Ganoderma lucidum promotes sleep through a gut microbiota-dependent and serotonin-involved pathway in mice.

Ganoderma lucidum is a medicinal mushroom used in traditional Chinese medicine with putative tranquilizing effects. However, the component of G. lucidum that promotes sleep has not been clearly identified. Here, the effect and mechanism of the acidic part of the alcohol extract of G. lucidum mycelia (GLAA) on sleep were studied in mice. Administration of 25, 50 and 100 mg/kg GLAA for 28 days promoted sleep in pentobarbital-treated mice by shortening sleep latency and prolonging sleeping time. GLAA administration increased the levels of the sleep-promoting neurotransmitter 5-hydroxytryptamine and the Tph2, Iptr3 and Gng13 transcripts in the sleep-regulating serotonergic synapse pathway in the hypothalamus during this process. Moreover, GLAA administration reduced lipopolysaccharide and raised peptidoglycan levels in serum. GLAA-enriched gut bacteria and metabolites, including Bifidobacterium, Bifidobacterium animalis, indole-3-carboxylic acid and acetylphosphate were negatively correlated with sleep latency and positively correlated with sleeping time and the hypothalamus 5-hydroxytryptamine concentration. Both the GLAA sleep promotion effect and the altered faecal metabolites correlated with sleep behaviours disappeared after gut microbiota depletion with antibiotics. Our results showed that GLAA promotes sleep through a gut microbiota-dependent and serotonin-associated pathway in mice.

ß-sitosterol reduces anxiety and synergizes with established anxiolytic drugs in mice.

Anxiety and stress-related conditions represent a significant health burden in modern society. Unfortunately, most anxiolytic drugs are prone to side effects, limiting their long-term usage. Here, we employ a bioinformatics screen to identify drugs for repurposing as anxiolytics. Comparison of drug-induced gene-expression profiles with the hippocampal transcriptome of an importin α5 mutant mouse model with reduced anxiety identifies the hypocholesterolemic agent ß-sitosterol as a promising candidate. ß-sitosterol activity is validated by both intraperitoneal and oral application in mice, revealing it as the only clear anxiolytic from five closely related phytosterols. ß-sitosterol injection reduces the effects of restraint stress, contextual fear memory, and c-Fos activation in the prefrontal cortex and dentate gyrus. Moreover, synergistic anxiolysis is observed when combining sub-efficacious doses of ß-sitosterol with the SSRI fluoxetine. These preclinical findings support further development of ß-sitosterol, either as a standalone anxiolytic or in combination with low-dose SSRIs.

N-Acetylcysteine Augmentation for Patients With Major Depressive Disorder and Bipolar Depression.

Major depressive disorder (MDD) and bipolar depression (BD) can often be difficult to treat. N-acetylcysteine (NAC) is a nutraceutical product that has been trialed in a large number of neuropsychiatric and medical disorders, with mixed results. Many randomized controlled trials (RCTs) have studied NAC augmentation as an intervention in MDD and BD. These RCTs were pooled in 2 recent meta-analyses. One meta-analysis with 7 RCTs (pooled N = 728) conducted in patients with MDD or BD found that NAC was not superior to placebo in the attenuation of depression ratings in either main or sensitivity analyses. The other meta-analysis with 6 RCTs (pooled N = 248) conducted in patients with BD found a small, imprecise effect size for NAC (standardized mean difference, 0.45; 95% confidence interval, 0.06-0.84). The advantage for NAC in this meta-analysis would almost certainly have been lost had the authors excluded from analysis 2 RCTs, both of which had problematic characteristics and findings and both of which also obtained a large and statistically significant advantage for NAC. At present, therefore, evidence does not encourage the use of NAC as an augmentation treatment for patients with MDD or BD. It remains to be seen whether NAC augmentation benefits depressed subpopulations, such as those with higher levels of inflammatory biomarkers at baseline.

Etizolam: A rapid review on pharmacology, non-medical use and harms.

ISSUES: Etizolam is a thienodiazepine derivative, with high affinity for the benzodiazepine site of GABAA receptors. It is often referred to as a new (or novel) psychoactive substance, a 'designer' benzodiazepine or a 'street benzodiazepine'. Increasing reports of non-medical use, identification of etizolam as an ingredient in counterfeit medications and the common identification of etizolam in drug-related deaths, highlight the need for a greater understanding of etizolam. APPROACH: A rapid narrative review was conducted using PubMed and Google Scholar to synthesise what is known about etizolam to answer two research questions: (i) Does the pharmacological or toxicological profile of etizolam differ from other benzodiazepines?; and (ii) What is the nature and context of non-medical use and harms related to etizolam? KEY FINDINGS: Etizolam has a higher potency as an anxiolytic but lower lethality compared with diazepam. Few harms are documented with the therapeutic use of pharmaceutical products. Harms appear to be predominantly related to the use of etizolam in illicitly manufactured pills and occur almost exclusively in the context of mixed-drug toxicity. CONCLUSION: In therapeutic doses, there is little to suggest that etizolam is more harmful than other benzodiazepines. Most harms with etizolam appear to be related to the wide availability of illicitly manufactured pills, which are taken in unknown doses and combined with other substances. Current harm reduction advice, including avoiding combining opioids and benzodiazepines, remains relevant and increasingly important within an emerging culture of non-medical use.

Effects of Gaba Derivatives on Anxious and Compulsive Behavior in Offspring of Rats with Experimental Preeclampsia.

We studied the effects of GABA derivatives on anxious and compulsive behavior of progeny of rats with experimental preeclampsia provoked by replacement of drinking water for 1.8% NaCl solution from the first day of pregnancy to delivery. In comparison with progeny of health rats, the offspring of dams with complicated pregnancy demonstrated high level of anxiety and the development of obsessive-compulsive disorder both at the early (40 and 70 days) and late (6 and 12 months) stages of ontogeny. GABA derivatives succicard, salifen, and phenibut reduced symptoms of experimental preeclampsia in offspring of various age by decreasing the level of anxiety and reducing compulsive behavior. The efficacy of the examined derivatives was similar to that of the reference drug Pantogam.

Serum testosterone levels in bipolar and unipolar depressed female patients and the role of medication status.

Objective: to compare testosterone levels between female depressed patients and female bipolar patients.Methods: Sixty-one female patients with major depressive disorder (MDD) (n = 23) or bipolar disorder (BD) (n = 38) between 18 and 45 years old were included in the study. Participants were evaluated during a depressive or manic episode with the Hamilton depression rating scale (HDRS) or Young mania rating scale (YMRS), respectively. No patients in the MDD group were taken valproate while in the BD group 14 (36.84%) were taken valproate. Total testosterone (TT) and free testosterone (FT) levels were quantified during the early follicular phase of the cycle, with radioimmunoassay or solid phase enzyme-linked immunoassay. Data were collected from May 2016 to February 2017.Results: Mean TT serum levels were significantly higher in BD patients in comparison to MDD patients. Although age and diagnosis were related to TT levels, however when we added valproate use in the analysis, only the relation between TT and valproate use remained significant.Conclusions: In this sample, TT levels were related to valproate use in patients with BD. More studies regarding the role of testosterone in affective symptoms should be conducted to clarify the relation between testosterone, affective disorders, and medication.KeypointsWe observed that testosterone levels were significant higher in bipolar women compared to women with MDD.The use of valproate could be associated with the testosterone levels in female patients with BD.Evaluation of women suffering BD should include a testosterone levels determination, particularly when they are taking valproate.

Binding of Glyprolines to L-Arginine Inverts Its Analgesic and Antiagressogenic Effects.

We studied the effects of intraperitoneal administration of L-arginine in doses of 5, 15, and 50 µg/kg and peptides in doses containing equimolar amount of this amino acid on aggressive-defensive behavior of rats (footshock model). The peptides were synthesized by binding of Pro-Gly-Pro sequence to one or both ends of the L-arginine molecule. The analgesic and antiagressogenic effects of L-arginine and opposite effects of arginine-containing peptides (except Pro-Gly-Pro tripeptide) were demonstrated. The combination of arginine with glyprolines yielded peptides with intrinsic regulatory properties. This expands the possibilities of synthesis of drugs for correction of pain and aggression caused by pain.

Sources of Prescription Medication Misuse Among Young Adults in the United States: The Role of Educational Status.

OBJECTIVE: This study examined prescription drug misuse (PDM), sources of PDM, and substance use disorder (SUD) symptoms as a function of educational status among US young adults based on a large nationally representative sample. METHODS: Data from the 2009-2014 National Survey on Drug Use and Health came from a sample of 106,845 young adults aged 18-25 years. Respondents were categorized by educational status and PDM, sources of PDM, other substance use, and SUD symptoms, with analyses performed separately for prescription opioids, stimulants, and sedatives/tranquilizers. RESULTS: Prescription opioid (past-year: 11.9%) and sedative/tranquilizer (past-year: 5.8%) misuse were most prevalent among young adults not attending college, especially among high school dropouts. In contrast, full-time college students and college graduates had the highest rates of prescription stimulant misuse (past-year: 4.3% and 3.9%, respectively). Obtaining prescription medications from friends/relatives for free was the most common source of PDM, especially among college students/graduates. Prescription drug misusers who obtained medications from theft/fake prescriptions, purchases, or multiple sources were more likely to report past-year SUDs and had the most severe overall risk profile of concurrent substance use and SUD. More than 70% of past-month prescription drug misusers who reported multiple sources for PDM had at least 1 past-year SUD. CONCLUSIONS: Sources of PDM vary by educational status among US young adults, and the college environment is associated with sharing prescription medications. Clinicians can help assess an individual's risk for SUD by determining whether the individual engaged in PDM and the source of prescription medication the individual is misusing.

Effects of Tripeptide Gly-His-Lys in Pain-Induced Aggressive-Defensive Behavior in Rats.

We studied the effect of Gly-His -Lys tripeptide administered intraperitoneally in doses of 5, 15, 50 and 150 µg/kg on pain-induced aggressive-defensive behavior. A foot-shock model of aggression in rats grouped in pairs in an electrified chamber was used. Analgesic and antiaggresiogenic effects of the peptide were demonstrated. It was found the L-lysine residue plays the key role in these effects, because they were observed under the influence of L-lysine administration in doses close to its equimolar content in the studied tripeptide.

Effects of Oxytocin on the Levels and Metabolism of Monoamines in the Brain of White Outbred Mice during Long-Term Social Isolation.

The effects of intranasal administration of oxytocin on the levels and metabolism of monoamines in symmetrical structures of the brain of white outbred mice kept under conditions of long-term social isolation were studied by HPLC. Disappearance of initial right-sided asymmetry in the content of dopamine metabolites in the striatum, increased 5-hydroxyacetic acid content in the right striatum, and disappearance of the initial left-sided asymmetry in serotonin level in the cortex were noted; we also found a decrease in norepinephrine content in the left hippocampus with appearance of asymmetry and higher content in the right olfactory tubercle. It can be hypothesized that minor changes in the serotoninergic and dopaminergic systems against the background of high reactivity of noradrenergic system represent specific response of the brain to oxytocin in aggressive animals.

High-intensity drinking and nonmedical use of prescription drugs: Results from a national survey of 12th grade students.

BACKGROUND: Nearly 10% of U.S. 12th graders report high-intensity drinking (10+ or 15+ drinks in a row), but the extent to which these drinkers also engage in nonmedical use of prescription drugs (NMUPD) is largely unknown. This study examined the associations between different thresholds of past two-week high-intensity drinking and past-month NMUPD among U.S. 12th graders. METHODS: The sample consisted of eleven nationally representative cross-sections of 12th graders in the Monitoring the Future study (2005-2015) who answered questions on past two-week drinking behaviors and past-month nonmedical use of prescription opioids, sedative, stimulants, and tranquilizers (N=26,502 respondents). RESULTS: High-intensity drinking during the past two-weeks was associated with an increased risk of past-month NMUPD. The odds of NMUPD were four times larger among 12th graders who indicated drinking 15 or more drinks on at least one occasion (AOR=4.43, 95% CI=3.18, 5.01) relative to those who had 0-4 drinks during the past two-weeks, after adjusting for relevant covariates. These associations were similar across different classes of prescription drugs and tended to be stronger among non-white respondents. A sub-analysis revealed simultaneous co-ingestion of alcohol and NMUPD was more prevalent among high-intensity drinkers. CONCLUSIONS: More than 1 in every 4 U.S 12th graders who engage in high-intensity drinking (15+ drinks in a row) also report NMUPD. Given the greater likelihood of simultaneous co-ingestion of alcohol and prescription drugs among high-intensity drinkers, adolescent substance use interventions need to address the risks associated with mixing alcohol and prescription drugs.

[Noninvasive ventilation and sedation: evidence and practical tools for its utilization]. / Ventilazione non invasiva e sedazione: evidenze a supporto e consigli pratici.

Noninvasive ventilation (NIV) has gained increased acceptance inside the critical area, since it has been shown to be effective in reducing or avoiding the need for oro-tracheal intubation. NIV efficacy is dependent on the selection of the appropriate patients and on their compliance to therapy. Actually, full collaboration is not easily reached especially in agitated patients.Sedation during NIV is useful to reduce the rate of treatment failure, but robust data to guide the development of best practice are limited and sometimes local customs appear to exert a strong influence on patterns of care. Different sedative drugs are ready for use but none of currently available agents fulfill the criteria for the ideal drug. Knowledge of the pharmacological and hemodynamic characteristics of every single sedative agent is crucial to choose the right drug for every clinical scenario. Close monitoring is mandatory to avoid adverse effects. The aim of this article is to review the currently available literature, to recognize the contraindications for sedation use and to provide practical guidance.

Rapid Tranquilization for Psychiatric Patients with Psychomotor Agitation: What is Known About it?

Rapid tranquilization is an intervention used in control of agitation or aggression in patients with mental disorders. This study synthesized the available evidence regarding efficacy and safety of drugs used for rapid tranquilization in psychiatric patients with psychomotor agitation. It is an overview study of systematic reviews and meta-analysis of randomized controlled trials (RCT) identified in the database MEDLINE, EMBASE, CINAHL, Web of Science, Cochrane Library and LILACS until April 2015. A team of reviewers, in pairs and independently, identified eligible studies and assessed methodological quality using AMSTAR. Data were extracted from four studies (61 RCT, 8021 participants). The association of haloperidol with promethazine (H + P) promoted tranquilization and presented better safety profile, with moderate quality evidence. Olanzapine demonstrated benefit towards tranquilization and good safety profile, but needed additional administration to keep tranquilization. There was no benefit in the use of haloperidol alone or associated to another psychotropic to most outcomes evaluated. The evidence was of low quality to most of the interventions. H + P was considered a good option for rapid tranquilization, however, more RCT are necessary to confirm the efficacy and safety of the available interventions.

Participation of dorsal periaqueductal gray 5-HT1A receptors in the panicolytic-like effect of the κ-opioid receptor antagonist Nor-BNI.

Panic patients may have abnormalities in serotonergic and opioidergic neurotransmission. The dorsal periaqueductal gray (dPAG) plays an important role in organizing proximal defense, related to panic attacks. The 5-HT1A receptor (5-HT1A-R) is involved in regulating escape behavior that is organized in the dPAG. Activation of κ-opioid receptor (KOR) in this region causes anxiogenic effects. In this study, we investigated the involvement of KOR in regulating escape behavior, using systemic and intra-dPAG injection of the KOR antagonist Nor-BNI. As panic models, we used the elevated T-maze (ETM) and the dPAG electrical stimulation test (EST). We also evaluated whether activation of the 5-HT1A-R or the µ-opioid receptor (MOR) in the dPAG contributes to the Nor-BNI effects. The results showed that systemic administration of Nor-BNI, either subcutaneously (2.0 and 4.0mg/kg) or intraperitoneally (2.0mg/kg), impaired escape in the EST, indicating a panicolytic-like effect. Intra-dPAG injection of this antagonist (6.8nmol) caused the same effect in the EST and in the ETM. Association of ineffective doses of Nor-BNI and the 5-HT1A-R agonist 8-OH-DPAT caused panicolytic-like effect in these two tests. Previous administration of the 5-HT1A-R antagonist WAY-100635, but not of the MOR antagonist CTOP, blocked the panicolytic-like effect of Nor-BNI. These results indicate that KOR enhances proximal defense in the dPAG through 5-HT1A-R modulation, independently of MOR. Because former results indicate that the 5-HT1A-R is involved in the antipanic action of antidepressants, KOR antagonists may be useful as adjunctive or alternative drug treatment of panic disorder.

Mood stabilizers inhibit cytomegalovirus infection.

Cytomegalovirus (CMV) infection can generate debilitating disease in immunocompromised individuals and neonates. It is also the most common infectious cause of congenital birth defects in infected fetuses. Available anti-CMV drugs are partially effective but are limited by some toxicity, potential viral resistance, and are not recommended for fetal exposure. Valproate, valpromide, and valnoctamide have been used for many years to treat epilepsy and mood disorders. We report for the first time that, in contrast to the virus-enhancing actions of valproate, structurally related valpromide and valnoctamide evoke a substantial and specific inhibition of mouse and human CMV in vitro. In vivo, both drugs safely attenuate mouse CMV, improving survival, body weight, and developmental maturation of infected newborns. The compounds appear to act by a novel mechanism that interferes with CMV attachment to the cell. Our work provides a novel potential direction for CMV therapeutics through repositioning of agents already approved for use in psychiatric disorders.

[EFFECT OF MEDIATOR-TYPE DRUGS ON HUMAN PSYCHOPHYSIOLOGICAL STATUS DURING MODEL OPERATOR ACTIVITY].

In a placebo-controlled study, changes in psychophysiological status of operators (38 healthy male volunteers aged 23-35 years) performing 4-hour model operator activity were evaluated after a single oral administration of typical representatives of the different classes of drugs (haloperidol, proroxan, yohimbine hydrochloride, propranolol, mesocarb, isoprenaline, Belladonna extract, anabasine hydrochloride, valproate sodium, and phenazepam), which are used for the treatment, rehabilitation and prophylaxis of common diseases. It was found that all the drugs modified to a greater or lesser extent some components of the model operator activity. Isoprenaline and phenazepam had the most negative effect on the psychophysiological indicators and quality of the modeled operator activity. The results should be considered before administration of such drugs to working operators.

Cortical Structure Alterations and Social Behavior Impairment in p50-Deficient Mice.

Alterations in genes that regulate neurodevelopment can lead to cortical malformations, resulting in malfunction during postnatal life. The NF-κB pathway has a key role during neurodevelopment by regulating the maintenance of the neural progenitor cell pool and inhibiting neuronal differentiation. In this study, we evaluated whether mice lacking the NF-κB p50 subunit (KO) present alterations in cortical structure and associated behavioral impairment. We found that, compared with wild type (WT), KO mice at postnatal day 2 present an increase in radial glial cells, an increase in Reelin protein expression levels, in addition to an increase of specific layer thickness. Moreover, adult KO mice display abnormal columnar organization in the somatosensory cortex, a specific decrease in somatostatin- and parvalbumin-expressing interneurons, altered neurite orientation, and a decrease in Synapsin I protein levels. Concerning behavior, KO mice, in addition to an increase in locomotor and exploratory activity, display impairment in social behaviors, with a reduction in social interaction. Finally, we found that risperidone treatment decreased hyperactivity of KO mice, but had no effect on defective social interaction. Altogether, these data add complexity to a growing body of data, suggesting a link between dysregulation of the NF-κB pathway and neurodevelopmental disorders pathogenesis.

Tagetes lucida Cav.: Ethnobotany, phytochemistry and pharmacology of its tranquilizing properties.

ETHNOPHARMACOLOGICAL RELEVANCE: Morelos State is one of the most important regions of Mexico where several plant species are used in traditional medicine to influence central nervous system (CNS) activity; for example Tagetes lucida Cav. AIM OF THE STUDY: To investigate the ethnobotany, phytochemistry and pharmacology of the tranquilizing properties of T. lucida aerial parts. MATERIAL AND METHODS: Data on the medicinal uses of T. lucida were explored by interviewing healers and merchants of local markets in different regions of Morelos State by using a questionnaire. Anxiolytic and/or sedative-like responses of the T. lucida were investigated in experimental models in mice such as: open-field, exploration cylinder, hole-board, plus-maze, and the barbituric-induced hypnosis potentiation. The possible mechanism of action was explored in the presence of WAY100635 (0.32mg/kg, i.p.) and flumazenil (10mg/kg, i.p.) antagonists. A feasible active compound was isolated and identified by using conventional chromatography, including UHPLC and MS (DART) [M+H]+ techniques. RESULTS: Interviews of healers and merchants from ten local regions of Morelos State showed that they recommended T. lucida as infusion and as tincture for several culture-bound syndromes associated with the CNS. Anxiolytic and sedative-like activities of polar extracts were corroborated in the experimental models; these effects were inhibited in the presence of 5-HT1A and GABA/BDZ receptor antagonists. Dimethylfraxetin was identified as one possible active compound. CONCLUSIONS: The results support the anxiolytic and sedative-like properties of T. lucida in traditional medicine by involving serotonergic and GABAergic neurotransmission and coumarinic constituents.

Use of haloperidol and risperidone in highly aggressive Swiss Webster mice by applying the model of spontaneous aggression (MSA).

Aggression is defined as the act in which an individual intentionally harms or injures another of their own species. Antipsychotics are a form of treatment used in psychiatric routine. They have been used for decades in treatment of patients with aggressive behavior. Haloperidol and risperidone promote the control of psychiatric symptoms, through their respective mechanisms of action. Experimental models are obtained by behavioral, genetic, and pharmacological manipulations, and use a reduced number of animals. In this context, we applied the model of spontaneous aggression (MSA), originating the presence of highly aggressive mice (AgR) when reassembled in adulthood. We administered haloperidol and risperidone in escalating doses, for ten consecutive days. Using positive and negative control groups, we evaluated the effectiveness of these drugs and the reversal of the aggressive behavior, performing the tail suspension test (TST) and open field test (OFT) on 10th day of treatment and 10 days after its discontinuation. The results showed that both antipsychotic drugs were effective in AgR and reversed the aggressive phenotype, reducing the number of attacks by AgR and the extent of lesions in the subordinate mice (AgD) exposed to the pattern of aggressive behavior (PAB) of the aggressors. This conclusion is based on the reduction in the animals' motor and exploratory activity, and on the reversal of patterns of aggressive behavior. The association between the MSA and experiments with other therapeutic protocols and different antipsychotics can be an important methodology in the study of aggressive behavior in psychiatric patients.

Use of an Intravascular Heat Exchange Catheter and Intravenous Lipid Emulsion for Hypothermic Cardiac Arrest After Cyclobenzaprine Overdose.

In this case report, a 22-year-old male developed severe hypothermia after an accidental overdose of cyclobenzaprine. During transport, the patient developed cardiac arrest. He received active rewarming measures, including pleural lavage, gastric lavage, an intravascular heat exchange catheter, and cardiopulmonary bypass. Intravenous lipid emulsion (ILE) was also administered. A discussion of cyclobenzaprine toxicity, hypothermia, ILE, and accidental hypothermic cardiac arrest follows.