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Extrasynaptic δ subunit‐containing γ‐aminobutyric acid type A receptors (δ‐GABAARs) are emerging as targets for a number of neuropsychopharmacological drugs, including the direct GABA site agonist gaboxadol and neuroactive steroids. Among other regions, these δ‐GABAARs are functionally expressed in the ventral tegmental area (VTA), the cell body region of mesocorticolimbic dopamine (DA) system important for motivated behaviours, and in the target region, the nucleus accumbens. Gaboxadol and neurosteroids induce VTA DA neuron plasticity ex vivo, by inhibiting the VTA GABA neurons, and aversive place conditioning, which are absent in the δ‐GABAAR knockout mice (δ‐KO). It is not known whether δ‐GABAARs are important for the effects of other drugs, such as opioids (that also inhibit GABA neurons) and stimulants (that primarily elevate monoamine levels). Here, we used δ‐KO mice and conditioned place preference (CPP) test to study the rewarding effects of morphine (20 mg/kg), methamphetamine (1 mg/kg) and mephedrone (5 mg/kg). Morphine‐induced nociception was also assessed using tail‐flick and hot‐plate tests. We found that the δ‐KO mice failed to express morphine‐induced CPP, but that they were more sensitive to morphine‐induced analgesia in the tail‐flick test. In contrast, stimulant‐induced CPP in the δ‐KO mice was similar to that in the wild‐type controls. Thus, the conditioned rewarding effect by opioids, but not that of stimulants, was impaired in the absence of δ‐GABAARs. Further studies are warranted to assess the potential of δ‐GABAAR antagonists as possible targets for reducing morphine reward and potentiating morphine analgesia. [ABSTRACT FROM AUTHOR]

Abstract Numerous novel neuroscience-based drug targets have been identified in recent years. However, it remains unclear how these targets relate to the expression of symptoms in central nervous system (CNS) disorders in general and psychiatric disorders in particular. To discuss this issue, a New Frontiers Meetings of European College of Neuropsychopharmacology (ECNP) was organized to address the challenges in translational neuroscience research that are impeding the effective development of new treatments. The main aim of this meeting was to discuss scientific insights, concepts and methodologies in order to improve drug development for psychiatric disorders. The meeting was designed to bring together stakeholders from academia, pharmaceutical industry, and regulatory agencies. Here we provide a synopsis of the proceedings from the meeting entitled ‘New approaches to psychiatric drug development’. New views on psychiatric drug development were presented to address the challenges and pitfalls as identified by the different stakeholders. The general conclusion of the meeting was that drug discovery could be stimulated by designing new classification and sensitive assessment tools for psychiatric disorders, which bear closer relationships to neuropharmacological and neuroscientific developments. This is in line with the vision of precision psychiatry in which patients are clustered, not merely on symptoms, but primarily on biological phenotypes that represent pathophysiological relevant and ‘drugable’ processes. To achieve these goals, a closer collaboration between all stakeholders in early stages of development is essential to define the research criteria together and to reach consensus on new quantitative biological methodologies and etiology-directed treatments. [ABSTRACT FROM AUTHOR]

University of Michigan Pharmacology Professor Ed Domino is an expert in the field of neuropsychopharmacology. For over six decades, Dr. Domino has made many contributions to our understanding of psychoactive drugs, but is most well-known for his role in the development of ketamine anesthesia. This article covers the story behind this discovery, along with many other fascinating personal and professional anecdotes, all of which provide insight into the career of a remarkable scientist. [ABSTRACT FROM AUTHOR]

Abstract: Background: North America is facing a severe public health crisis in the form of excessive numbers of deaths due to overdose from self‐administration of opioids by individuals who are dependent on these substances. Aims: There are many factors that must be addressed in order to gain control over this tragedy. Of particular relevance to neuropsychopharmacology is the fact that the problem is due in part to misuse of pharmaceuticals and especially the illicit production of the powerful synthetic opioids, fentanyl, and carfentanil. Method: The development and adoption of appropriate pharmacotherapies are of critical importance. We discuss specific options to deal effectively with both withdrawal from opioid dependence and substitution of clinically approved drugs in place of illicit substances. Conclusion: Hopefully, this crisis will reinvigorate both basic and clinical neuropsychopharmacological research leading to the develop new and more effective options for dealing with the many and varied elements of the current opioid crisis as described in the present commentary. [ABSTRACT FROM AUTHOR]

The consumption of nootropic drugs has increased tremendously in the last decade, though the studies on their environmental fate are still scarce. Nootropics are bioactive compounds designed to alter human's physiology therefore the adverse effects towards wildlife can be expected. In order to understand their environmental impact, the knowledge on their transformation pathways is necessary. Methylphenidate belongs to the most prescribed neuro-enhancers and is among the most favored smart drugs used in non-medical situations. It is metabolized in human liver and excreted as ritalinic acid. Here, we showed for the first time that ritalinic acid can be biodegraded and used as a sole carbon and nitrogen source by various microbial strains originating from different environmental samples. Five axenic strains were isolated and identified as: Arthrobacter sp. strain MW1, MW2 and MW3, Phycicoccus sp. strain MW4 and Nocardioides sp. strain MW5. Our research provides the first insight into the metabolism of ritalinic acid and suggests that it may differ depending on the strain and growth conditions, especially on availability of nitrogen. The isolates obtained in this study can serve as model organisms in further studies on the catabolism of ritalinic acid and methylphenidate but potentially also other compounds with similar structures. Our findings have important implication for the sewage epidemiology. We demonstrated that ritalinic acid is subject to quick and efficient biodegradation thus its use as a stable biomarker should be reconsidered. [ABSTRACT FROM AUTHOR]

Taurine is a highly abundant “amino acid” in the brain. Although the potential neuroactive role of taurine in vertebrates has long been recognized, the underlying molecular mechanisms related to its pleiotropic effects in the brain remain poorly understood. Due to the genetic tractability, rich behavioral repertoire, neurochemical conservation, and small size, the zebrafish ( Danio rerio ) has emerged as a powerful candidate for neuropsychopharmacology investigation and in vivo drug screening. Here, we summarize the main physiological roles of taurine in mammals, including neuromodulation, osmoregulation, membrane stabilization, and antioxidant action. In this context, we also highlight how zebrafish models of brain disorders may present interesting approaches to assess molecular mechanisms underlying positive effects of taurine in the brain. Finally, we outline recent advances in zebrafish drug screening that significantly improve neuropsychiatric translational research and small molecule screens. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Tryptophan 2,3‐dioxygenase (TDO2) is an initial rate‐limiting enzyme of the kynurenine (Kyn) pathway in tryptophan (Trp) metabolism. The Trp‐degrading enzymes, TDO2 and indoleamine 2,3‐dioxygenase, are activated by stress and/or inflammation. Dysregulation of Trp metabolism, which causes shifts in the balance between Kyn and serotonin (5‐HT) pathways, is associated with psychiatric and neurological disorders. In genetic studies, single‐nucleotide polymorphisms in the TDO2 gene were shown to be involved in psychiatric disorders, such as schizophrenia and depression. It has been reported that targeted deletion of the Tdo2 gene in mice resulted in reduced anxiety‐like behavior, enhanced exploratory activity and cognitive performance, and increased levels of Trp and 5‐HT in the hippocampus and midbrain. However, the effect of Tdo2 gene deletion on behavioral phenotypes has not yet been investigated extensively. Materials & Methods: We conducted tests to further examine the behavioral effects of knockout (KO) of Tdo2 in mice. Results: Deletion of Tdo2 resulted in seemingly lower anxiety‐like behavior, higher locomotor activity, and abnormal gait pattern in mice, though none of them reached study‐wide statistical significance. Tdo2 deficiency had no significant effects on other behaviors, such as prepulse inhibition, and depression‐like and social behaviors. Discussion and Conclusion: He lack of clear phenotypes in Tdo2KO mice in this study might be due to the absence of stress and inflammatory conditions, which could induce expression of Tdo2 mRNA. Further studies are necessary to elucidate the roles of Tdo2 in behavioral phenotypes related to psychiatric disorders. [ABSTRACT FROM AUTHOR]

There are many reasons why novel therapeutics fail in clinical trials but these failures are often attributed to lacking quality of preclinical data. These problems are not limited to any specific therapeutic area, academic or industrial research and are due in large part to several generic factors influencing research quality (e.g., related to definition of pre-specified endpoints, principles of study design and analysis, biased reporting, and lack of proper training). Yet, neuroscience drug discovery is often said to be affected more than the other fields. Within neuroscience, behavioral studies are the most blamed for being poorly designed, underpowered and mis-reported and there are indeed several factors that may be rather unique for behavioral research, such as a multitude of environmental conditions that are difficult to control and that are often not reported, ethical concerns about in vivo research and the pressure to reduce animal numbers, contributing to under-powered studies, and the complexity of study design and analysis, creating too much room for post hoc data massaging and selective reporting. Also, the blood-brain barrier as a frequently neglected complicating factor has to be considered in CNS research. The importance of these factors is increasingly recognized and urgent efforts are needed to demonstrate that behavioral methods of preclinical neuroscience research deliver results that can be as robust as with the non-behavioral methods Until this goal is achieved, behavioral neuroscience and neuroscience in general may be losing young talent, CNS drug discovery may lack the needed investment and this field may indeed be amongst the most affected by the current preclinical data quality crisis. [ABSTRACT FROM AUTHOR]

Objectives: Therapeutic drug monitoring (TDM) combines the quantification of drug concentrations in blood, pharmacological interpretation and treatment guidance. TDM introduces a precision medicine tool in times of increasing awareness of the need for personalized treatment. In neurology and psychiatry, TDM can guide pharmacotherapy for patient subgroups such as children, adolescents, pregnant women, elderly patients, patients with intellectual disabilities, patients with substance use disorders, individuals with pharmacokinetic peculiarities and forensic patients. Clear indications for TDM include lack of clinical response in the therapeutic dose range, assessment of drug adherence, tolerability issues and drug-drug interactions.Methods: Based upon existing literature, recommended therapeutic reference ranges, laboratory alert levels, and levels of recommendation to use TDM for dosage optimization without specific indications, conversion factors, factors for calculation of dose-related drug concentrations and metabolite-to-parent ratios were calculated.Results: This summary of the updated consensus guidelines by the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie offers the practical and theoretical knowledge for the integration of TDM as part of pharmacotherapy with neuropsychiatric agents into clinical routine.Conclusions: The present guidelines for TDM application for neuropsychiatric agents aim to assist clinicians in enhancing safety and efficacy of treatment. [ABSTRACT FROM AUTHOR]

Objectives: Therapeutic drug monitoring (TDM) combines the quantification of drug concentrations in blood, pharmacological interpretation and treatment guidance. TDM introduces a precision medicine tool in times of increasing awareness of the need for personalized treatment. In neurology and psychiatry, TDM can guide pharmacotherapy for patient subgroups such as children, adolescents, pregnant women, elderly patients, patients with intellectual disabilities, patients with substance use disorders, individuals with pharmacokinetic peculiarities and forensic patients. Clear indications for TDM include lack of clinical response in the therapeutic dose range, assessment of drug adherence, tolerability issues and drug-drug interactions.Methods: Based upon existing literature, recommended therapeutic reference ranges, laboratory alert levels, and levels of recommendation to use TDM for dosage optimization without specific indications, conversion factors, factors for calculation of dose-related drug concentrations and metabolite-to-parent ratios were calculated.Results: This summary of the updated consensus guidelines by the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie offers the practical and theoretical knowledge for the integration of TDM as part of pharmacotherapy with neuropsychiatric agents into clinical routine.Conclusions: The present guidelines for TDM application for neuropsychiatric agents aim to assist clinicians in enhancing safety and efficacy of treatment. [ABSTRACT FROM AUTHOR]

Background:Selective serotonin reuptake inhibitor (SSRI) exposures among children younger than 6 years of age are generally well tolerated. Vilazodone is an SSRI with partial agonism at the 5-HT1Areceptor with demonstrated clinical efficacy for depression whose off-label usage is likely to increase. Recent evidence suggests that unintentional ingestion of vilazodone in children under 6 years old is associated with more severe clinical effects than other SSRIs. We chose to evaluate dose and outcomes for pediatric vilazodone ingestions. Methods:A retrospective analysis of single-substance exposures associated with vilazodone among children younger than 6 years of age from 2011 through 2016 was conducted using data from the National Poison Data System. Results:During 2011–2016, 753 vilazodone ingestions among children <6 years old were reported to US poison control centers. A near majority (49.0%,n = 369) experienced one or more clinical effects. The dose ingested was reported for 596 children (79%). The median dose associated with major effects was 50.0mg (Mean: 106.0) compared with 40.0mg (Mean 81.1) for moderate effects. Half (50.0%) of children with a major effect and 54.0% with a moderate effect ingested ≤40 mg of vilazodone. As the dose of vilazodone ingested increased, the proportions of exposures admitted to a healthcare facility (HCF) (p < .001) and with serious outcomes (p < .001) both increased. Children ≤2 years had higher proportions of HCF admission (33.8% vs 23.1%) and serious outcomes (27.0% vs 17.7%) than children 3–5 years of age. Clinical effects, such as coma, seizures, ataxia, and hallucinations/delusions, were observed among children ingesting doses of vilazodone as low as 10 mg. Conclusions:Exposure to vilazodone poses a unique and potentially serious threat to children <6 years of age. Children in this age group who are exposed to vilazodone should be evaluated promptly in a clinical setting. Off-label use of vilazodone in children under 6 years should be discouraged until further research is conducted regarding its safety in this population. [ABSTRACT FROM AUTHOR]

Nicotine has been shown to enhance the reinforcement and reward-responsiveness of non-nicotine stimuli. To determine whether nicotine enhances the strength of conditioning to context, undergraduate participants with varying levels of nicotine dependence were recruited for a two-day study and tested on a virtual reality (VR) conditioned place preference (CPP) paradigm. On day one, participants explored two virtual rooms where they received multiple pairings of M&M rewards in one room and no rewards in the other room, followed by a free-access test session with no rewards. On day two, participants received three test sessions to assess extinction. Subsequently, participants received M&Ms. in a novel context and were then tested for reinstatement. Prior to testing on each day, subjects were administered either nicotine (4mg) or placebo lozenges, in a between-subjects, four-group, 2×2 design (nicotine or placebo on days 1 and 2). After conditioning on day one, only participants who received placebo exhibited a CPP by spending significantly more time in the room previously-paired with M&Ms. Contrary to our hypothesis, nicotine-treated participants did not display a significant CPP, and there were no significant differences between treatment groups. However, post hoc analysis indicated that in a subset of participants with greater nicotine dependence, the nicotine group displayed a CPP by rating the M&M-paired room as significantly more enjoyable than those who received placebo. Additionally, while neither treatment group showed significant place preferences during the first two extinction sessions on Day 2, individuals who received nicotine on Day 1 or placebo on Day 2 spent significantly more time in the M&M-paired room during the final extinction session. Finally, those who received nicotine on Day 2 exhibited significantly greater reinstatement compared to placebo-treated participants. These results partially support preclinical evidence that nicotine can affect learning, extinction, and reinstatement. [ABSTRACT FROM AUTHOR]

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs. [ABSTRACT FROM AUTHOR]

Zebrafish ( Danio rerio ) have become a powerful tool in neuroscience research due to their genetic tractability, molecular/physiological conservation, small body size, ease of experimental manipulations in vivo, and rich behavioral repertoire. Zebrafish models and tests are particularly useful in genetics research, neurophenotyping, CNS drug screening, as well as in modeling complex neurological and psychiatric disorders. Here, we discuss selected examples of successful application of zebrafish models to mimicking various aspects of brain pathology, and emphasize their developing utility for studying the underlying molecular and genetic mechanisms. We also summarize recent advances in zebrafish-based CNS disease modeling, and outline new research strategies that may significantly improve translational neuroscience and experimental neurology research, and drug discovery. [ABSTRACT FROM AUTHOR]

The neuronal mechanisms how anesthetics lead to loss of consciousness are unclear. Thalamocortical interactions are crucially involved in conscious perception; hence the thalamocortical network might be a promising target for anesthetic modulation of neuronal information pertaining to arousal and waking behavior. General anesthetics affect the neurophysiology of the thalamus and the cortex but the exact mechanisms of how anesthetics interfere with processing thalamocortical information remain to be elucidated. Here we investigated the effect of the anesthetic agents sevoflurane and propofol on thalamocortical network activity in vitro. We used voltage-sensitive dye imaging techniques to analyze the cortical depolarization in response to stimulation of the thalamic ventrobasal nucleus in brain slices from mice. Exposure to sevoflurane globally decreased cortical depolarization in a dose-dependent manner. Sevoflurane reduced the intensity and extent of cortical depolarization and delayed thalamocortical signal propagation. In contrast, propofol neither affected area nor amplitude of cortical depolarization. However, propofol exposure resulted in regional changes in spatial distribution of maximum fluorescence intensity in deep regions of the cortex. In summary, our experiments revealed substance-specific effects on the thalamocortical network. Functional changes of the neuronal network are known to be pivotally involved in the anesthetic-induced loss of consciousness. Our findings provide further evidence that the mechanisms of anesthetic-mediated loss of consciousness are drug- and pathway-specific. [ABSTRACT FROM AUTHOR]

Lipids are predominant components of the brain and key regulators for neural structure and function. The neuropsychopharmacological effect of cocaine has been intensively investigated; however, the impact of cocaine on brain lipid profiles is largely unknown. In this study, we used a LC-MS-based lipidomic approach to investigate the impact of cocaine on brain lipidome in two mouse models, cocaine-conditioned place preference (CPP) and hyperlocomotor models and the lipidome was profoundly modified in the nucleus accumbens (NAc) and striatum respectively. We comprehensively analyzed the lipids among 21 subclasses across 7 lipid classes and found that cocaine profoundly modified brain lipidome. Notably, the lipid metabolites significantly modified were sphingolipids and glycerophospholipids in the NAc, showing a decrease in ceramide and an increase in its up/downstream metabolites levels, and decrease lysophosphatidylcholine (LPC) and lysophosphoethanolamine (LPE) and increase phosphatidylcholine (PC) and phosphatidylethanolamines (PE) levels, respectively. Moreover, long and polyunsaturated fatty acid phospholipids were also markedly increased in the NAc. Our results show that cocaine can markedly modify brain lipidomic profiling. These findings reveal a link between the modified lipidome and psychopharmacological effect of cocaine, providing a new insight into the mechanism of cocaine addiction. [ABSTRACT FROM AUTHOR]

Taurine is a highly abundant “amino acid” in the brain. Despite the potential neuroactive role of taurine in vertebrates has long been recognized, the underlying molecular mechanisms related to its pleiotropic effects in the brain remain poorly understood. Due to the genetic tractability, rich behavioral repertoire, neurochemical conservation, and small size, the zebrafish ( Danio rerio ) has emerged as a powerful candidate for neuropsychopharmacology investigation and in vivo drug screening. Here, we summarize the main physiological roles of taurine in mammals, including neuromodulation, osmoregulation, membrane stabilization, and antioxidant action. In this context, we also highlight how zebrafish models of brain disorders may present interesting approaches to assess molecular mechanisms underlying positive effects of taurine in the brain. Finally, we outline recent advances in zebrafish drug screening that significantly improve neuropsychiatric translational researches and small molecule screens. [ABSTRACT FROM AUTHOR]