs (APDs) are more effective in reducing symptoms in women than in men, and that women are more sensitive to the side effects of APDs. Therefore, it is of great importance that sex differences in drug responses are considered already in the early stages of drug development. In this study, we investigated whether sex-specific differences could be observed in response to the commonly prescribed APDs olanzapine and risperidone using the conditioned avoidance response (CAR) test. To this end we tested the effect of 1.25 and 2.5 mg/kg olanzapine and 0.25 and 0.4 mg/kg risperidone using female and male Wistar rats in the CAR test. Whereas there were no significant differences between the female and male rats in response to either dose of olanzapine administration, an injection of 0.4 mg/kg risperidone significantly suppressed avoidance more in female rats than in male rats. In addition, we found that the estrous cycle of the female rats did not have a significant effect on the avoidance response. In conclusion, we show that there are sex-specific differences as well as similarities between female and male rats in the CAR test and novel APDs should be tested on female and male rats in the future.

Sodium nitroprusside enhances the antipsychotic-like effect of olanzapine but not clozapine in the conditioned avoidance response test in rats.

The nitric oxide (NO)-donor, sodium nitroprusside (SNP) has been proposed as an adjunct treatment to enhance the effect of antipsychotic drugs (APDs). As NO constitutes an important downstream signaling molecule of N-methyl-D-aspartate receptors, SNP may alleviate symptoms of schizophrenia by modulating glutamatergic signaling. We previously showed that SNP enhances the antipsychotic-like effect of a sub-effective dose of risperidone in the conditioned avoidance response (CAR) test, indicating that adjunct SNP may be used to lower the dose of risperidone and in this way reduce the risk of side effects. By using the CAR test, we here investigated if SNP also enhances the antipsychotic-like effect of olanzapine or clozapine. Importantly, SNP (1.5 mg/kg) significantly enhanced the antipsychotic-like effect of olanzapine (1.25 and 2.5mg/kg) to a clinically relevant level, supporting the potential clinical use of SNP as an adjunct treatment to improve the effect of APDs. However, SNP (1.5 mg/kg) did not increase the antipsychotic-like effect of clozapine (5 and 6 mg/kg). Moreover, we found that the rats developed tolerance towards clozapine after repeated administrations. Thus, our study motivates further investigation using different preclinical models to assess the effect of adjunct treatment of SNP to APDs, also targeting the negative symptoms and cognitive deficits seen in schizophrenia.

The Importance of Ventral Hippocampal Dopamine and Norepinephrine in Recognition Memory.

Dopaminergic neurons originating from the ventral tegmental area (VTA) and the locus coeruleus are innervating the ventral hippocampus and are thought to play an essential role for efficient cognitive function. Moreover, these VTA projections are hypothesized to be part of a functional loop, in which dopamine regulates memory storage. It is hypothesized that when a novel stimulus is encountered and recognized as novel, increased dopamine activity in the hippocampus induces long-term potentiation and long-term storage of memories. We here demonstrate the importance of increased release of dopamine and norepinephrinein the rat ventral hippocampus on recognition memory, using microdialysis combined to a modified novel object recognition test. We found that presenting rats to a novel object significantly increased dopamine and norepinephrine output in the ventral hippocampus. Two hours after introducing the first object, a second object (either novel or familiar) was placed in the same position as the first object. Presenting the animals to a second novel object significantly increased dopamine and norepinephrine release in the ventral hippocampus, compared to a familiar object. In conclusion, this study suggests that dopamine and norepinephrine output in the ventral hippocampus has a crucial role in recognition memory and signals novelty.

Enhancement of the antipsychotic effect of risperidone by sodium nitroprusside in rats.

Recently, a single injection of the nitric oxide donor sodium nitroprusside (SNP) was found to induce a rapid and sustained antipsychotic effect in treatment-resistant schizophrenia (TRS). Moreover, a single i.p. injection of SNP in rats was found to generate both rapid and persisting changes in brain synaptic plasticity, including enhanced excitatory postsynaptic current responses and spine morphology in layer V pyramidal cells in the medial prefrontal cortex (mPFC) brain slices. Here we used the conditioned avoidance response (CAR) test in rats to investigate the antipsychotic-like efficacy of SNP in combination with low-dose risperidone. In addition, we performed microdialysis experiments in freely moving rats to measure neurotransmitter efflux in the mPFC and the nucleus accumbens (NAc). Risperidone caused only 20% suppression of CAR, which is far below the degree of CAR suppression required to predict a significant clinical antipsychotic effect. Addition of a low dose of SNP to risperidone dramatically enhanced the antipsychotic-like effect to a clinically relevant level. SNP significantly enhanced the risperidone-induced dopamine output in the mPFC but not in the NAc. The increased prefrontal dopamine release induced by the drug combination may also improve cognition as indicated by previous preclinical and clinical studies and, furthermore, via enhanced synaptic spine function and morphology in mPFC generate a both rapid and prolonged antipsychotic and pro-cognitive effect. Our results delineate SNP as a promising new treatment option for schizophrenia, including TRS, when added to currently available antipsychotic medication in order to improve efficacy at maintained or even reduced dosage.