Study of pharmacological activities of methanol extract of Jatropha gossypifolia fruits

PubMed Central

Apu, Apurba Sarker; Hossain, Faruq; Rizwan, Farhana; Bhuyan, Shakhawat Hossan; Matin, Maima; Jamaluddin, A.T.M

2012-01-01

Objective: The present study was carried out to investigate the possible in vivo analgesic, neuropharmacological and anti-diarrheal activities of the methanol extract of Jatropha gossypifolia fruits. Materials and Methods: The analgesic activity was measured by acetic acid induced writhing inhibition test. The neuropharmacological activities were evaluated by hole cross, hole-board, and elevated plus-maze (EPM) tests and the anti-diarrheal activity was assessed by castor oil induced diarrhea inhibition method. Findings: The extract showed highly significant (P < 0.001) analgesic activity with % inhibitions of writhing response at doses 200 and 400 mg/kg body weight were 77.86% and 71.25%, respectively. The extract at both doses showed significant (P < 0.05) sedative effect in-hole cross test. In-hole board test, the extract showed highly significant (P < 0.001) anxiolytic activity at lower dose whereas this activity was observed at higher dose in EPM test. The extract also showed highly significant (P < 0.001) anti-diarrheal activity. Conclusion: The findings of the study clearly indicate the presence of significant analgesic, neuropharmacological and anti-diarrheal properties of the plant, which demands further investigation including, compound isolation. PMID:24808665

A review of Neuropharmacology Effects of Nigella sativa and Its Main Component, Thymoquinone.

PubMed

Javidi, Soheila; Razavi, Bibi Marjan; Hosseinzadeh, Hossein

2016-08-01

Neuropharmacology is the scientific study of drug effect on nervous system. In the last few years, different natural plants and their active constituents have been used in neurological therapy. The availability, lower price, and less toxic effects of herbal medicines compared with synthetic agents make them as simple and excellent choice in the treatment of nervous diseases. Nigella sativa, which belongs to the botanical family of Ranunculaceae, is a widely used medicinal plant all over the world. In traditional and modern medicines several beneficial properties have been attributed to N. sativa and its main component, thymoquinone (TQ). In this review, various studies in scientific databases regarding the neuropharmacological aspects of N. sativa and TQ have been introduced. Results of these studies showed that N. sativa and TQ have several properties including anticonvulsant, antidepressant, anxiolytic, anti-ischemic, analgesic, antipsychotic, and memory enhancer. Furthermore, its protective effects against neurodegenerative diseases such as Alzheimer, Parkinson and multiple sclerosis have been discussed. Although there are many studies indicating the beneficial actions of this plant in nervous system, the number of research projects relating to the human reports is rare. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

From systems biology to dynamical neuropharmacology: proposal for a new methodology.

PubMed

Erdi, P; Kiss, T; Tóth, J; Ujfalussy, B; Zalányi, L

2006-07-01

The concepts and methods of systems biology are extended to neuropharmacology in order to test and design drugs for the treatment of neurological and psychiatric disorders. Computational modelling by integrating compartmental neural modelling techniques and detailed kinetic descriptions of pharmacological modulation of transmitter-receptor interaction is offered as a method to test the electrophysiological and behavioural effects of putative drugs. Even more, an inverse method is suggested as a method for controlling a neural system to realise a prescribed temporal pattern. In particular, as an application of the proposed new methodology, a computational platform is offered to analyse the generation and pharmacological modulation of theta rhythm related to anxiety.

Herbal Highs: Review on Psychoactive Effects and Neuropharmacology

PubMed Central

Graziano, Silvia; Orsolini, Laura; Rotolo, Maria Concetta; Tittarelli, Roberta; Schifano, Fabrizio; Pichini, Simona

2017-01-01

Background: A new trend among users of new psychoactive substances’ the consumption of “herbal highs”: plant parts containing psychoactive substances. Most of the substances extracted from herbs, in old centuries were at the centre of religious ceremonies of ancient civilizations. Currently, these herbal products are mainly sold by internet web sites and easily obtained since some of them have no legal restriction. Objective: We reviewed psychoactive effects and neuropharmacology of the most used “herbal highs” with characterized active principles, with studies reporting mechanisms of action, pharmacological and subjective effects, eventual secondary effects including intoxications and/or fatalities Method: The PubMed database was searched using the following key.words: herbal highs, Argyreia nervosa, Ipomoea violacea and Rivea corymbosa; Catha edulis; Datura stramonium; Piper methysticum; Mitragyna speciosa. Results: Psychoactive plants here reviewed have been known and used from ancient times, even if for some of them limited information still exist regarding subjective and neuropharmacological effects and consequent eventual toxicity when plants are used alone or in combination with “classical” drugs of abuse. Conclusion: Some “herbal highs” should be classified as harmful drugs since chronic administration has been linked with addiction and cognitive impairment; for some others taking into consideration only the recent trends of abuse, studies investigating these aspects are lacking. PMID:27799032

[Intervening in the neural basis of one's personality: a practice-oriented ethical analysis of neuropharmacology and deep-brain stimulation].

PubMed

Synofzik, M

2007-12-01

Through the rapid progress in neuropharmacology it seems to become possible to effectively improve our cognitive capacities and emotional states by easily applicable means. Moreover, deep-brain stimulation may allow an effective therapeutic option for those neurological and psychiatric diseases which still can not be sufficiently treated by pharmacological measures. So far, however, both the benefit and the harm of these techniques are only insufficiently understood by neuroscience and detailed ethical analyses are still missing. In this article ethical criteria and most recent empirical evidence are systematically brought together for the first time. This analysis shows that it is irrelevant for an ethical evaluation whether a drug or a brain-machine interface is categorized as "enhancement" or "treatment" or whether it changes "human nature". The only decisive criteria are whether the intervention (1.) benefits the patient, (2.) does not harm the patient and (3.) is desired by the patient. However, current empirical data in both fields, neuropharmacology and deep-brain stimulation are still too sparse to adequately evaluate these criteria. Moreover, the focus in both fields has been strongly misled by neglecting the distinction between "benefit" and "efficacy": In past years research and clinical practice have only focused on physiological effects, but not on the actual benefit to the patient.

Herbal Highs: Review on Psychoactive Effects and Neuropharmacology.

PubMed

Graziano, Silvia; Orsolini, Laura; Rotolo, Maria Concetta; Tittarelli, Roberta; Schifano, Fabrizio; Pichini, Simona

2017-01-01

A new trend among users of new psychoactive substances' the consumption of "herbal highs": plant parts containing psychoactive substances. Most of the substances extracted from herbs, in old centuries were at the centre of religious ceremonies of ancient civilizations. Currently, these herbal products are mainly sold by internet web sites and easily obtained since some of them have no legal restriction. We reviewed psychoactive effects and neuropharmacology of the most used "herbal highs" with characterized active principles, with studies reporting mechanisms of action, pharmacological and subjective effects, eventual secondary effects including intoxications and/or fatalities Method: The PubMed database was searched using the following key.words: herbal highs, Argyreia nervosa, Ipomoea violacea and Rivea corymbosa; Catha edulis; Datura stramonium; Piper methysticum; Mitragyna speciosa. Psychoactive plants here reviewed have been known and used from ancient times, even if for some of them limited information still exist regarding subjective and neuropharmacological effects and consequent eventual toxicity when plants are used alone or in combination with "classical" drugs of abuse. Some "herbal highs" should be classified as harmful drugs since chronic administration has been linked with addiction and cognitive impairment; for some others taking into consideration only the recent trends of abuse, studies investigating these aspects are lacking. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The neuropharmacology of L-theanine(N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent.

PubMed

Nathan, Pradeep J; Lu, Kristy; Gray, M; Oliver, C

2006-01-01

L-theanine (N-ethyl-L-glutamine) or theanine is a major amino acid uniquely found in green tea. L-theanine has been historically reported as a relaxing agent, prompting scientific research on its pharmacology. Animal neurochemistry studies suggest that L-theanine increases brain serotonin, dopamine, GABA levels and has micromolar affinities for AMPA, Kainate and NMDA receptors. In addition has been shown to exert neuroprotective effects in animal models possibly through its antagonistic effects on group 1 metabotrophic glutamate receptors. Behavioural studies in animals suggest improvement in learning and memory. Overall, L-theanine displays a neuropharmacology suggestive of a possible neuroprotective and cognitive enhancing agent and warrants further investigation in animals and humans.

TARPs differentially decorate AMPA receptors to specify neuropharmacology.

PubMed

Kato, Akihiko S; Gill, Martin B; Yu, Hong; Nisenbaum, Eric S; Bredt, David S

2010-05-01

Transmembrane AMPA receptor regulatory proteins (TARPs) are the first identified auxiliary subunits for a neurotransmitter-gated ion channel. Although initial studies found that stargazin, the prototypical TARP, principally chaperones AMPA receptors, subsequent research demonstrated that it also regulates AMPA receptor kinetics and synaptic waveforms. Recent studies have identified a diverse collection of TARP isoforms--types Ia, Ib II--that distinctly regulate AMPA receptor trafficking, gating and neuropharmacology. These TARP isoforms are heterogeneously expressed in specific neuronal populations and can differentially sculpt synaptic transmission and plasticity. Whole-genome analyses also link multiple TARP loci to childhood epilepsy, schizophrenia and bipolar disorder. TARPs emerge as vital components of excitatory synapses that participate both in signal transduction and in neuropsychiatric disorders. Copyright 2010 Elsevier Ltd. All rights reserved.

Translational neuropharmacology and the appropriate and effective use of animal models

PubMed Central

Green, AR; Gabrielsson, J; Fone, KCF

2011-01-01

This issue of the British Journal of Pharmacology is dedicated to reviews of the major animal models used in neuropharmacology to examine drugs for both neurological and psychiatric conditions. Almost all major conditions are reviewed. In general, regulatory authorities require evidence for the efficacy of novel compounds in appropriate animal models. However, the failure of many compounds in clinical trials following clear demonstration of efficacy in animal models has called into question both the value of the models and the discovery process in general. These matters are expertly reviewed in this issue and proposals for better models outlined. In this editorial, we further suggest that more attention be made to incorporate pharmacokinetic knowledge into the studies (quantitative pharmacology). We also suggest that more attention be made to ensure that full methodological details are published and recommend that journals should be more amenable to publishing negative data. Finally, we propose that new approaches must be used in drug discovery so that preclinical studies become more reflective of the clinical situation, and studies using animal models mimic the anticipated design of studies to be performed in humans, as closely as possible. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21545411

Ibogaine and addiction in the animal model, a systematic review and meta-analysis

PubMed Central

Belgers, M; Leenaars, M; Homberg, J R; Ritskes-Hoitinga, M; Schellekens, A F A; Hooijmans, C R

2016-01-01

Ibogaine is a naturally occurring substance which has been increasingly used in the lay-scene to reduce craving and relapse in patients with substance use disorders (SUDs). Although human clinical trials on the safety and efficacy of ibogaine are lacking, animal studies do support the efficacy of ibogaine. In this systematic review and meta-analysis (MA), we summarise these animal findings, addressing three questions: (1) does ibogaine reduce addictive behaviour in animal models of SUDs?; (2) what are the toxic effects of ibogaine on motor functioning, cerebellum and heart rhythm?; (3) what are neuropharmacological working mechanisms of ibogaine treatment in animal models of SUDs? MA of 27 studies showed that ibogaine reduced drug self-administration, particularly during the first 24 h after administration. Ibogaine had no effect on drug-induced conditioned place preference. Ibogaine administration resulted in motor impairment in the first 24 h after supplementation, and cerebral cell loss even weeks after administration. Data on ibogaines effect on cardiac rhythm, as well as on its neuropharmacological working mechanisms are limited. Our results warrant further studies into the clinical efficacy of ibogaine in SUD patients in reducing craving and substance use, but close monitoring of the patients is recommended because of the possible toxic effects. In addition, more work is needed to unravel the neuropharmacological working mechanisms of ibogaine and to investigate its effects on heart rhythm. PMID:27244235

Ibogaine and addiction in the animal model, a systematic review and meta-analysis.

PubMed

Belgers, M; Leenaars, M; Homberg, J R; Ritskes-Hoitinga, M; Schellekens, A F A; Hooijmans, C R

2016-05-31

Ibogaine is a naturally occurring substance which has been increasingly used in the lay-scene to reduce craving and relapse in patients with substance use disorders (SUDs). Although human clinical trials on the safety and efficacy of ibogaine are lacking, animal studies do support the efficacy of ibogaine. In this systematic review and meta-analysis (MA), we summarise these animal findings, addressing three questions: (1) does ibogaine reduce addictive behaviour in animal models of SUDs?; (2) what are the toxic effects of ibogaine on motor functioning, cerebellum and heart rhythm?; (3) what are neuropharmacological working mechanisms of ibogaine treatment in animal models of SUDs? MA of 27 studies showed that ibogaine reduced drug self-administration, particularly during the first 24 h after administration. Ibogaine had no effect on drug-induced conditioned place preference. Ibogaine administration resulted in motor impairment in the first 24 h after supplementation, and cerebral cell loss even weeks after administration. Data on ibogaines effect on cardiac rhythm, as well as on its neuropharmacological working mechanisms are limited. Our results warrant further studies into the clinical efficacy of ibogaine in SUD patients in reducing craving and substance use, but close monitoring of the patients is recommended because of the possible toxic effects. In addition, more work is needed to unravel the neuropharmacological working mechanisms of ibogaine and to investigate its effects on heart rhythm.

Drugs & the Brain: Case-based Instruction for an Undergraduate Neuropharmacology Course.

PubMed

Nagel, Anastasia; Nicholas, Andrea

2017-01-01

In order to transform a traditional large non-majors general education (GE) neurobiology lecture (Drugs & the Brain) into an active learning course, we developed a series of directed mini-cases targeting major drug classes. Humorous and captivating case-based situations were used to better engage and motivate students to solve problems related to neuropharmacology and physiology. Here we provide directed cases, questions and learning outcomes for our opiates mini-cases. In addition, we describe how case studies were incorporated into our course and assessed using peer review and online quizzing. An in-depth analysis of the overall course transformation on student exam performance, opinions and instructor evaluations can be found in the JUNE article Don't Believe the Gripe! Increasing Course Structure in a Large Non-majors Neuroscience Course.

Schizophrenia: a review of neuropharmacology.

PubMed

Lyne, J; Kelly, B D; O'Connor, W T

2004-01-01

The last few decades have seen significant advances in our understanding of the neurochemical basis of schizophrenia. To describe the neurotransmitter systems and nerve circuits implicated in schizophrenia; to compare the neuropharmacology of typical and atypical anti-psychotic agents; and to describe recent developments in the pharmacological treatment of schizophrenia. Relevant pharmacological, neurophysiological and psychiatric literature was examined and reviewed. Schizophrenia is associated with abnormalities of multiple neurotransmitter systems, including dopamine, serotonin, gamma-aminobutyric acid and glutamate. Typical and atypical antipsychotic agents differ in their receptor-binding affinities, which are related to their differing side-effect profiles. Novel therapeutic strategies include normalisation of synaptic dopamine or serotonin levels, serotonin receptor antagonism and modulation of cerebral protein synthesis. The ideal treatment for schizophrenia may not be a single pharmacological agent but several agents that match the different expressions of the illness, in combination with psycho-social interventions.

76 FR 28793 - Center for Scientific Review; Notice of Closed Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-18

...: Biobehavioral Regulation, Learning and Ethology. Date: June 8, 2011. Time: 1 p.m. to 3 p.m. Agenda: To review... Developmental Neuroscience Integrated Review Group; Molecular Neuropharmacology and Signaling Study Section...

The neurochemical and neuropharmacological basis of motion sickness

NASA Technical Reports Server (NTRS)

Walker, C. A.

1990-01-01

An apparatus suitable for producing motion sickness in laboratory animals and constructed at the university is herein described. The apparatus is a modified version of that previously described by Fox and Daunton. It consists of a 66-inch steel arm anchored at the center to a wooden platform and attached to a motor that makes the arm move in a see-saw fashion. At each end of the steel arm is mounted an aluminum disc that can be rotated by a motorized device. Detachable cages are mounted on each disc for animal holding. The animal can then be exposed to rotational motion by rotation of the aluminum disc, or to see-saw motion simultaneously (Cross-coupled). The apparatus is presently being used in our laboratory to study the neuropharmacological basis of motion sickness in the rat. The device can be adapted for use with other animal species by modifying the cage mounted on the aluminum discs.

Zebrafish neurobehavioral phenomics for aquatic neuropharmacology and toxicology research.

PubMed

Kalueff, Allan V; Echevarria, David J; Homechaudhuri, Sumit; Stewart, Adam Michael; Collier, Adam D; Kaluyeva, Aleksandra A; Li, Shaomin; Liu, Yingcong; Chen, Peirong; Wang, JiaJia; Yang, Lei; Mitra, Anisa; Pal, Subharthi; Chaudhuri, Adwitiya; Roy, Anwesha; Biswas, Missidona; Roy, Dola; Podder, Anupam; Poudel, Manoj K; Katare, Deepshikha P; Mani, Ruchi J; Kyzar, Evan J; Gaikwad, Siddharth; Nguyen, Michael; Song, Cai

2016-01-01

Zebrafish (Danio rerio) are rapidly emerging as an important model organism for aquatic neuropharmacology and toxicology research. The behavioral/phenotypic complexity of zebrafish allows for thorough dissection of complex human brain disorders and drug-evoked pathological states. As numerous zebrafish models become available with a wide spectrum of behavioral, genetic, and environmental methods to test novel drugs, here we discuss recent zebrafish phenomics methods to facilitate drug discovery, particularly in the field of biological psychiatry. Additionally, behavioral, neurological, and endocrine endpoints are becoming increasingly well-characterized in zebrafish, making them an inexpensive, robust and effective model for toxicology research and pharmacological screening. We also discuss zebrafish behavioral phenotypes, experimental considerations, pharmacological candidates and relevance of zebrafish neurophenomics to other 'omics' (e.g., genomic, proteomic) approaches. Finally, we critically evaluate the limitations of utilizing this model organism, and outline future strategies of research in the field of zebrafish phenomics. Copyright © 2015 Elsevier B.V. All rights reserved.

Marine snail venoms: use and trends in receptor and channel neuropharmacology.

PubMed

Favreau, Philippe; Stöcklin, Reto

2009-10-01

Venoms are rich mixtures of mainly peptides and proteins evolved by nature to catch and digest preys or for protection against predators. They represent extensive sources of potent and selective bioactive compounds that can lead to original active ingredients, for use as drugs, as pharmacological tools in research and for the biotechnology industry. Among the most fascinating venomous animals, marine snails offer a unique set of pharmacologically active components, targeting a wide diversity of receptors and ion channels. Recent advances still continue to demonstrate their huge neuropharmacological potential. In the quest for interesting pharmacological profiles, researchers face a vast number of venom components to investigate within time and technological constraints. A brief perspective on marine snail venom's complexity and features is given followed by the different discovery strategies and pharmacological approaches, exemplified with some recent developments. These advances will hopefully help further uncovering new pharmacologically important venom molecules.

Neuropsychology and neuropharmacology of P3a and P3b.

PubMed

Polich, John; Criado, José R

2006-05-01

Perspectives on the P300 event-related brain potential (ERP) are reviewed by outlining the distinction between the P3a and P3b subcomponents. The critical factor for eliciting P3a is how target/standard discrimination difficulty rather than novelty modulates task processing. The neural loci of P3a and P3b generation are sketched and a theoretical model is developed. P3a originates from stimulus-driven disruption of frontal attention engagement during task processing. P3b originates when temporal-parietal mechanisms process the stimulus information for memory storage. The neuropharmacological implications of this view are then outlined by evaluating how acute and chronic use of ethanol, marijuana, and nicotine affect P3a and P3b. The findings suggest that the circuit underlying ERP generation is influenced in a different ways for acute intake and varies between chronic use levels across drugs. Theoretical implications are assessed.

Teaching neurophysiology, neuropharmacology, and experimental design using animal models of psychiatric and neurological disorders.

PubMed

Morsink, Maarten C; Dukers, Danny F

2009-03-01

Animal models have been widely used for studying the physiology and pharmacology of psychiatric and neurological diseases. The concepts of face, construct, and predictive validity are used as indicators to estimate the extent to which the animal model mimics the disease. Currently, we used these three concepts to design a theoretical assignment to integrate the teaching of neurophysiology, neuropharmacology, and experimental design. For this purpose, seven case studies were developed in which animal models for several psychiatric and neurological diseases were described and in which neuroactive drugs used to treat or study these diseases were introduced. Groups of undergraduate students were assigned to one of these case studies and asked to give a classroom presentation in which 1) the disease and underlying pathophysiology are described, 2) face and construct validity of the animal model are discussed, and 3) a pharmacological experiment with the associated neuroactive drug to assess predictive validity is presented. After evaluation of the presentations, we found that the students had gained considerable insight into disease phenomenology, its underlying neurophysiology, and the mechanism of action of the neuroactive drug. Moreover, the assignment was very useful in the teaching of experimental design, allowing an in-depth discussion of experimental control groups and the prediction of outcomes in these groups if the animal model were to display predictive validity. Finally, the highly positive responses in the student evaluation forms indicated that the assignment was of great interest to the students. Hence, the currently developed case studies constitute a very useful tool for teaching neurophysiology, neuropharmacology, and experimental design.

Introduction to the College on Problems of Drug Dependence special issue: contemporary advances in opioid neuropharmacology.

PubMed

Walsh, Sharon L; Unterwald, Ellen M; Izenwasser, Sari

2010-05-01

Opioid receptors are critical therapeutic targets for medications development relevant to the treatment of drug dependence and pain. With recent advances in molecular neurobiology, it has become evident that the functional activity of opioid receptors, as ligand-regulated protein complexes, is modulated by multifarious intracellular and extracellular events, that there is genetic variation in coding for receptors, and that the activity of endogenous opioid systems may underlie actions common to other addictive disorders. This supplemental issue of Drug and Alcohol Dependence, arising from an invited symposium at the 71st Annual Meeting of the College on Problems of Drug Dependence, provides a series of contemporary reviews focused on recent advances in opioid neuropharmacology. Each speaker provides herein an invited comprehensive review of the state of knowledge on a specific topic in opioid neuropharmacology. Evans and colleagues describe the multi-faceted control of the opioid G-protein coupled receptor as a dynamic "sensor" complex and identify novel targets for drug development. von Zastrow focuses on opioid receptor-mediated events regulated by endocytosis and membrane trafficking through the endocytic pathway and differential responses to opioid agonists. Blendy and colleague provide a review of human association studies on the functional relevance of the mu opioid receptor variant, A118G, and presents data from the A112G knock-in model, an analogous mouse variant to A118G. Finally, Maldonado and colleagues provide a broader systems review from genetic, pharmacologic and behavioral studies implicating the endogenous opioid systems as a substrate for the mediation of substance use disorders spanning pharmacological classes.

Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

PubMed Central

Mantsch, John R; Baker, David A; Funk, Douglas; Lê, Anh D; Shaham, Yavin

2016-01-01

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse. PMID:25976297

Dynamical Systems in Neuropharmacology

DTIC Science & Technology

1992-04-15

induced hyperactivity with the selective serotonin uptake blockers fluoxetine , sertraline, or zimelidine or with the serotonin synthesis inhibitor PCPA. By...Conversely, the catecholamine synthesis inhibitor AMPT, which blocks the effects of amphetamine, did not affect the response to MDMA. We applied our scaling

75 FR 54893 - Center for Scientific Review; Notice of Closed Meetings

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2010-09-09

... 7850, Bethesda, MD 20892. 301-435-3009. [email protected] . Name of Committee: Molecular, Cellular and Developmental Neuroscience Integrated Review Group, Molecular Neuropharmacology and Signaling... . Name of Committee: Emerging Technologies and Training Neurosciences Integrated Review Group, Molecular...

Environmental Enrichment, Performance, and Brain Injury in Male and Female Rats

DTIC Science & Technology

2004-01-01

neurodevelopmental disorders characterized by deficits in processing novel information (e.g., autism ). 141 Table 8. Summary of Major...stimulated locomotor activity, dopamine synthesis, and dopamine release. Neuropharmacology, 32, 885-893. Braff, D.L., Swerdlow, N.R., & Geyer, M.A

Analgesic, neuropharmacological, anti-diarrheal, and cytotoxic activities of the extract of Solanum sisymbriifolium (Lam.) leaves.

PubMed

Apu, Apurba Sarker; Bhuyan, Shakhawat Hossan; Matin, Maima; Hossain, Faruq; Khatun, Farjana; Taiab, Abu; Jamaluddin

2013-01-01

The present study was undertaken to evaluate the possible analgesic, neuropharmacological, anti-diarrheal, and cytotoxic activities of the ethanol extract of leaves of Solanum sisymbriifolium Lam. (Family: Solanaceae). The analgesic activity was measured by acetic acid-induced writhing inhibition test. The neuropharmacological activities were evaluated using hole cross, hole board, and elevated plus-maze test and the anti-diarrheal activity was assessed using castor oil-induced diarrhea inhibition method. Brine shrimp lethality bioassay was carried out for assessing the cytotoxicity of the ethanol extract of the leaves. Except cytotoxic activity, all the tests were conducted on mice. The extract at oral doses of 200 and 400 mg/kg body weight showed highly significant (p<0.001) decrease in number of writhing, 52.1±0.66 and 4.4±0.64 compared with the control (78.6±0.29) with the percentage of inhibitions of writhing response were found to be 33.72% and 94.40%, respectively. Compare with the control, the extract at both doses showed significant sedative effect in hole cross test. In hole board test, the extract exhibited highly significant (p<0.001) anxiolytic activity at dose of (200 mg/kg), while the same activity was observed at dose of 400 mg/kg in elevated plus-maze test. The extract showed highly significant (p<0.001) anti-diarrheal activity in a dose-dependent manner. With the extract, significant lethality to brine shrimp was found with LC50 value of 61.66±0.9 μg/ml, which was comparable with the positive control (LC50: 11.89±0.8 µg/ml). The results from the present studies support the traditional uses of this plant part and could form the basis of further investigation including compound isolation.

75 FR 1397 - Center for Scientific Review; Notice of Closed Meetings

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2010-01-11

... personal privacy. Name of Committee: Molecular, Cellular and Developmental Neuroscience Integrated Review Group; Molecular Neuropharmacology and Signaling Study Section. Date: February 4-5, 2010. Time: 8 a.m....gov . Name of Committee: Genes, Genomes, and Genetics Integrated Review Group; Prokaryotic Cell and...

Neurological Effects of Honey: Current and Future Prospects

PubMed Central

Mijanur Rahman, Mohammad; Gan, Siew Hua; Khalil, Md. Ibrahim

2014-01-01

Honey is the only insect-derived natural product with therapeutic, traditional, spiritual, nutritional, cosmetic, and industrial value. In addition to having excellent nutritional value, honey is a good source of physiologically active natural compounds, such as polyphenols. Unfortunately, there are very few current research projects investigating the nootropic and neuropharmacological effects of honey, and these are still in their early stages. Raw honey possesses nootropic effects, such as memory-enhancing effects, as well as neuropharmacological activities, such as anxiolytic, antinociceptive, anticonvulsant, and antidepressant activities. Research suggests that the polyphenol constituents of honey can quench biological reactive oxygen species and counter oxidative stress while restoring the cellular antioxidant defense system. Honey polyphenols are also directly involved in apoptotic activities while attenuating microglia-induced neuroinflammation. Honey polyphenols are useful in improving memory deficits and can act at the molecular level. Therefore, the ultimate biochemical impact of honey on specific neurodegenerative diseases, apoptosis, necrosis, neuroinflammation, synaptic plasticity, and behavior-modulating neural circuitry should be evaluated with appropriate mechanistic approaches using biochemical and molecular tools. PMID:24876885

Proteomic approaches in brain research and neuropharmacology.

PubMed

Vercauteren, Freya G G; Bergeron, John J M; Vandesande, Frans; Arckens, Lut; Quirion, Rémi

2004-10-01

Numerous applications of genomic technologies have enabled the assembly of unprecedented inventories of genes, expressed in cells under specific physiological and pathophysiological conditions. Complementing the valuable information generated through functional genomics with the integrative knowledge of protein expression and function should enable the development of more efficient diagnostic tools and therapeutic agents. Proteomic analyses are particularly suitable to elucidate posttranslational modifications, expression levels and protein-protein interactions of thousands of proteins at a time. In this review, two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) investigations of brain tissues in neurodegenerative diseases such as Alzheimer's disease, Down syndrome and schizophrenia, and the construction of 2D-PAGE proteome maps of the brain are discussed. The role of the Human Proteome Organization (HUPO) as an international coordinating organization for proteomic efforts, as well as challenges for proteomic technologies and data analysis are also addressed. It is expected that the use of proteomic strategies will have significant impact in neuropharmacology over the coming decade.

77 FR 52751 - Center for Scientific Review; Notice of Closed Meetings

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2012-08-30

... personal privacy. Name of Committee: Molecular, Cellular and Developmental Neuroscience Integrated Review Group, Molecular Neuropharmacology and Signaling Study Section. Date: September 24-25, 2012. Time: 8 a.m... 7770, Bethesda, MD 20892, (301) 435- 0684, [email protected] . Name of Committee: Molecular, Cellular...

Award for Distinguished Scientific Early Career Contributions to Psychology: Ahmad R. Hariri

ERIC Educational Resources Information Center

American Psychologist, 2009

2009-01-01

Ahmad R. Hariri, recipient of the Award for Distinguished Scientific Early Career Contributions to Psychology, is cited for pioneering contributions to understanding the neurobiological mechanisms driving individual differences in complex behavior traits. Hariri has integrated molecular genetics, neuropharmacology, neuroimaging, and psychology in…

Neuropharmacology of Human Appetite Expression

ERIC Educational Resources Information Center

Halford, Jason C. G.; Harrold, Joanne A.

2008-01-01

The regulation of appetite relies on the integration of numerous episodic (meal) and tonic (energy storage) generated signals in energy regulatory centres within the central nervous system (CNS). These centers provide the pharmacological potential to modify human appetite (hunger and satiety) to increase or decrease caloric intake, or to normalize…

Frontal Decortication and Adaptive Changes in Striatal Cholinergic Neurons: Neuropharmacological and Behavioral Implications

DTIC Science & Technology

1990-09-28

the muscarinic cholinergic agonist oxotremorine (OT’O) in the striatulm. Frontal decortication did not affect the activation of phosphoinositjde...Congress abstracts 3 List of abbreviations: ACh, acetylcholine; C h A T cholitie-o-acetyl/transferase; OTMVN, oxotremorine ; OXI, oxirucetam:, SDHACU

77 FR 1704 - Center for Scientific Review; Notice of Closed Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-11

... Medicine. Date: February 1-2, 2012. Time: 11:30 a.m. to 5 p.m. Agenda: To review and evaluate grant...-7314, [email protected] . Name of Committee: Molecular, Cellular and Developmental Neuroscience Integrated Review Group; Molecular Neuropharmacology and Signaling Study Section. Date: February 6-7, 2012...

Neuronal Substrates of Relapse to Cocaine-Seeking Behavior: Role of Prefrontal Cortex

ERIC Educational Resources Information Center

Rebec, George V.; Sun, WenLin

2005-01-01

The return to drug seeking, even after prolonged periods of abstinence, is a defining feature of cocaine addiction. The neural circuitry underlying relapse has been identified in neuropharmacological studies of experimental animals, typically rats, and supported in brain imaging studies of human addicts. Although the nucleus accumbens (NAcc),…

Is Recurrent Perseveration a Product of Deafferented Functional Systems with Otherwise Normal Post-Activation Decay Rates?

ERIC Educational Resources Information Center

Buckingham, Hugh W.; Buckingham, Sarah S.

2011-01-01

Recent work in neuropsychology, clinical aphasiology and neuropharmacology have presented evidence that the causative substrates of recurrent perseveration in adults with aphasia are more recondite and subject to distinct interpretations than originally thought. This article will discuss and evaluate how various proposals from theory, from the…

"Asparagus Racemosus" Enhances Memory and Protects against Amnesia in Rodent Models

ERIC Educational Resources Information Center

Ojha, Rakesh; Sahu, Alakh N.; Muruganandam, A. V.; Singh, Gireesh Kumar; Krishnamurthy, Sairam

2010-01-01

"Asparagus Racemosus" (AR) is an Ayurvedic rasayana possessing multiple neuropharmacological activities. The adpatogenic and antidepressant activity of AR is well documented. The present study was undertaken to assess nootropic and anti-amnesic activities of MAR in rats. The Morris water maze (MWM) and elevated plus maze (EPM) models were employed…

75 FR 2878 - Center for Scientific Review; Amended Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-19

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health Center for Scientific Review; Amended Notice of Meeting Notice is hereby given of a change in the meeting of the Molecular Neuropharmacology and Signaling Study Section, February 4, 2010, 8 a.m. to February 5, 2010, 5 p.m., Hotel Monaco...

Computational Models of Neuronal Biophysics and the Characterization of Potential Neuropharmacological Targets

PubMed Central

Ferrante, Michele; Blackwell, Kim T.; Migliore, Michele; Ascoli, Giorgio A.

2012-01-01

The identification and characterization of potential pharmacological targets in neurology and psychiatry is a fundamental problem at the intersection between medicinal chemistry and the neurosciences. Exciting new techniques in proteomics and genomics have fostered rapid progress, opening numerous questions as to the functional consequences of ligand binding at the systems level. Psycho- and neuro-active drugs typically work in nerve cells by affecting one or more aspects of electrophysiological activity. Thus, an integrated understanding of neuropharmacological agents requires bridging the gap between their molecular mechanisms and the biophysical determinants of neuronal function. Computational neuroscience and bioinformatics can play a major role in this functional connection. Robust quantitative models exist describing all major active membrane properties under endogenous and exogenous chemical control. These include voltage-dependent ionic channels (sodium, potassium, calcium, etc.), synaptic receptor channels (e.g. glutamatergic, GABAergic, cholinergic), and G protein coupled signaling pathways (protein kinases, phosphatases, and other enzymatic cascades). This brief review of neuromolecular medicine from the computational perspective provides compelling examples of how simulations can elucidate, explain, and predict the effect of chemical agonists, antagonists, and modulators in the nervous system. PMID:18855673

Studies on chemotherapy of parasitic helminths (VI) effects of various neuropharmacological agents on the motility of Dipylidium caninum.

PubMed

Terada, M; Ishii, A I; Kino, H; Sano, M

1982-06-01

Effects of various neuropharmacological agents on the motility of Dipylidium caninum was studied. 5-HT stimulated the motility of D. caninum, while other drugs such as GABA, adrenaline, phenylephrine, isoproterenol, dibenamine, and propranolol showed little effect. The stimulatory action of 5-HT was antagonized by tryptophol. Stibnal caused paralysis which was blocked by the pretreatment with 5-HT. Paralytic effects were caused by eserine, dichlorovos, ACh, carbachol and DMPP, but not by pilocarpine and McN-A-343. d-Tubocurarine, hexamethonium, and atropine all showed little effect on the motility and on the paralytic action of eserine. Though guanidine showed little effect, strychnine remarkably stimulated the motility. The action of strychnine was stimulated by 5-HT but partially inhibited by tryptophol. Morphine and picrate slightly stimulated the motility, but showed little influence on the paralytic action of eserine. These two agents stimulated the paralyzed preparation by tryptophol transiently and sustainedly, respectively. These results on the cholinergic and serotonergic drugs basically showed good agreement with those reported in trematodes such as Schistosoma mansoni and Fasciola hepatica.

The "highs and lows" of the human brain on dopaminergics: Evidence from neuropharmacology.

PubMed

Martins, Daniel; Mehta, Mitul A; Prata, Diana

2017-09-01

Rewards are appetitive events that elicit approach. Ground-breaking findings from neurophysiological experiments in animals, alongside neuropharmacology and neuroimaging research in human samples have identified dopamine as the main neurochemical messenger of global reward processing in the brain. However, dopamine's contribution to the different components of reward processing remains to be precisely defined. To facilitate the informed design and interpretation of reward studies in humans, we have systematically reviewed all existing human pharmacological studies investigating how drug manipulation of the dopamine system affects reward-related behaviour and its neural correlates. Pharmacological experiments in humans face methodological challenges in terms of the: 1) specificity and safety of the available drugs for administration in humans, 2) uncertainties about pre- or post-synaptic modes of action, and 3) possible interactions with inter-individual neuropsychological or genotypic variables. In order to circumvent some of these limitations, future research should rely on the combination of different levels of observation, in integrative pharmaco-genetics-neurobehavioral approaches, to more completely characterize dopamine's role in both general and modality-specific processing of reward. Copyright © 2017 Elsevier Ltd. All rights reserved.

The neuropsychopharmacology of action inhibition: cross-species translation of the stop-signal and go/no-go tasks.

PubMed

Eagle, Dawn M; Bari, Andrea; Robbins, Trevor W

2008-08-01

The term 'action inhibition' encapsulates the ability to prevent any form of planned physical response. Growing evidence suggests that different 'stages' or even subtypes of action inhibition activate subtly different neuropharmacological and neuroanatomical processes. In this review, we present evidence from two commonly used and apparently similar behavioural tests, the stop-signal task and the go/no-go task, to determine if these have similar neuroanatomical and neurochemical modulation. Whilst performance of the stop-signal and go/no-go tasks is modulated across only subtly different anatomical networks, serotonin (5-HT) is strongly implicated in inhibitory control on the go/no-go but not the stop-signal task, whereas the stop-signal reaction time appears more sensitive to the action of noradrenaline. There is clear neuropharmacological and neuroanatomical evidence that stop-signal and go/no-go tasks represent different forms of action inhibition. This evidence translates with remarkable consistency across species. We discuss the possible implications of this evidence with respect to the development of novel therapeutic treatments for disorders in which inhibitory deficits are prominent and debilitating.

Ethanol, 3,4-methylenedioxymethamphetamine (ecstasy) and their combination: long-term behavioral, neurochemical and neuropharmacological effects in the rat.

PubMed

Cassel, Jean-Christophe; Riegert, Céline; Rutz, Susanne; Koenig, Julie; Rothmaier, Katharina; Cosquer, Brigitte; Lazarus, Christine; Birthelmer, Anja; Jeltsch, Hélène; Jones, Byron C; Jackisch, Rolf

2005-10-01

This study investigated long-term behavioral, neurochemical, and neuropharmacological effects of ethanol-(+/-)-3,4-methylenedioxymethamphetamine (MDMA, ecstasy) combinations. Over 4 consecutive days, male Long-Evans rats received 1.5 g/kg ethanol and/or 10 mg/kg MDMA, or saline. Rectal temperatures were taken in some rats. Starting 4 days after the last injection, we tested working memory, sensory-motor coordination, and anxiety. Subsequently, we measured cortical, striatal, septal, and hippocampal monoamines (last MDMA injection-euthanasia delay: 20 days), or electrically evoked release of serotonin (5-HT) in cortical and hippocampal slices, and its modulation in the presence of CP 93,129 (3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrollo[3,2-b]pyrid-5-one) or methiotepin (last MDMA injection-euthanasia delays: 3-6 weeks). Ethanol attenuated the MDMA-induced hyperthermia, but only on the first day. In the long-term, MDMA reduced 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) content in most brain regions. The behavioral and neurochemical effects of the ethanol-MDMA combination were comparable to those of MDMA alone; sensory-motor coordination was altered after ethanol and/or MDMA. In hippocampal slices from rats given ethanol and MDMA, the CP 93,129-induced inhibition and methiotepin-induced facilitation of 5-HT release were stronger and weaker, respectively, than in the other groups. This is the first study addressing long-term effects of repeated MDMA and EtOH combined treatments in experimental animals. Whereas the drug combination produced the same behavioral and neurochemical effects as MDMA alone, our neuropharmacological results suggest that MDMA-EtOH interactions may have specific long-term consequences on presynaptic modulation of hippocampal 5-HT release, but not necessarily related to MDMA-induced depletion of 5-HT. Thus, it is likely that the psycho(patho)logical problems reported by ecstasy users drinking alcohol are not solely due to the consumption of MDMA.

Analgesic, neuropharmacological, anti-diarrheal, and cytotoxic activities of the extract of Solanum sisymbriifolium (Lam.) leaves

PubMed Central

Apu, Apurba Sarker; Bhuyan, Shakhawat Hossan; Matin, Maima; Hossain, Faruq; Khatun, Farjana; Taiab, Abu; Jamaluddin

2013-01-01

Objective: The present study was undertaken to evaluate the possible analgesic, neuropharmacological, anti-diarrheal, and cytotoxic activities of the ethanol extract of leaves of Solanum sisymbriifolium Lam. (Family: Solanaceae). Materials and Methods: The analgesic activity was measured by acetic acid-induced writhing inhibition test. The neuropharmacological activities were evaluated using hole cross, hole board, and elevated plus-maze test and the anti-diarrheal activity was assessed using castor oil-induced diarrhea inhibition method. Brine shrimp lethality bioassay was carried out for assessing the cytotoxicity of the ethanol extract of the leaves. Except cytotoxic activity, all the tests were conducted on mice. Results: The extract at oral doses of 200 and 400 mg/kg body weight showed highly significant (p<0.001) decrease in number of writhing, 52.1±0.66 and 4.4±0.64 compared with the control (78.6±0.29) with the percentage of inhibitions of writhing response were found to be 33.72% and 94.40%, respectively. Compare with the control, the extract at both doses showed significant sedative effect in hole cross test. In hole board test, the extract exhibited highly significant (p<0.001) anxiolytic activity at dose of (200 mg/kg), while the same activity was observed at dose of 400 mg/kg in elevated plus-maze test. The extract showed highly significant (p<0.001) anti-diarrheal activity in a dose-dependent manner. With the extract, significant lethality to brine shrimp was found with LC50 value of 61.66±0.9 μg/ml, which was comparable with the positive control (LC50: 11.89±0.8 µg/ml). Conclusion: The results from the present studies support the traditional uses of this plant part and could form the basis of further investigation including compound isolation. PMID:25050287

Polymethoxyflavones from Nicotiana plumbaginifolia (Solanaceae) Exert Antinociceptive and Neuropharmacological Effects in Mice

PubMed Central

Shajib, Md. Shafiullah; Rashid, Ridwan B.; Ming, Long C.; Islam, Shanta; Sarker, Md. Moklesur R.; Nahar, Lutfun; Sarker, Satyajit D.; Datta, Bidyut K.; Rashid, Mohammad A.

2018-01-01

Polymethoxylavones (PMFs) are known to exhibit significant anti-inflammatory and neuroprotective properties. Nicotiana plumbaginifolia, an annual Bangladeshi herb, is rich in polymethoxyflavones that possess significant analgesic and anxiolytic activities. The present study aimed to determine the antinociceptive and neuropharmacological activities of polyoxygenated flavonoids namely- 3,3′,5,6,7,8-hexamethoxy-4′,5′-methylenedioxyflavone (1), 3,3′,4′,5′,5,6,7,8-octamethoxyflavone (exoticin) (2), 6,7,4′,5′-dimethylenedioxy-3,5,3′-trimethoxyflavone (3), and 3,3′,4′,5,5′,8-hexamethoxy-6,7-methylenedioxyflavone (4), isolated and identified from N. plumbaginifolia. Antinociceptive activity was assessed using the acetic-acid induced writhing, hot plate, tail immersion, formalin and carrageenan-induced paw edema tests, whereas neuropharmacological effects were evaluated in the hole cross, open field and elevated plus maze test. Oral treatment of compounds 1, 3, and 4 (12.5–25 mg/kg b.w.) exhibited dose-dependent and significant (p < 0.01) antinociceptive activity in the acetic-acid, formalin, carrageenan, and thermal (hot plate)-induced pain models. The association of ATP-sensitive K+ channel and opioid systems in their antinociceptive effect was obvious from the antagonist effect of glibenclamide and naloxone, respectively. These findings suggested central and peripheral antinociceptive activities of the compounds. Compound 1, 3, and 4 (12.5 mg/kg b.w.) demonstrated significant (p < 0.05) anxiolytic-like activity in the elevated plus-maze test, while the involvement of GABAA receptor in the action of compound 3 and 4 was evident from the reversal effects of flumazenil. In addition, compounds 1 and 4 (12.5–25 mg/kg b.w) exhibited anxiolytic activity without altering the locomotor responses. The present study suggested that the polymethoxyflavones (1–4) from N. Plumbaginifolia could be considered as suitable candidates for the development of analgesic and anxiolytic agents. PMID:29515437

Polymethoxyflavones from Nicotiana plumbaginifolia (Solanaceae) Exert Antinociceptive and Neuropharmacological Effects in Mice.

PubMed

Shajib, Md Shafiullah; Rashid, Ridwan B; Ming, Long C; Islam, Shanta; Sarker, Md Moklesur R; Nahar, Lutfun; Sarker, Satyajit D; Datta, Bidyut K; Rashid, Mohammad A

2018-01-01

Polymethoxylavones (PMFs) are known to exhibit significant anti-inflammatory and neuroprotective properties. Nicotiana plumbaginifolia , an annual Bangladeshi herb, is rich in polymethoxyflavones that possess significant analgesic and anxiolytic activities. The present study aimed to determine the antinociceptive and neuropharmacological activities of polyoxygenated flavonoids namely- 3,3',5,6,7,8-hexamethoxy-4',5'-methylenedioxyflavone ( 1 ), 3,3',4',5',5,6,7,8-octamethoxyflavone (exoticin) ( 2 ), 6,7,4',5'-dimethylenedioxy-3,5,3'-trimethoxyflavone ( 3 ), and 3,3',4',5,5',8-hexamethoxy-6,7-methylenedioxyflavone ( 4 ), isolated and identified from N. plumbaginifolia . Antinociceptive activity was assessed using the acetic-acid induced writhing, hot plate, tail immersion, formalin and carrageenan-induced paw edema tests, whereas neuropharmacological effects were evaluated in the hole cross, open field and elevated plus maze test. Oral treatment of compounds 1 , 3 , and 4 (12.5-25 mg/kg b.w.) exhibited dose-dependent and significant ( p < 0.01) antinociceptive activity in the acetic-acid, formalin, carrageenan, and thermal (hot plate)-induced pain models. The association of ATP-sensitive K + channel and opioid systems in their antinociceptive effect was obvious from the antagonist effect of glibenclamide and naloxone, respectively. These findings suggested central and peripheral antinociceptive activities of the compounds. Compound 1 , 3 , and 4 (12.5 mg/kg b.w.) demonstrated significant ( p < 0.05) anxiolytic-like activity in the elevated plus-maze test, while the involvement of GABA A receptor in the action of compound 3 and 4 was evident from the reversal effects of flumazenil. In addition, compounds 1 and 4 (12.5-25 mg/kg b.w) exhibited anxiolytic activity without altering the locomotor responses. The present study suggested that the polymethoxyflavones ( 1-4 ) from N. Plumbaginifolia could be considered as suitable candidates for the development of analgesic and anxiolytic agents.

78 FR 65344 - Center for Scientific Review Amended Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-31

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health Center for Scientific Review Amended Notice of Meeting Notice is hereby given of a change in the meeting of the Molecular Neuropharmacology and Signaling Study Section, October 7, 2013, 8:00 a.m. to October 8, 2013, 12:00 p.m., The Dupont...

Drugs and the Brain: An Introduction to Neuropharmacology. Pamphlet Series.

ERIC Educational Resources Information Center

Brick, John

The thousands of different drugs on the market can be separated into two categories: drugs that affect behavior, called psychoactive drugs, and drugs that do not affect behavior. Drugs get into the body by mouth, inhalation into the lungs, by injection into a vein, muscle or under the skin, and by absorption through mucous membranes. Regardless of…

Teaching Neurophysiology, Neuropharmacology, and Experimental Design Using Animal Models of Psychiatric and Neurological Disorders

ERIC Educational Resources Information Center

Morsink, Maarten C.; Dukers, Danny F.

2009-01-01

Animal models have been widely used for studying the physiology and pharmacology of psychiatric and neurological diseases. The concepts of face, construct, and predictive validity are used as indicators to estimate the extent to which the animal model mimics the disease. Currently, we used these three concepts to design a theoretical assignment to…

Therapeutic and Imaging Applications of Dopamine Receptors in Breast Cancer

DTIC Science & Technology

2015-09-01

neuroblastoma ,31 leukemia,29 ovarian,32 breast29,33,34 and colon33 cancer cells. However, most studies did not identify which DAR was expressed in their...the human neuroblastoma SH-SY5Y cell line. Neuropharmacology 2007; 53: 724–732. 32 Moreno-Smith M, Lu C, Shahzad MM, Pena GN, Allen JK, Stone RL et al

The neurocircuitry of addiction: an overview

PubMed Central

Feltenstein, M W; See, R E

2008-01-01

Drug addiction presents as a chronic relapsing disorder characterized by persistent drug-seeking and drug-taking behaviours. Given the significant detrimental effects of this disease both socially and economically, a considerable amount of research has been dedicated to understanding a number of issues in addiction, including behavioural and neuropharmacological factors that contribute to the development, loss of control and persistence of compulsive addictive behaviours. In this review, we will give a broad overview of various theories of addiction, animal models of addiction and relapse, drugs of abuse, and the neurobiology of drug dependence and relapse. Although drugs of abuse possess diverse neuropharmacological profiles, activation of the mesocorticolimbic system, particularly the ventral tegmental area, nucleus accumbens, amygdala and prefrontal cortex via dopaminergic and glutamatergic pathways, constitutes a common pathway by which various drugs of abuse mediate their acute reinforcing effects. However, long-term neuroadaptations in this circuitry likely underlie the transition to drug dependence and cycles of relapse. As further elucidated in more comprehensive reviews of various subtopics on addiction in later sections of this special issue, it is anticipated that continued basic neuroscience research will aid in the development of effective therapeutic interventions for the long-term treatment of drug-dependent individuals. PMID:18311189

Human Drug Discrimination: A Primer and Methodological Review

PubMed Central

Bolin, B. Levi; Alcorn, Joseph L.; Reynolds, Anna R.; Lile, Joshua A.; Rush, Craig R.

2016-01-01

Drug-discrimination procedures empirically evaluate the control that internal drug states exert over behavior. They provide a highly selective method to investigate the neuropharmacological underpinnings of the interoceptive effects of drugs. Historically, drug discrimination has been one of the most widely used assays in the field of behavioral pharmacology. Drug-discrimination procedures have also been adapted for use with humans and are conceptually similar to preclinical drug-discrimination techniques in that a behavior is differentially reinforced contingent on the presence or absence of a specific interoceptive drug stimulus. This review gives some general history and background concerning the major theoretical concepts and principles of drug-discrimination research as well as its relevance to substance-use disorders. This article also provides a procedural overview and discusses key methodological issues that must be considered when designing and conducting a human drug-discrimination study. Although drug discrimination is unequivocally one of the most sophisticated and useful behavioral assays to investigate the underlying neuropharmacology of drugs in vivo, enthusiasm for its use has steadily declined in the last decade and a half. We conclude by commenting on the current state of drug-discrimination research and suggest potential avenues for future drug-discrimination research. PMID:27454673

Translational neuropharmacology and the appropriate and effective use of animal models.

PubMed

Green, A R; Gabrielsson, J; Fone, K C F

2011-10-01

This issue of the British Journal of Pharmacology is dedicated to reviews of the major animal models used in neuropharmacology to examine drugs for both neurological and psychiatric conditions. Almost all major conditions are reviewed. In general, regulatory authorities require evidence for the efficacy of novel compounds in appropriate animal models. However, the failure of many compounds in clinical trials following clear demonstration of efficacy in animal models has called into question both the value of the models and the discovery process in general. These matters are expertly reviewed in this issue and proposals for better models outlined. In this editorial, we further suggest that more attention be made to incorporate pharmacokinetic knowledge into the studies (quantitative pharmacology). We also suggest that more attention be made to ensure that full methodological details are published and recommend that journals should be more amenable to publishing negative data. Finally, we propose that new approaches must be used in drug discovery so that preclinical studies become more reflective of the clinical situation, and studies using animal models mimic the anticipated design of studies to be performed in humans, as closely as possible. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Prophylaxis and Therapy Against Chemical Agents

DTIC Science & Technology

2009-11-01

relationship of stress to neurologic function and the overall role of cholinergic neuropharmacology. These efforts were all directed on finding new ...high concentration in plasma; plasma CaE is synthesized in the liver and secreted into the circulation via the Golgi apparatus of hepatocytes [76...group and held in 1999, 2000, 2002, 2003 and 2005. The report also includes a summary report on bioscavengers as a new pre-treatment for nerve

Annual Research Review: New Frontiers in Developmental Neuropharmacology--Can Long-Term Therapeutic Effects of Drugs Be Optimized through Carefully Timed Early Intervention?

ERIC Educational Resources Information Center

Andersen, Susan L.; Navalta, Carryl P.

2011-01-01

Our aim is to present a working model that may serve as a valuable heuristic to predict enduring effects of drugs when administered during development. Our primary tenet is that a greater understanding of neurodevelopment can lead to improved treatment that intervenes early in the progression of a given disorder and prevents symptoms from…

Frontal Decortication and Adaptive Changes in Striatal Cholinergic Neurons: Neuropharmacological and Behavioral Implications

DTIC Science & Technology

1989-11-24

ACh); choline (Oh); apomnorphine (APO); oxotremorine (OTMN); OXI, oxiracetam; SDHACU, sodium-dependent high affinity choline uptake: PC...control group, Dunnett’s test. TABLE 3- Restoration of the ACh increasing effect of oxotremorine by piracetam in DC rats. Striatal ACh content (nmoles/g...ACh content induced by oxotremorine and apomorphine useful model for studying means to restore the deficit in stria- acting at muscarine and dopamine

Lactuca capensis reverses memory deficits in Aβ1-42-induced an animal model of Alzheimer's disease.

PubMed

Postu, Paula Alexandra; Noumedem, Jaures A K; Cioanca, Oana; Hancianu, Monica; Mihasan, Marius; Ciorpac, Mitica; Gorgan, Dragos Lucian; Petre, Brindusa Alina; Hritcu, Lucian

2018-01-01

We investigated the neuropharmacological effects of the methanolic extract from Lactuca capensis Thunb. leaves (100 and 200 mg/kg) for 21 days on memory impairment in an Alzheimer's disease (AD) rat model produced by direct intraventricular delivery of amyloid-β1-42 (Aβ1-42). Behavioural assays such as Y-maze and radial arm maze test were used for assessing memory performance. Aβ1-42 decreased cognitive performance in the behavioural tests which were ameliorated by pre-treatment with the methanolic extract. Acetylcholinesterase activity and oxidant-antioxidant balance in the rat hippocampus were abnormally altered by Aβ1-42 treatment while these deficits were recovered by pre-treatment with the methanolic extract. In addition, rats were given Aβ1-42 exhibited in the hippocampus decreased brain-derived neurotrophic factor (BDNF) mRNA copy number and increased IL-1β mRNA copy number which was reversed by the methanolic extract administration. These findings suggest that the methanolic extract could be a potent neuropharmacological agent against dementia via modulating cholinergic activity, increasing of BDNF levels and promoting antioxidant action in the rat hippocampus. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

4-dimensional functional profiling in the convulsant-treated larval zebrafish brain.

PubMed

Winter, Matthew J; Windell, Dylan; Metz, Jeremy; Matthews, Peter; Pinion, Joe; Brown, Jonathan T; Hetheridge, Malcolm J; Ball, Jonathan S; Owen, Stewart F; Redfern, Will S; Moger, Julian; Randall, Andrew D; Tyler, Charles R

2017-07-26

Functional neuroimaging, using genetically-encoded Ca 2+ sensors in larval zebrafish, offers a powerful combination of high spatiotemporal resolution and higher vertebrate relevance for quantitative neuropharmacological profiling. Here we use zebrafish larvae with pan-neuronal expression of GCaMP6s, combined with light sheet microscopy and a novel image processing pipeline, for the 4D profiling of chemoconvulsant action in multiple brain regions. In untreated larvae, regions associated with autonomic functionality, sensory processing and stress-responsiveness, consistently exhibited elevated spontaneous activity. The application of drugs targeting different convulsant mechanisms (4-Aminopyridine, Pentylenetetrazole, Pilocarpine and Strychnine) resulted in distinct spatiotemporal patterns of activity. These activity patterns showed some interesting parallels with what is known of the distribution of their respective molecular targets, but crucially also revealed system-wide neural circuit responses to stimulation or suppression. Drug concentration-response curves of neural activity were identified in a number of anatomically-defined zebrafish brain regions, and in vivo larval electrophysiology, also conducted in 4dpf larvae, provided additional measures of neural activity. Our quantification of network-wide chemoconvulsant drug activity in the whole zebrafish brain illustrates the power of this approach for neuropharmacological profiling in applications ranging from accelerating studies of drug safety and efficacy, to identifying pharmacologically-altered networks in zebrafish models of human neurological disorders.

Human drug discrimination: A primer and methodological review.

PubMed

Bolin, B Levi; Alcorn, Joseph L; Reynolds, Anna R; Lile, Joshua A; Rush, Craig R

2016-08-01

Drug-discrimination procedures empirically evaluate the control that internal drug states exert over behavior. They provide a highly selective method to investigate the neuropharmacological underpinnings of the interoceptive effects of drugs. Historically, drug discrimination has been one of the most widely used assays in the field of behavioral pharmacology. Drug-discrimination procedures have also been adapted for use with humans and are conceptually similar to preclinical drug-discrimination techniques in that a behavior is differentially reinforced contingent on the presence or absence of a specific interoceptive drug stimulus. This review gives some general history and background concerning the major theoretical concepts and principles of drug-discrimination research as well as its relevance to substance-use disorders. This article also provides a procedural overview and discusses key methodological issues that must be considered when designing and conducting a human drug-discrimination study. Although drug discrimination is unequivocally one of the most sophisticated and useful behavioral assays to investigate the underlying neuropharmacology of drugs in vivo, enthusiasm for its use has steadily declined in the last decade and a half. We conclude by commenting on the current state of drug-discrimination research and suggest potential avenues for future drug-discrimination research. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Moringa oleifera Seed Extract Alleviates Scopolamine-Induced Learning and Memory Impairment in Mice.

PubMed

Zhou, Juan; Yang, Wu-Shuang; Suo, Da-Qin; Li, Ying; Peng, Lu; Xu, Lan-Xi; Zeng, Kai-Yue; Ren, Tong; Wang, Ying; Zhou, Yu; Zhao, Yun; Yang, Li-Chao; Jin, Xin

2018-01-01

The extract of Moringa oleifera seeds has been shown to possess various pharmacological properties. In the present study, we assessed the neuropharmacological effects of 70% ethanolic M. oleifera seed extract (MSE) on cognitive impairment caused by scopolamine injection in mice using the passive avoidance and Morris water maze (MWM) tests. MSE (250 or 500 mg/kg) was administered to mice by oral gavage for 7 or 14 days, and cognitive impairment was induced by intraperitoneal injection of scopolamine (4 mg/kg) for 1 or 6 days. Mice that received scopolamine alone showed impaired learning and memory retention and considerably decreased cholinergic system reactivity and neurogenesis in the hippocampus. MSE pretreatment significantly ameliorated scopolamine-induced cognitive impairment and enhanced cholinergic system reactivity and neurogenesis in the hippocampus. Additionally, the protein expressions of phosphorylated Akt, ERK1/2, and CREB in the hippocampus were significantly decreased by scopolamine, but these decreases were reversed by MSE treatment. These results suggest that MSE-induced ameliorative cognitive effects are mediated by enhancement of the cholinergic neurotransmission system and neurogenesis via activation of the Akt, ERK1/2, and CREB signaling pathways. These findings suggest that MSE could be a potent neuropharmacological drug against amnesia, and its mechanism might be modulation of cholinergic activity via the Akt, ERK1/2, and CREB signaling pathways.

From neuroscience to application in neuropharmacology: A generation of progress in electrophysiology.

PubMed

Carozzo, S; Fornaro, S; Garbarino, S; Saturno, M; Sannita, W G

2006-04-01

A continuum from neuronal cellular/subcellular properties to system processes appears to exist in many instances and to allow privileged approaches in neuroscience and neuropharmacology research. Brain signals and the cholinergic and GABAergic systems, in vivo and in vitro evidence from studies on the retina, or the "gamma band" oscillations in neuron membrane potential/spiking rate and neuronal assemblies are examples in this respect. However, spontaneous and stimulus-event-related signals at any location and time point reflect brain state conditions that depend on neuromodulation, neurotransmitter interaction, hormones (e.g., glucocorticois, ACTH, estrogens) and neuroendocrine interaction at different levels of complexity, as well as on the spontaneous or experimentally-induced changes in metabolism (e.g., glucose, ammonia), blood flow, pO2, pCO2, acid/base balance, K activity, etc., that occur locally or systemically. Any of these factors can account for individual differences and/or changes over time that often are (or need to be) neglected in pharmaco-EEG studies or are dealt with statistically and by controlling the experimental conditions. As a result, the electrophysiological effects of neuroactive drugs are to an extent non-specific and require adequate modeling and precise correlation with independent parameters (e.g., drug kinetics, vigilance, hormonal profile or metabolic status, etc.) to avoid biased results in otherwise controlled studies.

BrainSnail: A dynamic information display system for the Sciences

PubMed Central

Telefont, Martin; Asaithambi, Asai

2009-01-01

Scientific reference management has become crucial in rapidly expanding fields of biology. Many of the reference management systems currently employed are reference centric and not object/process focused. BrainSnail is a reference management/knowledge representation application that tries to bridge disconnect between subject and reference in the fields of neuropharmacology, neuroanatomy and neurophysiology. BrainSnail has been developed with considering both individual researcher and research group efforts. PMID:19293992

Neuropharmacological Specificity of Brain Structures Involved in Soman-Induced Seizures

DTIC Science & Technology

2012-01-01

Bernabé Burckhart M-F, Lallement G. Efficacy of the ketamine-atropine combination in the delayed treatment of soman- induced status epilepticus ...The functional anatomy of limbic status epilepticus in the rat. I. Patterns of 14C-2-deoxyglucose uptake and fos immunochemistry. Journal of...Neuroscience 1993a;13(11):4787–801. White LE, Price JL. The functional anatomy of limbic status epilepticus in the rat. II. The effects of focal deactivation

Enduring Effects Of Traumatic Stress On Brain Neuropeptide Y (NPY) and Corticotropin-Releasing Factor (CRF) Systems: Molecular and Neuropharmacologic Studies

DTIC Science & Technology

2009-12-01

neuropeptide, corticotropin-releasing factor, neuropeptide Y, anxiety, depression, behavior, treatment , gene expression. 16. SECURITY CLASSIFICATION OF...preclinical evidence that neuropeptide Y (NPY) and corticotropin-releasing factor (CRF) systems acutely modulate stress and dysphoria responses and 2...2.5 weeks after the final defeat (data not shown). Treatment with twice daily imipramine (i.p., 2.5 mg/kg) for 2.5 weeks, eliminated the effects of

Alotamide A, a Novel Neuropharmacological Agent From the Marine Cyanobacterium Lyngbya bouillonii

PubMed Central

Soria-Mercado, Irma E.; Pereira, Alban; Cao, Zhengyu; Murray, Thomas F.; Gerwick, William H.

2009-01-01

Alotamide A (1), a structurally intriguing cyclic depsipeptide, was isolated from the marine mat-forming cyanobacterium Lyngbya bouillonii collected in Papua New Guinea. It features three contiguous peptidic residues and an unsaturated heptaketide with oxidations and methylations unlike those found in any other marine cyanobacterial metabolite. Pure alotamide A (1) displays an unusual calcium influx activation profile in murine cerebrocortical neurons with an EC50 of 4.18 μM. PMID:19754100

Too Hard to Control: Compromised Pain Anticipation and Modulation in Mild Traumatic Brain Injury

DTIC Science & Technology

2014-01-07

modulation) will be able to answer these questions. In a related prior study, quantitative sensory testing was conducted in moderate to severe TBI and...found significant loss of thermal and touch sensibility compared with healthy con- trols.67 Although detailed quantitative sensory testing was not...IA. Pain and post traumatic stress disorder ‚Äì Review of clinical and experimental evidence. Neuropharmacology 2012; 62: 586–597. 36 First MB, Spitzer

Neuropharmacological mechanisms of drug reward: beyond dopamine in the nucleus accumbens.

PubMed

Bardo, M T

1998-01-01

Multiple lines of research have implicated the mesolimbic dopamine system in drug reward measured by either the drug self-administration or conditioned place preference paradigm. The present review summarizes recent work that examines the neuropharmacological mechanisms by which drugs impinge on this dopaminergic neural circuitry, as well as other systems that provide input and output circuits to the mesolimbic dopamine system. Studies examining the effect of selective agonist and antagonist drugs administered systemically have indicated that multiple neurotransmitters are involved, including dopamine, serotonin, acetylcholine, glutamate, GABA, and various peptides. Direct microinjection studies have also provided crucial evidence indicating that, in addition to the mesolimbic dopamine system, other structures play a role in drug reward, including the ventral pallidum, amygdala, hippocampus, hypothalamus, and pedunculopontine tegmental nucleus. GABAergic circuitry descending from the nucleus accumbens to the pedunculopontine tegmental nucleus via the ventral pallidum appears to be especially important in directing the behavioral sequelae associated with reward produced by various drugs of abuse. However, activation of the reward circuitry is achieved differently for various drugs of abuse. With amphetamine and cocaine, initiation of reward is controlled within the nucleus accumbens and prefrontal cortex, respectively. With opiates, initiation of reward involves the ventral tegmental area, nucleus accumbens, hippocampus, and hypothalamus. It is not clear presently if these multiple anatomical structures mediate opiate reward by converging on a single output system or multiple output systems.

An integrated modelling framework for neural circuits with multiple neuromodulators.

PubMed

Joshi, Alok; Youssofzadeh, Vahab; Vemana, Vinith; McGinnity, T M; Prasad, Girijesh; Wong-Lin, KongFatt

2017-01-01

Neuromodulators are endogenous neurochemicals that regulate biophysical and biochemical processes, which control brain function and behaviour, and are often the targets of neuropharmacological drugs. Neuromodulator effects are generally complex partly owing to the involvement of broad innervation, co-release of neuromodulators, complex intra- and extrasynaptic mechanism, existence of multiple receptor subtypes and high interconnectivity within the brain. In this work, we propose an efficient yet sufficiently realistic computational neural modelling framework to study some of these complex behaviours. Specifically, we propose a novel dynamical neural circuit model that integrates the effective neuromodulator-induced currents based on various experimental data (e.g. electrophysiology, neuropharmacology and voltammetry). The model can incorporate multiple interacting brain regions, including neuromodulator sources, simulate efficiently and easily extendable to large-scale brain models, e.g. for neuroimaging purposes. As an example, we model a network of mutually interacting neural populations in the lateral hypothalamus, dorsal raphe nucleus and locus coeruleus, which are major sources of neuromodulator orexin/hypocretin, serotonin and norepinephrine/noradrenaline, respectively, and which play significant roles in regulating many physiological functions. We demonstrate that such a model can provide predictions of systemic drug effects of the popular antidepressants (e.g. reuptake inhibitors), neuromodulator antagonists or their combinations. Finally, we developed user-friendly graphical user interface software for model simulation and visualization for both fundamental sciences and pharmacological studies. © 2017 The Authors.

Moringa oleifera Seed Extract Alleviates Scopolamine-Induced Learning and Memory Impairment in Mice

PubMed Central

Zhou, Juan; Yang, Wu-shuang; Suo, Da-qin; Li, Ying; Peng, Lu; Xu, Lan-xi; Zeng, Kai-yue; Ren, Tong; Wang, Ying; Zhou, Yu; Zhao, Yun; Yang, Li-chao; Jin, Xin

2018-01-01

The extract of Moringa oleifera seeds has been shown to possess various pharmacological properties. In the present study, we assessed the neuropharmacological effects of 70% ethanolic M. oleifera seed extract (MSE) on cognitive impairment caused by scopolamine injection in mice using the passive avoidance and Morris water maze (MWM) tests. MSE (250 or 500 mg/kg) was administered to mice by oral gavage for 7 or 14 days, and cognitive impairment was induced by intraperitoneal injection of scopolamine (4 mg/kg) for 1 or 6 days. Mice that received scopolamine alone showed impaired learning and memory retention and considerably decreased cholinergic system reactivity and neurogenesis in the hippocampus. MSE pretreatment significantly ameliorated scopolamine-induced cognitive impairment and enhanced cholinergic system reactivity and neurogenesis in the hippocampus. Additionally, the protein expressions of phosphorylated Akt, ERK1/2, and CREB in the hippocampus were significantly decreased by scopolamine, but these decreases were reversed by MSE treatment. These results suggest that MSE-induced ameliorative cognitive effects are mediated by enhancement of the cholinergic neurotransmission system and neurogenesis via activation of the Akt, ERK1/2, and CREB signaling pathways. These findings suggest that MSE could be a potent neuropharmacological drug against amnesia, and its mechanism might be modulation of cholinergic activity via the Akt, ERK1/2, and CREB signaling pathways. PMID:29740317

An integrated modelling framework for neural circuits with multiple neuromodulators

PubMed Central

Vemana, Vinith

2017-01-01

Neuromodulators are endogenous neurochemicals that regulate biophysical and biochemical processes, which control brain function and behaviour, and are often the targets of neuropharmacological drugs. Neuromodulator effects are generally complex partly owing to the involvement of broad innervation, co-release of neuromodulators, complex intra- and extrasynaptic mechanism, existence of multiple receptor subtypes and high interconnectivity within the brain. In this work, we propose an efficient yet sufficiently realistic computational neural modelling framework to study some of these complex behaviours. Specifically, we propose a novel dynamical neural circuit model that integrates the effective neuromodulator-induced currents based on various experimental data (e.g. electrophysiology, neuropharmacology and voltammetry). The model can incorporate multiple interacting brain regions, including neuromodulator sources, simulate efficiently and easily extendable to large-scale brain models, e.g. for neuroimaging purposes. As an example, we model a network of mutually interacting neural populations in the lateral hypothalamus, dorsal raphe nucleus and locus coeruleus, which are major sources of neuromodulator orexin/hypocretin, serotonin and norepinephrine/noradrenaline, respectively, and which play significant roles in regulating many physiological functions. We demonstrate that such a model can provide predictions of systemic drug effects of the popular antidepressants (e.g. reuptake inhibitors), neuromodulator antagonists or their combinations. Finally, we developed user-friendly graphical user interface software for model simulation and visualization for both fundamental sciences and pharmacological studies. PMID:28100828

Electrophysiological properties of neurons derived from human stem cells and iNeurons in vitro.

PubMed

Halliwell, Robert F

2017-06-01

Functional studies of neurons have traditionally used nervous system tissues from a variety of non-human vertebrate and invertebrate species, even when the focus of much of this research has been directed at understanding human brain function. Over the last decade, the identification and isolation of human stem cells from embryonic, tissue (or adult) and induced pluripotent stem cells (iPSCs) has revolutionized the availability of human neurons for experimental studies in vitro. In addition, the direct conversion of terminally differentiated fibroblasts into Induced neurons (iN) has generated great excitement because of the likely value of such human stem cell derived neurons (hSCNs) and iN cells in drug discovery, neuropharmacology, neurotoxicology and regenerative medicine. This review addresses the current state of our knowledge of functional receptors and ion channels expressed in neurons derived from human stem cells and iNeurons and identifies gaps and questions that might be investigated in future studies; it focusses almost exclusively on what is known about the electrophysiological properties of neurons derived from human stem cells and iN cells in vitro with an emphasis on voltage and ligand gated ion channels, since these mediate synaptic signalling in the nervous system and they are at the heart of neuropharmacology. Copyright © 2016 Elsevier Ltd. All rights reserved.

Molecular Signaling Pathways Behind the Biological Effects of Salvia Species Diterpenes in Neuropharmacology and Cardiology.

PubMed

Akaberi, M; Iranshahi, M; Mehri, S

2016-06-01

The genus Salvia, from the Lamiaceae family, has diverse biological properties that are primarily attributable to their diterpene contents. There is no comprehensive review on the molecular signaling pathways of these active components. In this review, we investigated the molecular targets of bioactive Salvia diterpenes responsible for the treatment of nervous and cardiovascular diseases. The effects on different pathways, including apoptosis signaling, oxidative stress phenomena, the accumulation of amyloid beta plaques, and tau phosphorylation, have all been considered to be mechanisms of the anti-Alzheimer properties of Salvia diterpenes. Additionally, effects on the benzodiazepine and kappa opioid receptors and neuroprotective effects are noted as neuropharmacological properties of Salvia diterpenes, including tanshinone IIA, salvinorin A, cryptotanshinone, and miltirone. Tanshinone IIA, as the primary diterpene of Salvia miltiorrhiza, has beneficial activities in heart diseases because of its ability to scavenge free radicals and its effects on transcription factors, such as nuclear transcription factor-kappa B (NF-κB) and the mitogen-activated protein kinases (MAPKs). Additionally, tanshinone IIA has also been proposed to have cardioprotective properties including antiarrhythmic activities and effects on myocardial infarction. With respect to the potential therapeutic effects of Salvia diterpenes, comprehensive clinical trials are warranted to evaluate these valuable molecules as lead compounds. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Mesolimbic and Nigrostriatal Dopaminergic Systems: Behavioral Neuropharmacology.

DTIC Science & Technology

1985-08-01

presented in Table Table III List of drugs D ru gVeh i c l e Intracerebral infusions Dopamine agonist~s Apomorphine hydrochloride 0.1% Na metabisulfite...saline GABA 0.9% saline Picrotoxin 0 .9%saline Systemic injections Dopamine agents d-Amphetamine sulfate 0.9% saline Aponiorphine hydrochloride 0.9...3H)methionine (15 Ci/mmole, lmCi/ml. 16 Amersham), 122 ul of freshly prepared pargyline hydrochloride (10.2 mM), 326 ul of I M Tris pH 10.8, 246 ul

PET measurement of receptor occupancy as a tool to guide dose selection in neuropharmacology: are we asking the right questions?

PubMed

Barrett, Jeffrey S; McGuire, Jennifer; Vezina, Heather; Spitsin, Serguei; Douglas, Steven D

2013-12-01

Receptor occupancy studies are becoming commonplace for verifying drug mechanism of action and selecting early development candidates. Positron emission tomography (PET) has been applied to pharmacodynamic (PD) studies in several therapeutic areas including neurology, cardiology, and oncology. Prospective use of PET to define dosing requirements has been proposed particularly for central nervous system (CNS)-targeted drugs; however, correlations with clinical outcomes have been mostly anecdotal and not causally established.

Sedative effect of galphimine B, a nor-seco-triterpenoid from Galphimia glauca.

PubMed

Tortoriello, J; Ortega, A

1993-10-01

Galphimia glauca Cav. (Malpighiaceae) is used in Mexican traditional medicine as a sedative in the treatment of mental disorders. Sedative properties of a methanolic extract of the aerial parts of this plant have been established in animal trials and an active compound, named galphimine B, has already been isolated. This compound was submitted to neuropharmacological testing, where it was shown that galphimine B had no significant effect as an anticonvulsant, while it exhibited a strong depressant activity on the nervous system.

The control of male sexual responses.

PubMed

Courtois, Frédérique; Carrier, Serge; Charvier, Kathleen; Guertin, Pierre A; Journel, Nicolas Morel

2013-01-01

Male sexual responses are reflexes mediated by the spinal cord and modulated by neural circuitries involving both the peripheral and central nervous system. While the brain interact with the reflexes to allow perception of sexual sensations and to exert excitatory or inhibitory influences, penile reflexes can occur despite complete transections of the spinal cord, as demonstrated by the reviewed animal studies on spinalization and human studies on spinal cord injury. Neurophysiological and neuropharmacological substrates of the male sexual responses will be discussed in this review, starting with the spinal mediation of erection and its underlying mechanism with nitric oxide (NO), followed by the description of the ejaculation process, its neural mediation and its coordination by the spinal generator of ejaculation (SGE), followed by the occurrence of climax as a multisegmental sympathetic reflex discharge. Brain modulation of these reflexes will be discussed through neurophysiological evidence involving structures such as the medial preoptic area of hypothalamus (MPOA), the paraventricular nucleus (PVN), the periaqueductal gray (PAG), and the nucleus para-gigantocellularis (nPGI), and through neuropharmacological evidence involving neurotransmitters such as serotonin (5-HT), dopamine and oxytocin. The pharmacological developments based on these mechanisms to treat male sexual dysfunctions will complete this review, including phosphodiesterase (PDE-5) inhibitors and intracavernous injections (ICI) for the treatment of erectile dysfunctions (ED), selective serotonin reuptake inhibitor (SSRI) for the treatment of premature ejaculation, and cholinesterase inhibitors as well as alpha adrenergic drugs for the treatment of anejaculation and retrograde ejaculation. Evidence from spinal cord injured studies will be highlighted upon each step.

Novel Psychoactive Substances-Recent Progress on Neuropharmacological Mechanisms of Action for Selected Drugs.

PubMed

Hassan, Zurina; Bosch, Oliver G; Singh, Darshan; Narayanan, Suresh; Kasinather, B Vicknasingam; Seifritz, Erich; Kornhuber, Johannes; Quednow, Boris B; Müller, Christian P

2017-01-01

A feature of human culture is that we can learn to consume chemical compounds, derived from natural plants or synthetic fabrication, for their psychoactive effects. These drugs change the mental state and/or the behavioral performance of an individual and can be instrumentalized for various purposes. After the emergence of a novel psychoactive substance (NPS) and a period of experimental consumption, personal and medical benefits and harm potential of the NPS can be estimated on evidence base. This may lead to a legal classification of the NPS, which may range from limited medical use, controlled availability up to a complete ban of the drug form publically accepted use. With these measures, however, a drug does not disappear, but frequently continues to be used, which eventually allows an even better estimate of the drug's properties. Thus, only in rare cases, there is a final verdict that is no more questioned. Instead, the view on a drug can change from tolerable to harmful but may also involve the new establishment of a desired medical application to a previously harmful drug. Here, we provide a summary review on a number of NPS for which the neuropharmacological evaluation has made important progress in recent years. They include mitragynine ("Kratom"), synthetic cannabinoids (e.g., "Spice"), dimethyltryptamine and novel serotonergic hallucinogens, the cathinones mephedrone and methylone, ketamine and novel dissociative drugs, γ-hydroxybutyrate, γ-butyrolactone, and 1,4-butanediol. This review shows not only emerging harm potentials but also some potential medical applications.

Inhalant abuse among adolescents: neurobiological considerations

PubMed Central

Lubman, D I; Yücel, M; Lawrence, A J

2008-01-01

Experimentation with volatile substances (inhalants) is common during early adolescence, yet limited work has been conducted examining the neurobiological impact of regular binge use during this key stage of development. Human studies consistently demonstrate that chronic use is associated with significant toxic effects, including neurological and neuropsychological impairment, as well as diffuse and subtle changes in white matter. However, most preclinical research has tended to focus on acute exposure, with limited work examining the neuropharmacological or toxicological mechanisms underpinning these changes or their potential reversibility with abstinence. Nevertheless, there is growing evidence that commonly abused inhalants share common cellular mechanisms, and have similar actions to other drugs of abuse. Indeed, the majority of acute behavioural effects appear to be underpinned by changes in receptor and/or ion channel activity (for example, GABAA, glycine and 5HT3 receptor activation, NMDA receptor inhibition), although nonspecific interactions can also arise at high concentrations. Recent studies examining the effects of toluene exposure during the early postnatal period are suggestive of long-term alterations in the function of NMDA and GABAA receptors, although limited work has been conducted investigating exposure during adolescence. Given the critical role of neurotransmitter systems in cognitive, emotional and brain development, future studies will need to take account of the substantial neuromaturational changes that are known to occur in the brain during childhood and adolescence, and to specifically investigate the neuropharmacological and toxicological profile of inhalant exposure during this period of development. PMID:18332858

Neuropharmacological Evaluation of Toxic Chemicals. Part 1. Behavioral and EEG Correlates of Immobilization in the Rhesus Monkey. Part 2. Operant Conditioning of 12-15 Hz Sensorimotor Cortex EEG Activity in the Rhesus Monkey

DTIC Science & Technology

1977-06-01

especially when procedures involving catheterization of the cardiovascular system or electrical stimulation or recording of brain were desired in awake ...immobilization. Most commonly, the greatest magnitude of SMR activity occurring in the awake condition appeared during immobilization or during immobiliz- ation...level of arousal in the awake animal. We were impressed by the fact that the immobilization response continued throughout the 15 minute observation

Neuropharmacological effects of oleamide in male and female mice.

PubMed

Akanmu, Moses A; Adeosun, Samuel O; Ilesanmi, Olapade R

2007-08-22

Oleamide, a fatty acid amide accumulates selectively in the cerebrospinal fluid of sleep deprived cats and rats. Oleamide has been reported to have effects on a wide range of receptors and neurotransmitter systems especially the centrally acting ones for example, dopamine acetylcholine, serotonin, gamma aminobutyric acid (GABA), cannabinoid and vanilloid among others. This suggests a wide range of central nervous system effects of the compound. The effects of intraperitoneal administered oleamide on Novelty-induced behaviours, learning and memory and forced swimming-induced depression were studied. The relative effects of the compound on the male and female mice were also noted. Oleamide dose-dependently reduced (p<0.05) novelty induced rearing, grooming and locomotion. The effects on the all NIBs started within the first 10 min of the test and the peak of the effects was observed during the third 10 min period of the test. Effect of oleamide on short-term working memory was significantly (p<0.05) affected only with the dose of 5mg/kg while the other dose of 10mg/kg had no effect. In the forced swimming test, acute triple intraperitoneal administration of oleamide at 10mg/kg induced a significant reduction in the immobility duration in mice signifying an antidepressant effect. Sex differences in the effects of oleamide (10mg/kg, i.p.) were clearly evident in active behaviours in FST. These results confirm the multiplicity of central nervous system receptors and neurotransmitters that oleamide interacts with hence its numerous and diverse neuropharmacological effects. Most importantly, the present study suggests that oleamide has antidepressant-like property.

The Mechanisms of Psychedelic Visionary Experiences: Hypotheses from Evolutionary Psychology

PubMed Central

Winkelman, Michael J.

2017-01-01

Neuropharmacological effects of psychedelics have profound cognitive, emotional, and social effects that inspired the development of cultures and religions worldwide. Findings that psychedelics objectively and reliably produce mystical experiences press the question of the neuropharmacological mechanisms by which these highly significant experiences are produced by exogenous neurotransmitter analogs. Humans have a long evolutionary relationship with psychedelics, a consequence of psychedelics' selective effects for human cognitive abilities, exemplified in the information rich visionary experiences. Objective evidence that psychedelics produce classic mystical experiences, coupled with the finding that hallucinatory experiences can be induced by many non-drug mechanisms, illustrates the need for a common model of visionary effects. Several models implicate disturbances of normal regulatory processes in the brain as the underlying mechanisms responsible for the similarities of visionary experiences produced by psychedelic and other methods for altering consciousness. Similarities in psychedelic-induced visionary experiences and those produced by practices such as meditation and hypnosis and pathological conditions such as epilepsy indicate the need for a general model explaining visionary experiences. Common mechanisms underlying diverse alterations of consciousness involve the disruption of normal functions of the prefrontal cortex and default mode network (DMN). This interruption of ordinary control mechanisms allows for the release of thalamic and other lower brain discharges that stimulate a visual information representation system and release the effects of innate cognitive functions and operators. Converging forms of evidence support the hypothesis that the source of psychedelic experiences involves the emergence of these innate cognitive processes of lower brain systems, with visionary experiences resulting from the activation of innate processes based in the mirror neuron system (MNS). PMID:29033783

Neuroprotective effects of multifaceted hybrid agents targeting MAO, cholinesterase, iron and β-amyloid in ageing and Alzheimer's disease.

PubMed

Weinreb, Orly; Amit, Tamar; Bar-Am, Orit; Youdim, Moussa B H

2016-07-01

Alzheimer's disease (AD) is accepted nowadays as a complex neurodegenerative disorder with multifaceted cerebral pathologies, including extracellular deposition of amyloid β peptide-containing plaques, intracellular neurofibrillary tangles, progressive loss of cholinergic neurons, metal dyshomeostasis, mitochondrial dysfunction, neuroinflammation, glutamate excitoxicity, oxidative stress and increased MAO enzyme activity. This may explain why it is currently widely accepted that a more effective therapy for AD would result from the use of multifunctional drugs, which may affect more than one brain target involved in the disease pathology. The current review will discuss the potential benefits of novel multimodal neuroprotective, brain permeable drugs, recently developed by Youdim and collaborators, as a valuable therapeutic approach for AD treatment. The pharmacological and neuroprotective properties of these multitarget-directed ligands, which target MAO enzymes, the cholinergic system, iron accumulation and amyloid β peptide generation/aggregation are described, with a special emphasis on their potential therapeutic value for ageing and AD-associated cognitive functions. This review is conceived as a tribute to the broad neuropharmacology work of Professor Moussa Youdim, Professor Emeritus in the Faculty of Medicine and Director of Eve Topf Center of Excellence in Technion-Israel Institute of Technology, and Chief Scientific Officer of ABITAL Pharma Pipeline Ltd., at the occasion of his 75th birthday. This article is part of a themed section on Updating Neuropathology and Neuropharmacology of Monoaminergic Systems. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.13/issuetoc. © 2015 The British Pharmacological Society.

Novel Psychoactive Substances—Recent Progress on Neuropharmacological Mechanisms of Action for Selected Drugs

PubMed Central

Hassan, Zurina; Bosch, Oliver G.; Singh, Darshan; Narayanan, Suresh; Kasinather, B. Vicknasingam; Seifritz, Erich; Kornhuber, Johannes; Quednow, Boris B.; Müller, Christian P.

2017-01-01

A feature of human culture is that we can learn to consume chemical compounds, derived from natural plants or synthetic fabrication, for their psychoactive effects. These drugs change the mental state and/or the behavioral performance of an individual and can be instrumentalized for various purposes. After the emergence of a novel psychoactive substance (NPS) and a period of experimental consumption, personal and medical benefits and harm potential of the NPS can be estimated on evidence base. This may lead to a legal classification of the NPS, which may range from limited medical use, controlled availability up to a complete ban of the drug form publically accepted use. With these measures, however, a drug does not disappear, but frequently continues to be used, which eventually allows an even better estimate of the drug’s properties. Thus, only in rare cases, there is a final verdict that is no more questioned. Instead, the view on a drug can change from tolerable to harmful but may also involve the new establishment of a desired medical application to a previously harmful drug. Here, we provide a summary review on a number of NPS for which the neuropharmacological evaluation has made important progress in recent years. They include mitragynine (“Kratom”), synthetic cannabinoids (e.g., “Spice”), dimethyltryptamine and novel serotonergic hallucinogens, the cathinones mephedrone and methylone, ketamine and novel dissociative drugs, γ-hydroxybutyrate, γ-butyrolactone, and 1,4-butanediol. This review shows not only emerging harm potentials but also some potential medical applications. PMID:28868040

ISOLATION OF NOVEL PARA-PENTYL PHENYL BENZOATE FROM MONDIA WHITEI. (HOOK.F.) SKEELS (PERIPLOCACEAE), ITS STRUCTURE, SYNTHESIS AND NEUROPHARMACOLOGICAL EVALUATION.

PubMed

Bamigboye J, Taiwo; Josephine Y, Osasan; Olujide O, Olubiyi; A, Oyemitan Idris; Shakir A M, Atoyebi; Mark R J, Elsegood; Raymond C F, Jones

2017-01-01

Mondia whitei L. (Hook. F.) Skeels (Periplocaceae) is a medicinal plant used locally in managing pain, fever, loss of appetite and as aphrodiasc in the South-Western states of Nigeria. However, the fruit is consumed habitually in the South-Eastern states of Nigeria, leading to speculation that it may possess some central nervous system effect but which has not been scientifically investigated, hence this study. Fresh fruits of Mondia whitei were collected and identified by a taxonomist. They were chopped into small pieces and extracted with absolute ethanol. The crude extract was subjected to various chromatographic techniques to isolate a novel compound whose structure was elucidated from the analysis of the crystal data and by extensive use of spectroscopy. The structure was confirmed by synthesis. The compound was subjected to anxiolytic and sedative activity assay. Computational analysis of the receptor binding event of isolated compound at the gamma amino butyric acid A receptor was also evaluated. The structure of the compound was elucidated as para pentyl phenyl benzoate. The neuropharmacological evaluation of the compound indicated significant (p<0.05) depression of the central nervous system. The binding characteristics of the compound to gamma amino butyric acid A receptors appears to be more favorable than those obtained for gamma amino butyric acid, chlorpromazine, benzamidine, and is comparable with the affinity obtained for pentobarbitone and diazepam. These present data provide evidence for the role of para pentyl phenyl benzoate in the habitual consumption of the fruit as well as its central nervous system activities.

Naloxone-induced seizures in rats infected with Borna disease virus.

PubMed

Solbrig, M V; Koob, G F; Lipkin, W I

1996-04-01

The opioid antagonist naloxone is widely used in the emergency treatment of nontraumatic coma. Although it is uncommon for serious side effects to result from administration of opiate antagonists, we report that naloxone can have epileptogenic effects in the context of encephalitis. In an experimental model of viral encephalitis, rats infected with Borna disease virus developed myoclonic, generalized clonic, or atonic seizures; behavior arrest; and staring spells when treated with naloxone. These findings suggest a novel neuropharmacologic link, through opioid peptide systems, between epilepsy and encephalitis and disclose a potential contraindication to use of opioid antagonists in nontraumatic coma.

Computational neuropharmacology: dynamical approaches in drug discovery.

PubMed

Aradi, Ildiko; Erdi, Péter

2006-05-01

Computational approaches that adopt dynamical models are widely accepted in basic and clinical neuroscience research as indispensable tools with which to understand normal and pathological neuronal mechanisms. Although computer-aided techniques have been used in pharmaceutical research (e.g. in structure- and ligand-based drug design), the power of dynamical models has not yet been exploited in drug discovery. We suggest that dynamical system theory and computational neuroscience--integrated with well-established, conventional molecular and electrophysiological methods--offer a broad perspective in drug discovery and in the search for novel targets and strategies for the treatment of neurological and psychiatric diseases.

Exposure therapy in eating disorders revisited.

PubMed

Koskina, Antonia; Campbell, Iain C; Schmidt, Ulrike

2013-02-01

Exposure therapy is a widely used and effective form of treatment in anxiety disorders and addictions but evidence for its usefulness in eating disorders (ED) is inconsistent. This paper systematically reviews the literature on the use of exposure therapy in ED, the theory underpinning its use, and the deficits in current knowledge. Databases were searched to 2012. In addition, potential improvements in the use of exposure techniques in ED are considered by drawing upon theory and research involving neuropharmacology, basic and clinical neuroscience, contemporary behavioural and neurobiological research, and technologies such as virtual reality (VR). Copyright © 2012 Elsevier Ltd. All rights reserved.

Acute Effects of Anticholinesterase Agents on Pupillary Function

DTIC Science & Technology

1986-09-16

Neuropharmacology, 24(4):325-328, 1985. Richardson, J.S., T.G. Mattio and E. Giacobini, Amitriptyline and imipramine inhibit the release of...Gidcobini 217, 785-2185 Satellite meeting of Intl. Soc. Neuro - - chem., Iraklion, Crete, Greece 5/26-29/85 THE ISOLATEO IRIS AS A :IODEL OF AG13G...104 t" lil 9( f H aid "Itti .&i kilo, Sf61014 WR(I Artv 400.4*f914 4 1qitlt il.911 l eo 14 11 1..4 14 h *ttl4 4fotIogoto tIritl f ol r e s ("ol i 46 f

Closed-Loop Neuropharmacology For Epilepsy: Distant Dream Or Future Reality?

PubMed

Aicua-Rapun, Irene; Andre, Pascal; Novy, Jan

2018-03-08

Epilepsy is considered the most frequent severe neurological condition but most patients treated with medication become seizure free. The management of treatment however is highly empirical, mainly relying on observation. A closed-loop therapy for epilepsy would be very valuable for more efficient treatment regimens. Here we discuss monitoring treatment (therapeutic drug monitoring) and the potential developments in this field, as well as providing a review of potential biomarkers that could be used to monitor the disease activity. Finally, we consider the pharmacogenetic input in epilepsy treatment. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Medicinal Plants in Neurodegenerative Diseases: Perspective of Traditional Persian Medicine.

PubMed

Farzaei, Mohammad Hosein; Shahpiri, Zahra; Mehri, Mohammad Reza; Bahramsoltani, Roodabeh; Rezaei, Mahdi; Raeesdana, Azade; Rahimi, Roja

2018-01-01

Neurodegenerative diseases are a progressive loss of structure and/or function of neurons. Weak therapeutic response and progressive nature of the diseases, as well as a wide range of side effects caused by conventional therapeutic approaches make patients seek for complementary and alternative medicine. The aim of the present paper is to discuss the neuropharmacological basis of medicinal plants and their principle phytochemicals which have been used in traditional Persian medicine for different types of neurodegenerative diseases. Medicinal plants introduced in traditional Persian medicine perform beneficial effects in neurodegenerative diseases via various cellular and molecular mechanisms including suppression of apoptosis mediated by an increase in the expression of anti-apoptotic agents (e.g. Bcl-2) as well as a decrease in the expression and activity of proapoptotic proteins (e.g. Bax, caspase 3 and 9). Alleviating inflammatory responses and suppressing the expression and function of pro-inflammatory cytokines like Tumor necrosis factor α and interleukins, as well as improvement in antioxidative performance mediated by superoxide dismutase and catalase, are among other neuroprotective mechanisms of traditional medicinal plants. Modulation of transcription, transduction, intracellular signaling pathways including ERK, p38, and MAPK, with upstream regulatory activity on inflammatory cascades, apoptosis and oxidative stress associated pathways, play an essential role in the preventive and therapeutic potential of the plants in neurodegenerative diseases. Medicinal plants used in traditional Persian medicine along with their related phytochemicals by affecting various neuropharmacological pathways can be considered as future drugs or adjuvant therapies with conventional pharmacotherapeutics; though, further clinical studies are necessary for the confirmation of their safety and efficacy. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Neuropharmacological reassessment of the discriminative stimulus properties of d-lysergic acid diethylamide (LSD).

PubMed

Cunningham, K A; Appel, J B

1987-01-01

The neuropharmacological mechanisms underlying the behavioral effects of d-lysergic acid diethylamide (LSD) were assessed by comparing the discriminative stimulus properties of LSD with those of agonists and antagonists that act selectively at putative serotonin (5-hydroxytryptamine; 5-HT) receptor subtypes (5-HT1 and 5-HT2). Male Sprague-Dawley rats (N = 23) were trained to discriminate LSD (0.08 mg/kg) from saline and given substitution tests with the following agents: 8-hydroxy-2(di-n-propyl-amino) tetralin (8-OHDPAT; 0.02-0.64 mg/kg), Ru 24969 (0.2-3.2 mg/kg), m-chlorophenylpiperazine (MCPP; 0.1-1.6 mg/kg), 1-(m-trifluoromethylphenyl)piperazine (TFMPP; 0.1-1.6 mg/kg), and quipazine (0.2-3.2 mg/kg). Only quipazine mimicked LSD. In combination tests, BC 105 (0.2-3.2 mg/kg), 2-bromolysergic acid diethylamide (BOL; 0.1-1.6 mg/kg), Ly 53857 (0.4-3.2 mg/kg), metergoline (0.05-0.8 mg/kg), ketanserin (0.2-3.2 mg/kg), and pipenperone (0.0025-0.08 mg/kg), all of which act as 5-HT2 antagonists, blocked the LSD cue; only spiperone (0.02-0.32 mg/kg) was without effect. Although commonalities may exist among "5-HT agonists", the present results demonstrate that such "agonists" are not identical. Since putative 5-HT1 agonists do not mimic LSD and the LSD cue is potently blocked by 5-HT2 antagonists, it appears that 5-HT2 neuronal systems are of greater importance than 5-HT1 systems in mediating the discriminative stimulus and, perhaps, other effects of LSD.

Neuropharmacology of 3,4-Methylenedioxypyrovalerone (MDPV), Its Metabolites, and Related Analogs

PubMed Central

Baumann, Michael H.; Bukhari, Mohammad O.; Lehner, Kurt R.; Anizan, Sebastien; Rice, Kenner C.; Concheiro, Marta; Huestis, Marilyn A.

2017-01-01

3,4-Methylenedioxypyrovalerone (MDPV) is a psychoactive component of so-called bath salts products that has caused serious medical consequences in humans. In this chapter, we review the neuropharmacology of MDPV and related analogs, and supplement the discussion with new results from our preclinical experiments. MDPV acts as a potent uptake inhibitor at plasma membrane transporters for dopamine (DAT) and norepinephrine (NET) in nervous tissue. The MDPV formulation in bath salts is a racemic mixture, and the S isomer is much more potent than the R isomer at blocking DAT and producing abuse-related effects. Elevations in brain extracellular dopamine produced by MDPV are likely to underlie its locomotor stimulant and addictive properties. MDPV displays rapid pharmacokinetics when injected into rats (0.5–2.0 mg/kg), with peak plasma concentrations achieved by 10–20 min and declining quickly thereafter. MDPV is metabolized to 3,4-dihydroxypyrovalerone (3,4-catechol-PV) and 4-hydroxy-3-methoxypyrovalerone (4-OH-3-MeO-PV) in vivo, but motor activation produced by the drug is positively correlated with plasma concentrations of parent drug and not its metabolites. 3,4-Catechol-PV is a potent uptake blocker at DAT in vitro but has little activity after administration in vivo. 4-OH-3-MeO-PV is the main MDPV metabolite but is weak at DAT and NET. MDPV analogs, such as α-pyrrolidinovalerophenone (α-PVP), display similar ability to inhibit DAT and increase extracellular dopamine concentrations. Taken together, these findings demonstrate that MDPV and its analogs represent a unique class of transporter inhibitors with a high propensity for abuse and addiction. PMID:27830575

Neuropharmacological profile and chemical analysis of fresh rhizome essential oil of Curcuma longa (turmeric) cultivated in Southwest Nigeria.

PubMed

Oyemitan, Idris A; Elusiyan, Christianah A; Onifade, Ayoola O; Akanmu, Moses A; Oyedeji, Adebola O; McDonald, Armando G

2017-01-01

Curcuma longa (turmeric) is commonly used as spice and also used to treat fever, cough and febrile convulsions in Nigeria. This study determined the chemical composition of the essential oil of C. longa and evaluated its neuropharmacological activity in mice. Essential oil of C. longa (EOCL) fresh rhizome was obtained by hydrodistillation and its chemical composition determined by GC-MS. Acute toxicity (LD 50 ) profile of the essential oil was determined orally (p.o.) and intraperitoneally (i.p.); and the EOCL (50-200 mg/kg, i.p.) was evaluated for its behavioural, anxiolytic, sedative and anticonvulsant activities using appropriate models in Albino mice (Vom Strain, Jos, Nigeria). Analysis of the oil showed the presence of 23 compounds with turmerone (35.9%) being the major component. The LD 50 values obtained for the mice were 2154 mg/kg, p.o., and 693 mg/kg, i.p. The EOCL (50-200 mg/kg, i.p.) caused significant (p < 0.01) inhibition of rearing {F (4,20)  = 9} and locomotor {F (3,16)  = 42} activity; decreased head dips in hole board {F (4,20)  = 4}; increased the time spent in the open arms of the elevated pus maze {F (4,20)  = 9}; prolonged total sleeping time {F (4,20)  = 21} induced by ketamine injection, and protected mice against pentylenetetrazol-induced convulsions. The major component of the essential oil of this C. longa species was turmerone; the oil was slightly toxic orally but moderately toxic intraperitoneally in mice; exhibited significant anxiolytic, sedative and anticonvulsant activities in mice.

Iranians' contribution to world literature on neuroscience.

PubMed

Ashrafi, Farzad; Mohammadhassanzadeh, Hafez; Shokraneh, Farhad; Valinejadi, Ali; Johari, Karim; Saemi, Nazanin; Zali, Alireza; Mohaghegh, Niloofar; Ashayeri, Hassan

2012-12-01

The purpose of this study is to analyse Iranian scientific publications in the neuroscience subfields by librarians and neuroscientists, using Science Citation Index Expanded (SCIE) via Web of Science data over the period, 2002-2008. Data were retrieved from the SCIE. Data were collected from the 'subject area' of the database and classified by neuroscience experts into 14 subfields. To identify the citation patterns, we applied the 'impact factor' and the 'number of publication'. Data were also analysed using HISTCITE, Excel 2007 and SPSS. Seven hundred and thirty-four papers have been published by Iranian between 2002 and 2008. Findings showed a growing trend of neuroscience papers in the last 3 years with most papers (264) classified in the neuropharmacology subfield. There were fewer papers in neurohistory, psychopharmacology and artificial intelligence. International contributions of authors were mostly in the neurology subfield, and 'Collaboration Coefficient' for the neuroscience subfields in Iran was 0.686 which is acceptable. Most international collaboration between Iranians and developed countries was from USA. Eighty-seven percent of the published papers were in journals with the impact factor between 0 and 4; 25% of papers were published by the researchers affiliated to Tehran University of Medical Sciences. Progress of neuroscience in Iran is mostly seen in the neuropharmacology and the neurology subfields. Other subfields should also be considered as a research priority by health policymakers. As this study was carried out by the collaboration of librarians and neuroscientists, it has been proved valuable for both librarians and policymakers. This study may be encouraging for librarians from other developing countries. © 2012 The authors. Health Information and Libraries Journal © 2012 Health Libraries Group.

Neuropharmacology of light-induced locomotor activation.

PubMed

Amato, Davide; Pum, Martin E; Groos, Dominik; Lauber, Andrea C; Huston, Joseph P; Carey, Robert J; de Souza Silva, Maria A; Müller, Christian P

2015-08-01

Presentation of non-aversive light stimuli for several seconds was found to reliably induce locomotor activation and exploratory-like activity. Light-induced locomotor activity (LIA) can be considered a convenient simple model to study sensory-motor activation. LIA was previously shown to coincide with serotonergic and dopaminergic activation in specific cortical areas in freely moving and anesthetized animals. In the present study we explore the neuropharmacology of LIA using a receptor antagonist/agonist approach in rats. The non-selective 5-HT2-receptor antagonist ritanserin (1.5-6 mg/kg, i.p.) dose-dependently reduced LIA. Selective antagonism of either the 5-HT2A-receptor by MDL 11,939 (0.1-0.4 mg/kg, i.p.), or the 5-HT2C-receptor by SDZ SER 082 (0.125-0.5 mg/kg, i.p.), alone or in combination, had no significant influence on LIA. Also the selective 5-HT1A-receptor antagonist, WAY 100635 (0.4 mg/kg, i.p.) did not affect LIA. Neither did the preferential dopamine D2-receptor antagonist, haloperidol (0.025-0.1 mg/kg, i.p.) nor the D2/D3-receptor agonist, quinpirole (0.025-0.5 mg/kg, i.p.) affect the expression of LIA. However, blocking the glutamatergic NMDA-receptor with phencyclidine (PCP, 1.5-6 mg/kg, i.p.) dose-dependently reduced LIA. This effect was also observed with ketamine (10 mg/kg, i.p.). These findings suggest that serotonin and dopamine receptors abundantly expressed in the cortex do not mediate light-stimulus triggered locomotor activity. PCP and ketamine effects, however, suggest an important role of NMDA receptors in LIA. Copyright © 2015 Elsevier Ltd. All rights reserved.

Stereochemistry and neuropharmacology of a 'bath salt' cathinone: S-enantiomer of mephedrone reduces cocaine-induced reward and withdrawal in invertebrates.

PubMed

Vouga, Alexandre; Gregg, Ryan A; Haidery, Maryah; Ramnath, Anita; Al-Hassani, Hassan K; Tallarida, Christopher S; Grizzanti, David; Raffa, Robert B; Smith, Garry R; Reitz, Allen B; Rawls, Scott M

2015-04-01

Knowledge about the neuropharmacology of mephedrone (MEPH) applies primarily to the racemate, or street form of the drug, but not to its individual enantiomers. Here, through chemical isolation of MEPH enantiomers and subsequent behavioral characterization in established invertebrate (planarian) assays, we began separating adverse effects of MEPH from potential therapeutic actions. We first compared stereotypical and environmental place conditioning (EPC) effects of racemic MEPH, S-MEPH, and R-MEPH. Stereotypy was enhanced by acute treatment (100-1000 μM) with each compound; however, S-MEPH was less potent and efficacious than racemate and R-MEPH. Both R-MEPH (10, 100, 250 μM) and racemate (100 μM) produced EPC, but S-MEPH was ineffective at all concentrations (10-100 μM). After showing that S-MEPH lacked rewarding efficacy, we investigated its ability to alter three of cocaine's behavioral effects (EPC, withdrawal, and stereotypy). Cocaine (1 μM) produced EPC that was abolished when S-MEPH (100 μM) was administered after cocaine conditioning. Spontaneous withdrawal from chronic cocaine exposure caused a reduction in motility that was not evident during acute or continuous cocaine treatment but was attenuated by S-MEPH (100 μM) treatment during the cocaine abstinence interval. Acute stereotypy produced by 1 mM cocaine, nicotine or racemic MEPH was not affected by S-MEPH (10-250 μM). The present results obtained using planarian assays suggest that the R-enantiomer of MEPH is predominantly responsible for its stimulant and rewarding effects and the S-enantiomer is capable of antagonizing cocaine's addictive-like behaviors without producing rewarding effects of its own. Copyright © 2014 Elsevier Ltd. All rights reserved.

Translational neuropharmacology: the use of human isolated gastrointestinal tissues

PubMed Central

Sanger, GJ; Broad, J; Kung, V; Knowles, CH

2013-01-01

Translational sciences increasingly emphasize the measurement of functions in native human tissues. However, such studies must confront variations in patient age, gender, genetic background and disease. Here, these are discussed with reference to neuromuscular and neurosecretory functions of the human gastrointestinal (GI) tract. Tissues are obtained after informed consent, in collaboration with surgeons (surgical techniques help minimize variables) and pathologists. Given the difficulties of directly recording from human myenteric neurones (embedded between muscle layers), enteric motor nerve functions are studied by measuring muscle contractions/relaxations evoked by electrical stimulation of intrinsic nerves; responses are regionally dependent, often involving cholinergic and nitrergic phenotypes. Enteric sensory functions can be studied by evoking the peristaltic reflex, involving enteric sensory and motor nerves, but this has rarely been achieved. As submucosal neurones are more accessible (after removing the mucosa), direct neuronal recordings are possible. Neurosecretory functions are studied by measuring changes in short-circuit current across the mucosa. For all experiments, basic questions must be addressed. Because tissues are from patients, what are the controls and the influence of disease? How long does it take before function fully recovers? What is the impact of age- and gender-related differences? What is the optimal sample size? Addressing these and other questions minimizes variability and raises the scientific credibility of human tissue research. Such studies also reduce animal use. Further, the many differences between animal and human GI functions also means that human tissue research must question the ethical validity of using strains of animals with unproved translational significance. Linked Article BJP published a themed issue on Translational Neuropharmacology in 2011. To view the articles in this themed issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:22946540

What have positron emission tomography and 'Zippy' told us about the neuropharmacology of drug addiction?

PubMed

Cumming, Paul; Caprioli, Daniele; Dalley, Jeffrey W

2011-08-01

Translational molecular imaging with positron emission tomography (PET) and allied technologies offer unrivalled applications in the discovery of biomarkers and aetiological mechanisms relevant to human disease. Foremost among clinical PET findings during the past two decades of addiction research is the seminal discovery of reduced dopamine D(2/3) receptor expression in the striatum of drug addicts, which could indicate a predisposing factor and/or compensatory reaction to the chronic abuse of stimulant drugs. In parallel, recent years have witnessed significant improvements in the performance of small animal tomographs (microPET) and a refinement of animal models of addiction based on clinically relevant diagnostic criteria. This review surveys the utility of PET in the elucidation of neuropharmacological mechanisms underlying drug addiction. It considers the consequences of chronic drug exposure on regional brain metabolism and neurotransmitter function and identifies those areas where further research is needed, especially concerning the implementation of PET tracers targeting neurotransmitter systems other than dopamine, which increasingly have been implicated in the pathophysiology of drug addiction. In addition, this review considers the causal effects of behavioural traits such as impulsivity and novelty/sensation-seeking on the emergence of compulsive drug-taking. Previous research indicates that spontaneously high-impulsive rats--as exemplified by 'Zippy'--are pre-disposed to escalate intravenous cocaine self-administration, and subsequently to develop compulsive drug taking tendencies that endure despite concurrent adverse consequences of such behaviour, just as in human addiction. The discovery using microPET of pre-existing differences in dopamine D(2/3) receptor expression in the striatum of high-impulsive rats suggests a neural endophenotype that may likewise pre-dispose to stimulant addiction in humans. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Principles of motivation revealed by the diverse functions of neuropharmacological and neuroanatomical substrates underlying feeding behavior

PubMed Central

Baldo, Brian A.; Pratt, Wayne E.; Will, Matthew J.; Hanlon, Erin C.; Bakshi, Vaishali P.; Cador, Martine

2013-01-01

Circuits that participate in specific subcomponents of feeding (e.g., gustatory perception, peripheral feedback relevant to satiety and energy balance, reward coding, etc.) are found at all levels of the neural axis. Further complexity is conferred by the wide variety of feeding-modulatory neurotransmitters and neuropeptides that act within these circuits. An ongoing challenge has been to refine the understanding of the functional specificity of these neurotransmitters and circuits, and there have been exciting advances in recent years. We focus here on foundational work of Dr. Ann Kelley that identified distinguishable actions of striatal opioid peptide modulation and dopamine transmission in subcomponents of reward processing. We also discuss her work in overlaying these neuropharmacological effects upon anatomical pathways that link the telencephalon (cortex and basal ganglia) with feeding-control circuits in the hypothalamus. Using these seminal contributions as a starting point, we will discuss new findings that expand our understanding of (1) the specific, differentiable motivational processes that are governed by central dopamine and opioid transmission, (2) the manner in which other striatal neuromodulators, specifically acetylcholine, endocannabinoids and adenosine, modulate these motivational processes (including via interactions with opioid systems), and (3) the organization of the cortical-subcortical network that subserves opioid-driven feeding. The findings discussed here strengthen the view that incentive-motivational properties of food are coded by substrates and neural circuits that are distinguishable from those that mediate the acute hedonic experience of food reward. Striatal opioid transmission modulates reward processing by engaging frontotemporal circuits, possibly via a hypothalamic-thalamic axis, that ultimately impinges upon hypothalamic modules dedicated to autonomic function and motor pattern control. We will conclude by discussing implications for understanding disorders of “non-homeostatic” feeding. PMID:23466532

Evaluation of n-hexane extract of Viola betonicifolia for its neuropharmacological properties.

PubMed

Muhammad, Naveed; Saeed, Muhammad; Khan, Haroon; Haq, Ikramul

2013-01-01

Viola betonicifolia (whole plant) has been used as a sedative and in various nervous disorders in Pakistani traditional medicines. The n-hexane extract of the whole plant of V. betonicifolia (HEVB) was investigated for neuropharmacological properties such as anxiolytic, muscle relaxant, sleep induction, antidepressant and sedative to ascertain its folk use. Anxiolytic activity was tested using the staircase test, while the muscle relaxing property of the extract was tested in various muscle relaxant paradigms, i.e. chimney test, traction test, rota rod and inclined plane. In anxiolytic and muscle relaxant tests, HEVB (0.3, 0.4 and 0.5 g/kg, i.p.), diazepam (1 mg/kg, i.p.) or distilled water (10 ml/kg i.p.) were administered 30, 60 and 90 min before performing the tests in mice. HEVB was also screened for a sleep-inducing effect. The antidepressant activity was determined by using the forced swimming test (FST), while line crossing in a special box was used for locomotor activity. HEVB showed a significant (P < 0.05) dose-dependent anxiolytic action in the staircase test. In muscle relaxant paradigms, a dose-dependent muscle relaxation was observed. For the phenobarbitone sleep induction test, HEVB notably (P < 0.05) reduced the latency time and increased the total sleeping duration. However, HEVB was devoid of any antidepressant activity, while the movements of mice were reduced significantly (P < 0.05) in locomotor activity. The results suggest that HEVB has anxiolytic, muscle relaxant, sleep-inducing (sedative) activity and, thus, provides pharmacological justification for the use of this plant as a sedative and for the relief of various nervous disorders.

The neuropharmacology of prolactin secretion elicited by 3,4-methylenedioxymethamphetamine (“ecstasy”): A concurrent microdialysis and plasma analysis study

PubMed Central

Murnane, K.S.; Kimmel, H.L.; Rice, K.C.; Howell, L.L

2012-01-01

3,4-methylenedioxymethamphetamine (MDMA) is a substituted phenethylamine that is widely abused as the street drug “ecstasy”. Racemic MDMA (S,R(+/−)-MDMA) and its stereoisomers elicit complex spectrums of psychobiological, neurochemical, and hormonal effects. In this regard, recent findings demonstrated that S,R(+/−)-MDMA and its stereoisomer R(−)-MDMA elicit increases in striatal extracellular serotonin levels and plasma levels of the hormone prolactin in rhesus monkeys. In the present mechanistic study, we evaluated the role of the serotonin transporter and the 5-HT2A receptor in S,R(+/−)-MDMA- and R(−)-MDMA-elicited prolactin secretion in rhesus monkeys through concurrent microdialysis and plasma analysis determinations and drug interaction experiments. Concurrent neurochemical and hormone determinations showed a strong positive temporal correlation between serotonin release and prolactin secretion. Consistent with their distinct mechanisms of action and previous studies showing that the serotonin transporter inhibitor fluoxetine attenuates the behavioral and neurochemical effects of S,R(+/−)-MDMA, pretreatment with fluoxetine attenuated serotonin release elicited by either S,R(+/−)-MDMA or R(−)-MDMA. As hypothesized, at a dose that had no significant effects on circulating prolactin levels when administered alone, fluoxetine also attenuated prolactin secretion elicited by S,R(+/−)-MDMA. In contrast, combined pretreatment with both fluoxetine and the selective 5-HT2A receptor antagonist M100907 was required to attenuate prolactin secretion elicited by R(−)-MDMA, suggesting that this stereoisomer of S,R(+/−)-MDMA elicits prolactin secretion through both serotonin release and direct agonism of 5-HT2A receptors. Accordingly, these findings inform our understanding of the neuropharmacology of both S,R(+/−)-MDMA and R(−)-MDMA and the regulation of prolactin secretion. PMID:22197270

Principles of motivation revealed by the diverse functions of neuropharmacological and neuroanatomical substrates underlying feeding behavior.

PubMed

Baldo, Brian A; Pratt, Wayne E; Will, Matthew J; Hanlon, Erin C; Bakshi, Vaishali P; Cador, Martine

2013-11-01

Circuits that participate in specific subcomponents of feeding (e.g., gustatory perception, peripheral feedback relevant to satiety and energy balance, reward coding, etc.) are found at all levels of the neural axis. Further complexity is conferred by the wide variety of feeding-modulatory neurotransmitters and neuropeptides that act within these circuits. An ongoing challenge has been to refine the understanding of the functional specificity of these neurotransmitters and circuits, and there have been exciting advances in recent years. We focus here on foundational work of Dr. Ann Kelley that identified distinguishable actions of striatal opioid peptide modulation and dopamine transmission in subcomponents of reward processing. We also discuss her work in overlaying these neuropharmacological effects upon anatomical pathways that link the telencephalon (cortex and basal ganglia) with feeding-control circuits in the hypothalamus. Using these seminal contributions as a starting point, we will discuss new findings that expand our understanding of (1) the specific, differentiable motivational processes that are governed by central dopamine and opioid transmission, (2) the manner in which other striatal neuromodulators, specifically acetylcholine, endocannabinoids and adenosine, modulate these motivational processes (including via interactions with opioid systems), and (3) the organization of the cortical-subcortical network that subserves opioid-driven feeding. The findings discussed here strengthen the view that incentive-motivational properties of food are coded by substrates and neural circuits that are distinguishable from those that mediate the acute hedonic experience of food reward. Striatal opioid transmission modulates reward processing by engaging frontotemporal circuits, possibly via a hypothalamic-thalamic axis, that ultimately impinges upon hypothalamic modules dedicated to autonomic function and motor pattern control. We will conclude by discussing implications for understanding disorders of "non-homeostatic" feeding. Copyright © 2013 Elsevier Ltd. All rights reserved.

Modulation of cholinergic functions by serotonin and possible implications in memory: general data and focus on 5-HT(1A) receptors of the medial septum.

PubMed

Jeltsch-David, Hélène; Koenig, Julie; Cassel, Jean-Christophe

2008-12-16

Cholinergic systems were linked to cognitive processes like attention and memory. Other neurotransmitter systems having minor influence on cognitive functions - as shown by the weakness of the effects of their selective lesions - modulate cholinergic functions. The serotonergic system is such a system. Conjoined functional changes in cholinergic and serotonergic systems may have marked cognitive consequences [Cassel JC, Jeltsch H. Serotoninergic modulation of cholinergic function in the central nervous system: cognitive implications. Neuroscience 1995;69(1):1-41; Steckler T, Sahgal A. The role of serotoninergic-cholinergic interactions in the mediation of cognitive behaviour. Behav Brain Res 1995;67:165-99]. A crucial issue in that concern is the identification of the neuroanatomical and neuropharmacological substrates where functional effects of serotonergic/cholinergic interactions originate. Approaches relying on lesions and intracerebral cell grafting, on systemic drug-cocktail injections, or even on intracerebral drug infusions represent the main avenues on which our knowledge about the role of serotonergic/cholinergic interactions has progressed. The present review will visit some of these avenues and discuss their contribution to what is currently known on the potential or established implication(s) into memory functions of serotonergic/cholinergic interactions. It will then focus on a brain region and a neuropharmacological substrate that have been poorly studied as regards serotonergic modulation of memory functions, namely the medial septum and its 5-HT(1A) receptors. Based on recent findings of our laboratory, we suggest that these receptors, located on both cholinergic and GABAergic septal neurons, take part in a mechanism that controls encoding, to some extent consolidation, but not retrieval, of hippocampal-dependent memories. This control, however, does not occur by the way of an exclusive action of serotonin on cholinergic neurons.

Neuropharmacological Properties of Withania somnifera - Indian Ginseng: An Overview on Experimental Evidence with Emphasis on Clinical Trials and Patents.

PubMed

Yenisetti, Sarat C; Manjunath, M J; Muralidhara, C

2016-01-01

Owing to the increasing aged population globally, disorders and diseases of the CNS are anticipated to increase and profoundly impact the health care. As these neurodegenerative diseases (NDD) are complex, multifactorial and do not have identified etiological factors, unfortunately, drugs developed for the purpose have not met with the expected success. Hence, there has been a constant demand for the development of natural therapeutic adjuvants which are safe and possess the potential to attenuate multiple pathways. Numerous herbal/natural products have been used as therapeutics in Ayurvedic system of medicine to treat NDD and other memory-related disorders. Withania somnifera (Ashwagandha, WS), popularly called as "Indian Ginseng" is one such plant which possesses a variety of beneficial neuropharmacological properties. In this review, we have attempted to review critically the existing literature and patents related to the neuroprotective efficacy of WS roots and the underlying mechanism/s. Standardized extracts of Withania somnifera (WS) have been demonstrated to possess multidimensional neuromodulatory effects both in vitro and animal models. The spectrum of effects evidenced comprises of attenuation of oxidative damage by enhancing the antioxidant defense system with concomitant enhancement of the expression of marker proteins responsible for growth, differentiation and communication of neural cells. Specific effects of WS are attributable to its potential to modulate neurotrophic factors, cytoskeletal elements, cell adhesion molecules and synaptic proteins. Generation of new data by employing systematic contemporary approaches such as bioinformatics, molecular docking studies, identification of specific gene targets and epigenetic regulation would provide the necessary impetus to validate fully the neurotherapeutic potential of the phytochemicals derived from WS. More importantly, well-designed clinical trials are required to exploit the neuromodulatory propensity of WS extract/bioactives in specific neurodegenerative diseases such as AD and PD.

In vivo brain microdialysis: advances in neuropsychopharmacology and drug discovery.

PubMed

Darvesh, Altaf S; Carroll, Richard T; Geldenhuys, Werner J; Gudelsky, Gary A; Klein, Jochen; Meshul, Charles K; Van der Schyf, Cornelis J

2011-02-01

INTRODUCTION: Microdialysis is an important in vivo sampling technique, useful in the assay of extracellular tissue fluid. The technique has both pre-clinical and clinical applications but is most widely used in neuroscience. The in vivo microdialysis technique allows measurement of neurotransmitters such as acetycholine (ACh), the biogenic amines including dopamine (DA), norepinephrine (NE) and serotonin (5-HT), amino acids such as glutamate (Glu) and gamma aminobutyric acid (GABA), as well as the metabolites of the aforementioned neurotransmitters, and neuropeptides in neuronal extracellular fluid in discrete brain regions of laboratory animals such as rodents and non-human primates. AREAS COVERED: In this review we present a brief overview of the principles and procedures related to in vivo microdialysis and detail the use of this technique in the pre-clinical measurement of drugs designed to be used in the treatment of chemical addiction, neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and as well as psychiatric disorders such as attention-deficit/hyperactivity disorder (ADHD) and schizophrenia. This review offers insight into the tremendous utility and versatility of this technique in pursuing neuropharmacological investigations as well its significant potential in rational drug discovery. EXPERT OPINION: In vivo microdialysis is an extremely versatile technique, routinely used in the neuropharmacological investigation of drugs used for the treatment of neurological disorders. This technique has been a boon in the elucidation of the neurochemical profile and mechanism of action of several classes of drugs especially their effects on neurotransmitter systems. The exploitation and development of this technique for drug discovery in the near future will enable investigational new drug candidates to be rapidly moved into the clinical trial stages and to market thus providing new successful therapies for neurological diseases that are currently in demand.

Neuropharmacology of vision in goldfish: a review.

PubMed

Mora-Ferrer, Carlos; Neumeyer, Christa

2009-05-01

The goldfish is one of the few animals exceptionally well analyzed in behavioral experiments and also in electrophysiological and neuroanatomical investigations of the retina. To get insight into the functional organization of the retina we studied color vision, motion detection and temporal resolution before and after intra-ocular injection of neuropharmaca with known effects on retinal neurons. Bicuculline, strychnine, curare, atropine, and dopamine D1- and D2-receptor antagonists were used. The results reviewed here indicate separate and parallel processing of L-cone contribution to different visual functions, and the influence of several neurotransmitters (dopamine, acetylcholine, glycine, and GABA) on motion vision, color vision, and temporal resolution.

Neuropharmacology of Poststroke Motor and Speech Recovery.

PubMed

Keser, Zafer; Francisco, Gerard E

2015-11-01

Almost 7 million adult Americans have had a stroke. There is a growing need for more effective treatment options as add-ons to conventional therapies. This article summarizes the published literature for pharmacologic agents used for the enhancement of motor and speech recovery after stroke. Amphetamine, levodopa, selective serotonin reuptake inhibitors, and piracetam were the most commonly used drugs. Pharmacologic augmentation of stroke motor and speech recovery seems promising but systematic, adequately powered, randomized, and double-blind clinical trials are needed. At this point, the use of these pharmacologic agents is not supported by class I evidence. Copyright © 2015 Elsevier Inc. All rights reserved.

Behavior within fortuitous environments: The entwined history of Division 28 and the fields of behavioral pharmacology and toxicology.

PubMed

Campbell, Nancy D

2016-08-01

Behavioral pharmacology emerged in the early to mid-20th century as an experimental and observational science, helping to consolidate an empirically based psychological science of behavior. Behavioral psychologists came to play significant roles in toxicology, neuropharmacology, and psychopharmacology. This article traces the first 3 decades of American Psychological Association Division 28. Sources include the Division 28 Oral History Project; formal interviews conducted by the author in the early 2000s with behavioral, experimental, and clinical pharmacologists; and the archived newsletters of Division 28. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Valium without dependence? Individual GABAA receptor subtype contribution toward benzodiazepine addiction, tolerance, and therapeutic effects.

PubMed

Cheng, Tianze; Wallace, Dominique Marie; Ponteri, Benjamin; Tuli, Mahir

2018-01-01

Benzodiazepines are one of the most prescribed medications as first-line treatment of anxiety, insomnia, and epilepsy around the world. Over the past two decades, advances in the neuropharmacological understanding of gamma aminobutyric acid (GABA) A receptors revealed distinct contributions from each subtype and produced effects. Recent findings have highlighted the importance of α 1 containing GABA A receptors in the mechanisms of addiction and tolerance in benzodiazepine treatments. This has shown promise in the development of tranquilizers with minimal side effects such as cognitive impairment, dependence, and tolerance. A valium-like drug without its side effects, as repeatedly demonstrated in animals, is achievable.

Rabbit analgesia.

PubMed

Barter, Linda S

2011-01-01

With the increasing popularity of rabbits as household pets, the complexity of diagnostic and surgical procedures performed on rabbits is increasing, along with the frequency of routine surgical procedures. More practitioners are faced with the need to provide adequate analgesia for this species. Preemptive analgesia prior to planned surgical interventions may reduce nervous system changes in response to noxious input, as well as reduce postoperative pain levels and analgesic drug requirements. Concurrent administration of analgesic drugs to anesthetized rabbits undergoing painful procedures is warranted both pre- and intraoperatively as well as postoperatively. This article discusses the neuropharmacologic and pharmacologic aspects of pain in rabbits, and reviews current protocols for the use of analgesic drugs. Published by Elsevier Inc.

The hyperventilation-induced ischaemia model in human neuropharmacology: neurophysiological and psychometric studies of aniracetam and 3-OH aniracetam.

PubMed

Kraaier, V; van Huffelen, A C; Wieneke, G H

1989-01-01

Standardized hyperventilation in young subjects induces changes in the EEG, a decrease in the velocity of the cerebral blood flow and a decline in cognitive performance, which are comparable to those occurring in patients with cerebral ischaemia. The anti-ischaemic properties of aniracetam and 3-OH aniracetam were tested in this model. A single oral dose of 3-OH aniracetam 1500 mg appeared to have the most pronounced effect on hyperventilation-induced EEG changes and cognitive deterioration. The test drugs had no effect on the heart rate or blood flow velocity. The effects agree with those of other drugs classified as noötropics.

Neuropharmacology of drugs and alcohol in mother and fetus.

PubMed

Pollard, Irina

2007-04-01

Epidemiological evidence suggests that an adverse prenatal environment can have profound long-term health consequences throughout postnatal life. This chapter discusses the underlying mechanisms implicated in the consumption of mood-altering recreational drugs and teratogenicity in the fetus. The way metabolic parameters in pregnancy influence the pharmacokinetic characteristics of drugs and alcohol and the developmental stage of neurotoxicity are reviewed. The general underlying mechanisms that link multifaceted interactions between drug characteristics, gene polymorphisms, dietary deficiencies, changed endocrine indices and fetal programming are outlined, with specific examples throughout the text. As developmental injury is of significant social concern, the final section questions whether society provides adequate support for making appropriate and informed lifestyle choices to alleviate preventable transgenerational harm.

Advances in rehabilitation medicine.

PubMed

Ng, Yee Sien; Chew, Effie; Samuel, Geoffrey S; Tan, Yeow Leng; Kong, Keng He

2013-10-01

Rehabilitation medicine is the medical specialty that integrates rehabilitation as its core therapeutic modality in disability management. More than a billion people worldwide are disabled, and the World Health Organization has developed the International Classification of Functioning, Disability and Health as a framework through which disability is addressed. Herein, we explore paradigm shifts in neurorehabilitation, with a focus on restoration, and provide overviews on developments in neuropharmacology, rehabilitation robotics, virtual reality, constraint-induced therapy and brain stimulation. We also discuss important issues in rehabilitation systems of care, including integrated care pathways, very early rehabilitation, early supported discharge and telerehabilitation. Finally, we highlight major new fields of rehabilitation such as spasticity management, frailty and geriatric rehabilitation, intensive care and cancer rehabilitation.

Zebrafish models in neuropsychopharmacology and CNS drug discovery.

PubMed

Khan, Kanza M; Collier, Adam D; Meshalkina, Darya A; Kysil, Elana V; Khatsko, Sergey L; Kolesnikova, Tatyana; Morzherin, Yury Yu; Warnick, Jason E; Kalueff, Allan V; Echevarria, David J

2017-07-01

Despite the high prevalence of neuropsychiatric disorders, their aetiology and molecular mechanisms remain poorly understood. The zebrafish (Danio rerio) is increasingly utilized as a powerful animal model in neuropharmacology research and in vivo drug screening. Collectively, this makes zebrafish a useful tool for drug discovery and the identification of disordered molecular pathways. Here, we discuss zebrafish models of selected human neuropsychiatric disorders and drug-induced phenotypes. As well as covering a broad range of brain disorders (from anxiety and psychoses to neurodegeneration), we also summarize recent developments in zebrafish genetics and small molecule screening, which markedly enhance the disease modelling and the discovery of novel drug targets. © 2017 The British Pharmacological Society.

GABAA receptor: Positive and negative allosteric modulators.

PubMed

Olsen, Richard W

2018-01-31

gamma-Aminobutyric acid (GABA)-mediated inhibitory neurotransmission and the gene products involved were discovered during the mid-twentieth century. Historically, myriad existing nervous system drugs act as positive and negative allosteric modulators of these proteins, making GABA a major component of modern neuropharmacology, and suggesting that many potential drugs will be found that share these targets. Although some of these drugs act on proteins involved in synthesis, degradation, and membrane transport of GABA, the GABA receptors Type A (GABA A R) and Type B (GABA B R) are the targets of the great majority of GABAergic drugs. This discovery is due in no small part to Professor Norman Bowery. Whereas the topic of GABA B R is appropriately emphasized in this special issue, Norman Bowery also made many insights into GABA A R pharmacology, the topic of this article. GABA A R are members of the ligand-gated ion channel receptor superfamily, a chloride channel family of a dozen or more heteropentameric subtypes containing 19 possible different subunits. These subtypes show different brain regional and subcellular localization, age-dependent expression, and potential for plastic changes with experience including drug exposure. Not only are GABA A R the targets of agonist depressants and antagonist convulsants, but most GABA A R drugs act at other (allosteric) binding sites on the GABA A R proteins. Some anxiolytic and sedative drugs, like benzodiazepine and related drugs, act on GABA A R subtype-dependent extracellular domain sites. General anesthetics including alcohols and neurosteroids act at GABA A R subunit-interface trans-membrane sites. Ethanol at high anesthetic doses acts on GABA A R subtype-dependent trans-membrane domain sites. Ethanol at low intoxicating doses acts at GABA A R subtype-dependent extracellular domain sites. Thus GABA A R subtypes possess pharmacologically specific receptor binding sites for a large group of different chemical classes of clinically important neuropharmacological agents. Copyright © 2018 Elsevier Ltd. All rights reserved.

Injection of Oxotremorine in Nucleus Accumbens Shell Reduces Cocaine But Not Food Self-Administration in Rats

PubMed Central

Mark, Gregory P.; Kinney, Anthony E.; Grubb, Michele C.; Zhu, Xiaoman; Finn, Deborah A.; Mader, Sarah L.; Berger, S. Paul; Bechtholt, Anita J.

2006-01-01

Mesencephalic dopamine neurons form synapses with acetylcholine (ACh)-containing interneurons in the nucleus accumbens (NAcc). Although their involvement in drug reward has not been systematically investigated, these large aspiny interneurons may serve an important integrative function. We previously found that repeated activation of nicotinic cholinergic receptors enhanced cocaine intake in rats but the role of muscarinic receptors in drug reward is less clear. Here we examined the impact of local changes in muscarinic receptor activation within the NAcc on cocaine and food self-administration in rats trained on a progressive ratio (PR) schedule of reinforcement. Animals were given a minimum of 9 continuous days of drug access before testing in order to establish a stable breaking point (BP) for intravenous cocaine infusions (0.75 mg/kg/infusion). Rats in the food group acquired stable responding on the PR schedule within 7 days. On the test day, rats were bilaterally infused in the NAcc with the muscarinic receptor agonist oxotremorine methiodide (OXO: 0.1, 0.3 or 1 nmol/side), OXO plus the M1 selective antagonist pirenzepine (PIRENZ; 0.3 nmol/side) or aCSF 15 min before cocaine or food access. OXO dose dependently reduced BP values for cocaine reinforcement (-17%, -44% [p<0.05] and -91% [p<0.0001] for 0.1, 0.3 and 1.0 nmol, respectively) and these reductions dissipated by the following session. Pretreatment with PIRENZ blocked the BP-reducing effect of 0.3 nmol OXO. Notably, OXO (0.1, 0.3 and 1.0 nmol/side) injection in the NAcc did not affect BP for food reward. The results suggest that muscarinic ACh receptors in the caudomedial NAcc may play a role in mediating the behavior reinforcing effects of cocaine. Section: Neuropharmacology, Neuropharmacology and other forms of Intracellular Communication PMID:17045970

Psychedelics: Where we are now, why we got here, what we must do.

PubMed

Belouin, Sean J; Henningfield, Jack E

2018-02-21

The purpose of this commentary is to provide an introduction to this special issue of Neuropharmacology with a historical perspective of psychedelic drug research, their use in psychiatric disorders, research-restricting regulatory controls, and their recent emergence as potential breakthrough therapies for several brain-related disorders. It begins with the discovery of lysergic acid diethylamide (LSD) and its promising development as a treatment for several types of mental illnesses during the 1940s. This was followed by its abuse and stigmatization in the 1960s that ultimately led to the placement of LSD and other psychedelic drugs into the most restrictively regulated drug schedule of the United States Controlled Substances Act (Schedule I) in 1970 and its international counterparts. These regulatory controls severely constrained development of psychedelic substances and their potential for clinical research in psychiatric disorders. Despite the limitations, there was continued research into brain mechanisms of action for psychedelic drugs with potential clinical applications which began during the 1990s and early 2000s. Finding pathways to accelerate clinical research in psychedelic drug development is supported by the growing body of research findings that are documented throughout this special issue of Neuropharmacology. Accumulated research to date suggests psychedelic drug assisted psychotherapy may emerge as a potential breakthrough treatment for several types of mental illnesses including depression, anxiety, post-traumatic stress disorder, and addiction that are refractory to current evidenced based therapies. This research equally shows promise in advancing the understanding of the brain, brain related functioning, and the consequential effects of untreated brain related diseases that have been implicated in causing and/or exacerbating numerous physical disease state conditions. The authors conclude that more must be done to effectively address mental illnesses and brain related diseases which have become so pervasive, destructive, and whose treatments are becoming increasingly resistant to current evidenced based therapies. Published by Elsevier Ltd.

Mechanisms underlying the antimotion sickness effects of psychostimulants

NASA Technical Reports Server (NTRS)

Kohl, Randall L.; Lewis, Michael R.

1987-01-01

Data related to the mechanism responsible for the antimotion sickness effects of psychostimulants such as amphetamine are examined. From the analysis of current literature and new evidence, the following three hypotheses are suggested: (1) selective enhancement of dopaminergic, but not noradrenergic, transmission is sufficient to account for amphetamine-induced resistance and, perhaps, for natural resistance to motion sickness; (2) the site of this enhanced dopaminergic transmission is probably within the basal ganglia; and (3) the neuropharmacology of the basal ganglia, but not of the brain-stem vestibular areas, can account for the therapeutic synergism of scopolamine and amphetamine. The therapeutic action of psychostimulants may be dissociable from some of their side effects, particularly cardiovascular effects related to peripheral norepinephrine release.

The stiff-man syndrome: new pathophysiological aspects from abnormal exteroceptive reflexes and the response to clomipramine, clonidine, and tizanidine.

PubMed Central

Meinck, H M; Ricker, K; Conrad, B

1984-01-01

Neurophysiological investigations of a patient suffering from the stiff-man syndrome revealed that exteroceptive reflexes, in particular those elicited from the skin, were excessively enhanced. In contrast, no abnormalities were found within the monosynaptic reflex arc. Clomipramine injection severely aggravated the clinical symptoms whereas diazepam, clonidine, and tizanidine decreased both muscular stiffness and abnormal exteroceptive reflexes. The hypothesis is put forward that the stiff-man syndrome is a disorder of descending brain-stem systems which exert a net inhibitory control on axial and limb girdle muscle tone as well as on exteroceptive reflex transmission. Detection of abnormal exteroceptive reflex activity in conjunction with neuropharmacological testing might help in the diagnosis of this rare disease. PMID:6707674

Neuropharmacological profile of ethnomedicinal plants of Guatemala.

PubMed

Morales Cifuentes, C; Gómez-Serranillos, M P; Iglesias, I; Villar del Fresno, A M; Morales, C; Paredes, M E; Cáceres, A

2001-08-01

We carried out the Irwin's test with some different extracts of the aerial parts of Thidax procumbens L., the leaves of Neurolaena lobata (L.) R. Br., bark and leaves of Byrsonima crassifolia (L.) Kunth. and Gliricidia sepium Jacq. Walp., and root and leaves of Petiveria alliacea L. At dosage of 1.25 g dried plant/kg weight aqueous extracts of bark and leaves of Byrsonima crassifolia (L.) Kunth. and Gliricidia sepium Jacq. Walp. demonstrated the most activity: decrease in motor activity, back tonus, reversible parpebral ptosis, catalepsy and strong hypothermia. These extracts of both plants were assayed for effects on CNS and they caused very significant reductions in spontaneous locomotor activity, exploratory behavior and rectal temperature and they increased the sodium pentobarbital-induced sleeping time.

New developments in stroke rehabilitation.

PubMed

Rocksmith, Eugenio R; Reding, Michael J

2002-07-01

There is increasing evidence that environmental and neuropharmacologic treatments enhance stroke recovery. Functional magnetic resonance imaging and transcranial magnetic stimulation have significantly broadened our understanding of the neuroanatomic relationships involved in recovery from brain injury due to stroke. These tools have also demonstrated the role for pharmacologic enhancement of cortical plasticity coupled with behavioral interventions. Robot-assisted therapy and partial body weight-supported treadmill gait training have demonstrated the role for technologic intervention in the modern neuro-rehabilitation setting. Current research using hemi-field ocular prisms and patching techniques suggest a role in the rehabilitation of hemianopsia and visual neglect. Finally, many advances have been made in the understanding of common stroke complications, such as depression, dysphagia, venous thromboembolic disease, incontinence, and spasticity.

5-HT in the enteric nervous system: gut function and neuropharmacology.

PubMed

McLean, Peter G; Borman, Richard A; Lee, Kevin

2007-01-01

In recent times, the perception of functional gastrointestinal disorders such as irritable bowel syndrome (IBS) has shifted fundamentally. Such disorders are now thought of as serious diseases characterized by perturbations in the neuronal regulation of gastrointestinal function. The concept of visceral hypersensitivity, the characterization of neuronal networks in the 'brain-gut axis' and the identification of several novel 5-HT-mediated mechanisms have contributed to this shift. Here, we review how some of the more promising of these new mechanisms (e.g. those involving 5-HT transporters and the 5-HT(2B), 5-HT(7) and putative 5-HT(1p) receptors) might lead to a range of second-generation therapies that could revolutionize the treatment of functional gastrointestinal disorders, particularly IBS.

Development of pharmacotherapies for drug addiction: a Rosetta Stone approach

PubMed Central

Koob, George F.; Kenneth Lloyd, G.; Mason, Barbara J.

2009-01-01

Current pharmacotherapies for addiction represent opportunities for facilitating treatment and are forming a foundation for evaluating new medications. Furthermore, validated animal models of addiction and a surge in understanding of neurocircuitry and neuropharmacological mechanisms involved in the development and maintenance of addiction — such as the neuroadaptive changes that account for the transition to dependence and the vulnerability to relapse — have provided numerous potential therapeutic targets. Here, we emphasize a ‘Rosetta Stone approach’, whereby existing pharmacotherapies for addiction are used to validate and improve animal and human laboratory models to identify viable new treatment candidates. This approach will promote translational research and provide a heuristic framework for developing efficient and effective pharmacotherapies for addiction. PMID:19483710

Planarians in pharmacology: parthenolide is a specific behavioral antagonist of cocaine in the planarian Girardia tigrina.

PubMed

Pagán, Oné R; Baker, Debra; Deats, Sean; Montgomery, Erica; Tenaglia, Matthew; Randolph, Clinita; Kotturu, Dharini; Tallarida, Christopher; Bach, Daniel; Wilk, Galia; Rawls, Scott; Raffa, Robert B

2012-01-01

Planarians are traditional animal models in developmental and regeneration biology. Recently, these organisms are arising as vertebrate-relevant animal models in neuropharmacology. Using an adaptation of published behavioral protocols, we have described the alleviation of cocaine-induced planarian seizure-like movements (pSLM) by a naturally-occurring sesquiterpene lactone, parthenolide. Interestingly, parthenolide does not prevent the expression of pSLM induced by amphetamines; in vertebrates, amphetamines interact with the same protein target as cocaine. Parthenolide is also unable to prevent pSLM elicited by the cholinergic com-pounds nicotine and cytisine or by the glutamatergic agents L- or D- glutamic acid or NMDA. Thus, we conclude that parthenolide is a specific anti-cocaine agent in this experimental organism.

The neuropharmacology of upper airway motor control in the awake and asleep states: implications for obstructive sleep apnoea

PubMed Central

Horner, Richard L

2001-01-01

Obstructive sleep apnoea is a common and serious breathing problem that is caused by effects of sleep on pharyngeal muscle tone in individuals with narrow upper airways. There has been increasing focus on delineating the brain mechanisms that modulate pharyngeal muscle activity in the awake and asleep states in order to understand the pathogenesis of obstructive apnoeas and to develop novel neurochemical treatments. Although initial clinical studies have met with only limited success, it is proposed that more rational and realistic approaches may be devised for neurochemical modulation of pharyngeal muscle tone as the relevant neurotransmitters and receptors that are involved in sleep-dependent modulation are identified following basic experiments. PMID:11686898

Behavioral barcoding in the cloud: embracing data-intensive digital phenotyping in neuropharmacology.

PubMed

Kokel, David; Rennekamp, Andrew J; Shah, Asmi H; Liebel, Urban; Peterson, Randall T

2012-08-01

For decades, studying the behavioral effects of individual drugs and genetic mutations has been at the heart of efforts to understand and treat nervous system disorders. High-throughput technologies adapted from other disciplines (e.g., high-throughput chemical screening, genomics) are changing the scale of data acquisition in behavioral neuroscience. Massive behavioral datasets are beginning to emerge, particularly from zebrafish labs, where behavioral assays can be performed rapidly and reproducibly in 96-well, high-throughput format. Mining these datasets and making comparisons across different assays are major challenges for the field. Here, we review behavioral barcoding, a process by which complex behavioral assays are reduced to a string of numeric features, facilitating analysis and comparison within and across datasets. Copyright © 2012 Elsevier Ltd. All rights reserved.

What have positron emission tomography and ‘Zippy’ told us about the neuropharmacology of drug addiction?

PubMed Central

Cumming, Paul; Caprioli, Daniele; Dalley, Jeffrey W

2011-01-01

Translational molecular imaging with positron emission tomography (PET) and allied technologies offer unrivalled applications in the discovery of biomarkers and aetiological mechanisms relevant to human disease. Foremost among clinical PET findings during the past two decades of addiction research is the seminal discovery of reduced dopamine D2/3 receptor expression in the striatum of drug addicts, which could indicate a predisposing factor and/or compensatory reaction to the chronic abuse of stimulant drugs. In parallel, recent years have witnessed significant improvements in the performance of small animal tomographs (microPET) and a refinement of animal models of addiction based on clinically relevant diagnostic criteria. This review surveys the utility of PET in the elucidation of neuropharmacological mechanisms underlying drug addiction. It considers the consequences of chronic drug exposure on regional brain metabolism and neurotransmitter function and identifies those areas where further research is needed, especially concerning the implementation of PET tracers targeting neurotransmitter systems other than dopamine, which increasingly have been implicated in the pathophysiology of drug addiction. In addition, this review considers the causal effects of behavioural traits such as impulsivity and novelty/sensation-seeking on the emergence of compulsive drug-taking. Previous research indicates that spontaneously high-impulsive rats – as exemplified by ‘Zippy’– are pre-disposed to escalate intravenous cocaine self-administration, and subsequently to develop compulsive drug taking tendencies that endure despite concurrent adverse consequences of such behaviour, just as in human addiction. The discovery using microPET of pre-existing differences in dopamine D2/3 receptor expression in the striatum of high-impulsive rats suggests a neural endophenotype that may likewise pre-dispose to stimulant addiction in humans. LINKED ARTICLES This article is part of a themed section on Imaging. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2011.163.issue-8BJP has previously published an Imaging in Pharmacology themed section, edited by A Davenport and C Daly. To view this section visit http://dx.doi.org/10.1111/bph.2010.159.issue-4 PMID:20846139

Neuroendocrine control of seasonal plasticity in the auditory and vocal systems of fish

PubMed Central

Forlano, Paul M.; Sisneros, Joseph A.; Rohmann, Kevin N.; Bass, Andrew H.

2014-01-01

Seasonal changes in reproductive-related vocal behavior are widespread among fishes. This review highlights recent studies of the vocal plainfin midshipman fish, Porichthys notatus, a neuroethological model system used for the past two decades to explore neural and endocrine mechanisms of vocal-acoustic social behaviors shared with tetrapods. Integrative approaches combining behavior, neurophysiology, neuropharmacology, neuroanatomy, and gene expression methodologies have taken advantage of simple, stereotyped and easily quantifiable behaviors controlled by discrete neural networks in this model system to enable discoveries such as the first demonstration of adaptive seasonal plasticity in the auditory periphery of a vertebrate as well as rapid steroid and neuropeptide effects on vocal physiology and behavior. This simple model system has now revealed cellular and molecular mechanisms underlying seasonal and steroid-driven auditory and vocal plasticity in the vertebrate brain. PMID:25168757

Treatment of phenothiazine induced bulbar persistent dyskinesia with deanol acetamidobenzoate.

PubMed

Curran, D J; Nagaswami, S; Mohan, K J

1975-02-01

The late manifestation of neuroleptic-induced dyskinesia (persistent dyskinesia) is an irreversible complication of long-term treatment that is poorly understood and difficult to treat. Recently, a theory of dopamine receptor hypersensitivity in the dopaminergic-cholinergic system has suggested an explanation of choreiform movements and, thus, an implication for the management of persistent dyskinesia. The case presented is that of bulbar persistent dyskinesia in a patient who had been prescribed a phenothiazine derivative for eleven years; his symptoms improved with the use of deanol, which probably converts to acetylcholine after crossing the blood brain barrier. This improvement suggests that deanol may shift the neuroleptic-induced dopaminergic-cholinergic system unbalance toward equilibrium by matching predominant dopaminergic effect or by enhancing deficient cholinergic action in the dopaminergic-cholinergic system. This isolated finding needs to be confirmed by more research in neuropharmacology.

The pleasures of play: pharmacological insights into social reward mechanisms.

PubMed

Trezza, Viviana; Baarendse, Petra J J; Vanderschuren, Louk J M J

2010-10-01

Like human children, most young mammals devote a significant amount of time and energy playing together, and social play is fun. Although social play is very pleasurable, it is more than just a frivolous activity: it is crucial for the development of behavioral flexibility, the acquisition of social and cognitive competence, and the maintenance of group cohesion. Social play is a natural reinforcer, and the neurotransmitter systems intimately implicated in the motivational, pleasurable and cognitive aspects of natural and drug rewards, such as opioids, endocannabinoids, dopamine and norepinephrine, play an important modulatory role in the performance of social play. In this review, we address the notion that social play is rewarding, and discuss recent developments in the neuropharmacology of this behavior. This provides a framework to understand how the brain processes social emotions, to make young individuals enjoy social play.

Neurobiological Pathways Linking Socioeconomic Position and Health

PubMed Central

Gianaros, Peter J.; Manuck, Stephen B.

2010-01-01

Across individuals, risk for poor health varies inversely with socioeconomic position (SEP). The pathways by which SEP affects health have been viewed from many epidemiological perspectives. Central to these perspectives is the notion that socioeconomic health disparities arise from an interplay between nested, recursive, and cumulative environmental, social, familial, psychological, behavioral, and physiological processes that unfold over the life span. Epidemiological perspectives on socioeconomic health disparities, however, have not yet formally integrated emerging findings from neuropharmacological, molecular genetic, and neuroimaging studies demonstrating that indicators of SEP relate to patterns of brain neurotransmission, brain morphology, and brain functionality implicated in the etiology of chronic medical conditions and psychological disorders. Here, we survey these emerging findings and consider how future neurobiological studies in this area can enhance our understanding of the pathways by which different dimensions of SEP become embodied by the brain to influence health throughout life. PMID:20498294

Rational Use of Second-Generation Antipsychotics for the Treatment of ICU Delirium.

PubMed

Mo, Yoonsun; Yam, Felix K

2017-02-01

Delirium, described as an acute neuropsychiatric syndrome, occurs commonly in critically ill patients and leads to many negative outcomes including increased mortality and long-term cognitive deficits. Despite the lack of clinical data supporting the use of antipsychotics for the management of intensive care unit (ICU) delirium, pharmacological interventions are often needed to control acutely agitated patients. Given that the most current guidelines do not advocate the use of haloperidol for either the prevention or treatment of ICU delirium due to a lack of evidence, second-generation antipsychotics (SGAs) have been commonly used as alternatives to haloperidol for ICU patients with delirium. Nonetheless, the evidence supporting the use of SGAs to treat ICU delirium remains limited. This review is designed to assess the available clinical evidence and highlights the different neuropharmacological and safety properties of SGAs in order to guide the rational use of SGAs for the treatment of ICU delirium.

[Instituto de Investigaciones Clinicas "Dr. Américo Negrette": 55 years of excellent research versus global economic recession].

PubMed

Valero Cedeño, Nereida Josefina

2014-12-01

The Instituto de Investigaciones Clínicas "Dr. Américo Negrette" belongs to the Faculty of Medicine at University of Zulia in Maracaibo, Zulia State, Venezuela. It was created on December 4, 1959 by Dr. Américo Negrette. Today, with 55 years of existence, the Institute seeks to fulfill the mission that characterizes it, based on the values instilled by its founder and maintained by subsequent generations, whose research projects are implemented through seven research sections: Biochemistry, Hematologic Research, Neuropharmacology and Neuroscience, Immunology and Cell Biology, Clinical Neurochemistry, Parasitology and Virology. The research originated in these laboratories have become national and international points of reference, despite the current economic situation with budget deficits that put at risk the quality and originality of their projects with negative consequences on the productivity and applications for health population, reasons of biomedical research.

Neuropharmacological and neurochemical properties of N-(2-cyanoethyl)-2-phenylethylamine, a prodrug of 2-phenylethylamine.

PubMed Central

Baker, G. B.; Coutts, R. T.; Rao, T. S.

1987-01-01

1 N-(2-cyanoethyl)-2-phenylethylamine (CEPEA) was examined as a possible prodrug of 2-phenylethylamine (PEA). 2 Pharmacokinetics of PEA and CEPEA were investigated in rat brain, blood and liver by gas chromatography with electron-capture detection (GC-ECD). Interactions of PEA and CEPEA with putative neurotransmitter amines were investigated by use of high performance liquid chromatography with electrochemical detection (h.p.l.c.-e.c.). 3 Administration of PEA caused transient increases in PEA concentrations which decreased rapidly in brain and blood and at a slower rate in liver. Administration of CEPEA caused sustained elevations of PEA concentrations and elimination of PEA was markedly decreased in these tissues relative to the situation after administration of PEA itself. 4 Administration of CEPEA caused more prolonged decreases in brain noradrenaline, dopamine and 5-hydroxytryptamine concentrations than those observed after PEA administration, although values increased to control levels eventually. PMID:2890391

Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action.

PubMed

Canal, Clinton E

2018-03-13

Recent, well-controlled - albeit small-scale - clinical trials show that serotonergic psychedelics, including psilocybin and lysergic acid diethylamide, possess great promise for treating psychiatric disorders, including treatment-resistant depression. Additionally, fresh results from a deluge of clinical neuroimaging studies are unveiling the dynamic effects of serotonergic psychedelics on functional activity within, and connectivity across, discrete neural systems. These observations have led to testable hypotheses regarding neural processing mechanisms that contribute to psychedelic effects and therapeutic benefits. Despite these advances and a plethora of preclinical and clinical observations supporting a central role for brain serotonin 5-HT 2A receptors in producing serotonergic psychedelic effects, lingering and new questions about mechanisms abound. These chiefly pertain to molecular neuropharmacology. This chapter is devoted to illuminating and discussing such questions in the context of preclinical experimental approaches for studying mechanisms of action of serotonergic psychedelics, classic and new.

Neuropharmacology of N,N-Dimethyltryptamine

PubMed Central

Carbonaro, Theresa M.; Gatch, Michael B.

2016-01-01

N,N-Dimethyltryptamine (DMT) is an indole alkaloid widely found in plants and animals. It is best known for producing brief and intense psychedelic effects when ingested. Increasing evidence suggests that endogenous DMT plays important roles for a number of processes in the periphery and central nervous system, and may act as a neurotransmitter. This paper reviews the current literature of both the recreational use of DMT and its potential roles as an endogenous neurotransmitter. Pharmacokinetics, mechanisms of action in the periphery and central nervous system, clinical uses and adverse effects are also reviewed. DMT appears to have limited neurotoxicity and other adverse effects except for intense cardiovascular effects when administered intravenously in large doses. Because of its role in nervous system signaling, DMT may be a useful experimental tool in exploring how brain works, and may also be a useful clinical tool for treatment of anxiety and psychosis. PMID:27126737

Transcranial electric and magnetic stimulation: technique and paradigms.

PubMed

Paulus, Walter; Peterchev, Angel V; Ridding, Michael

2013-01-01

Transcranial electrical and magnetic stimulation techniques encompass a broad physical variety of stimuli, ranging from static magnetic fields or direct current stimulation to pulsed magnetic or alternating current stimulation with an almost infinite number of possible stimulus parameters. These techniques are continuously refined by new device developments, including coil or electrode design and flexible control of the stimulus waveforms. They allow us to influence brain function acutely and/or by inducing transient plastic after-effects in a range from minutes to days. Manipulation of stimulus parameters such as pulse shape, intensity, duration, and frequency, and location, size, and orientation of the electrodes or coils enables control of the immediate effects and after-effects. Physiological aspects such as stimulation at rest or during attention or activation may alter effects dramatically, as does neuropharmacological drug co-application. Non-linear relationships between stimulus parameters and physiological effects have to be taken into account. © 2013 Elsevier B.V. All rights reserved.

Neuropharmacological effects of Nigella sativa

PubMed Central

Beheshti, Farimah; Khazaei, Majid; Hosseini, Mahmoud

2016-01-01

Nigella sativa (NS) (Ranunculaceae family) is generally utilized as a therapeutic plant all over the world. The seeds of the plant have a long history of use in different frameworks of medicines and food. In Islamic literature, it is considered as one of the greatest forms of therapeutics. It has been widely used to treat nervous system diseases such as memory impairment, epilepsy, neurotoxicity, pain, etc. Additionally, this is uncovered that the majority of therapeutic properties of this plant are due to the presence of thymoquinone (TQ) which is a major bioactive component of the essential oil. Pharmacological studies have been done to evaluate the effects of NS on the central nervous system (CNS). The present review is an effort to provide a detailed scientific literature survey about pharmacological activities of the plant on nervous system. Our literature review showed that NS and its components can be considered as promising agents in the treatment of nervous system disorders. PMID:27247928

The effect of a beta-adrenoceptor antagonist on accommodative adaptation in Hong Kong children.

PubMed

Chen, Jennifer C; Schmid, Katrina L; Brown, Brian; Edwards, Marion H

2005-03-01

Increased susceptibility to nearwork-induced accommodative adaptation has been suggested as a risk factor for myopia development. We investigated whether accommodative adaptation may explain in part the high prevalence of myopia in Hong Kong children and examined the effect of beta-antagonism with topical timolol maleate on accommodative adaptation. Thirty children (10 emmetropes and 20 myopes) aged between 8 and 12 years were recruited. Tonic accommodation was measured before and after 5 min of video game-playing using an open-field Shin-Nippon autorefractor. Measurements were repeated 30 min after timolol instillation. Children with progressing myopia demonstrated accommodative adaptation following the near task, whereas stable myopes showed counter-adaptive, hyperopic accommodative changes. Timolol increased the magnitude of accommodative adaptation in the stable myopes but had little effect on responses of the progressing myopes or emmetropes. Neuropharmacological modulation of the accommodative system may have a possible etiological role in the progression of myopia.

Phytochemical comparison between Pet ether and ethanolic extracts of Bacopa monnieri, Evolvulus alsinoides and Tinospora cordifolia.

PubMed

Gupta, Avneet; Raj, Hem; Sharma, Bhartendu; Upmanyu, Neeraj

2014-04-01

Bacopa monnieri, Evolvulus alsinoides and Tinospora cordifolia are established ayurvedic herbs having neuropharmacological effect. In present study is aimed to Phytochemical Comparison between Pet ether and Ethanolic extracts of Bacopa monnieri (BME), Evolvulus alsinoides (EAE) and Tinospora cordifolia (TCE). To identify the presence (+) or absence (-) of different phytoconstituents in Pet ether and Ethanolic extracts of BME, EAE and TCE by using various phytochemical testing methods. Phytochemical investigation showed the presence of various phytochemical constituents in Pet ether and Ethanolic extracts of BME, EAE and TCE. When comparison between Pet ether and Ethanolic extracts of BME, EAE and TCE; Ethanolic extracts of these plants showed more phytoconstituents as compared to Pet ether extracts of these plants. From present investigation, it can be concluded that phytochemical comparison is subsequently momentous and useful in finding chemical constituents in the plant substances that may lead to their quantitative evaluation and also pharmacologically active chemical compounds.

Neuropharmacology of N,N-dimethyltryptamine.

PubMed

Carbonaro, Theresa M; Gatch, Michael B

2016-09-01

N,N-dimethyltryptamine (DMT) is an indole alkaloid widely found in plants and animals. It is best known for producing brief and intense psychedelic effects when ingested. Increasing evidence suggests that endogenous DMT plays important roles for a number of processes in the periphery and central nervous system, and may act as a neurotransmitter. This paper reviews the current literature of both the recreational use of DMT and its potential roles as an endogenous neurotransmitter. Pharmacokinetics, mechanisms of action in the periphery and central nervous system, clinical uses and adverse effects are also reviewed. DMT appears to have limited neurotoxicity and other adverse effects except for intense cardiovascular effects when administered intravenously in large doses. Because of its role in nervous system signaling, DMT may be a useful experimental tool in exploring how the brain works, and may also be a useful clinical tool for treatment of anxiety and psychosis. Copyright © 2016 Elsevier Inc. All rights reserved.

The use of virtual reality-based therapy to augment poststroke upper limb recovery.

PubMed

Samuel, Geoffrey S; Choo, Min; Chan, Wai Yin; Kok, Stanley; Ng, Yee Sien

2015-07-01

Stroke remains one of the major causes of disability worldwide. This case report illustrates the complementary use of biomechanical and kinematic in-game markers, in addition to standard clinical outcomes, to comprehensively assess and track a patient's disabilities. A 65-year-old patient was admitted for right-sided weakness and clinically diagnosed with acute ischaemic stroke. She participated in a short trial of standard stroke occupational therapy and physiotherapy with additional daily virtual reality (VR)-based therapy. Outcomes were tracked using kinematic data and conventional clinical assessments. Her Functional Independence Measure score improved from 87 to 113 and Fugl-Meyer motor score improved from 56 to 62, denoting clinically significant improvement. Corresponding kinematic analysis revealed improved hand path ratios and a decrease in velocity peaks. Further research is being undertaken to elucidate the optimal type, timing, setting and duration of VR-based therapy, as well as the use of neuropharmacological adjuncts.

The use of virtual reality-based therapy to augment poststroke upper limb recovery

PubMed Central

Samuel, Geoffrey S; Choo, Min; Chan, Wai Yin; Kok, Stanley; Ng, Yee Sien

2015-01-01

Stroke remains one of the major causes of disability worldwide. This case report illustrates the complementary use of biomechanical and kinematic in-game markers, in addition to standard clinical outcomes, to comprehensively assess and track a patient’s disabilities. A 65-year-old patient was admitted for right-sided weakness and clinically diagnosed with acute ischaemic stroke. She participated in a short trial of standard stroke occupational therapy and physiotherapy with additional daily virtual reality (VR)-based therapy. Outcomes were tracked using kinematic data and conventional clinical assessments. Her Functional Independence Measure score improved from 87 to 113 and Fugl-Meyer motor score improved from 56 to 62, denoting clinically significant improvement. Corresponding kinematic analysis revealed improved hand path ratios and a decrease in velocity peaks. Further research is being undertaken to elucidate the optimal type, timing, setting and duration of VR-based therapy, as well as the use of neuropharmacological adjuncts. PMID:26243983

Attention: oscillations and neuropharmacology.

PubMed

Deco, Gustavo; Thiele, Alexander

2009-08-01

Attention is a rich psychological and neurobiological construct that influences almost all aspects of cognitive behaviour. It enables enhanced processing of behaviourally relevant stimuli at the expense of irrelevant stimuli. At the cellular level, rhythmic synchronization at local and long-range spatial scales complements the attention-induced firing rate changes of neurons. The former is hypothesized to enable efficient communication between neuronal ensembles tuned to spatial and featural aspects of the attended stimulus. Recent modelling studies suggest that the rhythmic synchronization in the gamma range may be mediated by a fine balance between N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate postsynaptic currents, whereas other studies have highlighted the possible contribution of the neuromodulator acetylcholine. This review summarizes some recent modelling and experimental studies investigating mechanisms of attention in sensory areas and discusses possibilities of how glutamatergic and cholinergic systems could contribute to increased processing abilities at the cellular and network level during states of top-down attention.

[The neurochemistry and neuropharmacology of frontotemporal dementia].

PubMed

Alonso-Navarro, H; Jabbour-Wadih, T; Ayuso-Peralta, L; Jiménez-Jiménez, F J

To review the neurochemical features and therapeutic options for frontotemporal dementia (FTD). The main neurochemical alterations in FTD are the serotoninergic and dopamine depletion. In contrast with Alzheimer's and diffuse Lewy bodies disease, there are not significant alterations of the cholinergic system. Cerebral perfusion and glucose metabolism studies usually show hypoperfusion or hypometabolism, with predominant involvement of temporal and frontal cortices. There have been described some alterations related with oxidative stress and apoptosis, although its pathogenetic role in FTD is not well known. Treatment of FTD is not well established, because there are only a few studies with some drugs. The most studied drugs are serotonin reuptake inhibitors, however, despite the well-known serotoninergic deficiency described in FTD, the results are not conclusive. The main neurochemical alterations of FTD are serotoninergic and dopaminergic deficiencies. The treatment is not well established, although it should be theoretically ideal to use drugs which modulate these neurotransmitter systems.

Recent advances in the neurobiology and neuropharmacology of Alzheimer's disease.

PubMed

Kumar, Kushal; Kumar, Ashwani; Keegan, Richard M; Deshmukh, Rahul

2018-02-01

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive deterioration of cognitive functions. The pathological hallmarks are extracellular deposits of amyloid plaques and intracellular neurofibrillary tangles of tau protein. The cognitive deficits seen are thought to be due to synaptic dysfunction and neurochemical deficiencies. Various neurochemical abnormalities have been observed during progressive ageing, and are linked to cognitive abnormalities as seen with the sporadic form of AD. Acetylcholinesterase inhibitors are one of the major therapeutic strategies used for the treatment of AD. During the last decade, various new therapeutic strategies have shown beneficial effects in preclinical studies and under clinical development for the treatment of AD. The present review is aimed at discussing the neurobiology of AD and association of neurochemical abnormalities associated with cognitive deterioration and new therapeutic strategies for the treatment of AD. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Neuropharmacology of memory consolidation and reconsolidation: Insights on central cholinergic mechanisms.

PubMed

Blake, M G; Krawczyk, M C; Baratti, C M; Boccia, M M

2014-01-01

Central cholinergic system is critically involved in all known memory processes. Endogenous acetylcholine release by cholinergic neurons is necessary for modulation of acquisition, encoding, consolidation, reconsolidation, extinction, retrieval and expression. Experiments from our laboratory are mainly focused on elucidating the mechanisms by which acetylcholine modulates memory processes. Blockade of hippocampal alpha-7-nicotinic receptors (α7-nAChRs) with the antagonist methyllycaconitine impairs memory reconsolidation. However, the administration of a α7-nAChR agonist (choline) produce a paradoxical modulation, causing memory enhancement in mice trained with a weak footshock, but memory impairment in animals trained with a strong footshock. All these effects are long-lasting, and depend on the age of the memory trace. This review summarizes and discusses some of our recent findings, particularly regarding the involvement of α7-nAChRs on memory reconsolidation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Corticotropin-Releasing Factor (CRF) Neurocircuitry and Neuropharmacology in Alcohol Drinking.

PubMed

Schreiber, Allyson L; Gilpin, Nicholas W

2018-01-28

Alcohol use is pervasive in the United States. In the transition from nonhazardous drinking to hazardous drinking and alcohol use disorder, neuroadaptations occur within brain reward and brain stress systems. One brain signaling system that has received much attention in animal models of excessive alcohol drinking and alcohol dependence is corticotropin-releasing factor (CRF). The CRF system is composed of CRF, the urocortins, CRF-binding protein, and two receptors - CRF type 1 and CRF type 2. This review summarizes how acute, binge, and chronic alcohol dysregulates CRF signaling in hypothalamic and extra-hypothalamic brain regions and how this dysregulation may contribute to changes in alcohol reinforcement, excessive alcohol consumption, symptoms of negative affect during withdrawal, and alcohol relapse. In addition, it summarizes clinical work examining CRF type 1 receptor antagonists in humans and discusses why the brain CRF system is still relevant in alcohol research.

Astrocyte deletion of Bmal1 alters daily locomotor activity and cognitive functions via GABA signalling

PubMed Central

Barca-Mayo, Olga; Pons-Espinal, Meritxell; Follert, Philipp; Armirotti, Andrea; Berdondini, Luca; De Pietri Tonelli, Davide

2017-01-01

Circadian rhythms are controlled by a network of clock neurons in the central pacemaker, the suprachiasmatic nucleus (SCN). Core clock genes, such as Bmal1, are expressed in SCN neurons and in other brain cells, such as astrocytes. However, the role of astrocytic clock genes in controlling rhythmic behaviour is unknown. Here we show that ablation of Bmal1 in GLAST-positive astrocytes alters circadian locomotor behaviour and cognition in mice. Specifically, deletion of astrocytic Bmal1 has an impact on the neuronal clock through GABA signalling. Importantly, pharmacological modulation of GABAA-receptor signalling completely rescues the behavioural phenotypes. Our results reveal a crucial role of astrocytic Bmal1 for the coordination of neuronal clocks and propose a new cellular target, astrocytes, for neuropharmacology of transient or chronic perturbation of circadian rhythms, where alteration of astrocytic clock genes might contribute to the impairment of the neurobehavioural outputs such as cognition. PMID:28186121

A Role for Brain Stress Systems in Addiction

PubMed Central

Koob, George F.

2009-01-01

Drug addiction is a chronically relapsing disorder characterized by compulsion to seek and take drugs and has been linked to dysregulation of brain regions that mediate reward and stress. Activation of brain stress systems is hypothesized to be key to the negative emotional state produced by dependence that drives drug seeking through negative reinforcement mechanisms. This review explores the role of brain stress systems (corticotropin-releasing factor, norepinephrine, orexin [hypocretin], vasopressin, dynorphin) and brain antistress systems (neuropeptide Y, nociceptin [orphanin FQ]) in drug dependence, with emphasis on the neuropharmacological function of extrahypothalamic systems in the extended amygdala. The brain stress and antistress systems may play a key role in the transition to and maintenance of drug dependence once initiated. Understanding the role of brain stress and antistress systems in addiction provides novel targets for treatment and prevention of addiction and insights into the organization and function of basic brain emotional circuitry. PMID:18614026

Pharmacology of Vagal Afferent Influences on Disordered Breathing During Sleep

PubMed Central

Carley, David W; Radulovacki, Miodrag

2008-01-01

Sleep related breathing disorders (SRBD) are a significant public health concern, with a prevalence in the US general population of ∼2% of women and ∼4% of men. Although significant strides have been made in our understanding of these disorders with respect to epidemiology, risk factors, pathogenesis and consequences, work to understand these factors in terms of the underlying cellular, molecular and neuromodulatory processes remains in its infancy. Current primary treatments are surgical or mechanical, with no drug treatments available. Basic investigations into the neurochemistry and neuropharmacology of sleep-related changes in respiratory pattern generation and modulation will be essential to clarify the pathogenic processes underlying SRBD and to identify rational and specific pharmacotherapeutic opportunities. Here we summarize emerging work suggesting the importance of vagal afferent feedback systems in sleep related respiratory pattern disturbances and pointing toward a rich but complex array of neurochemical and neuromodulatory processes that may be involved. PMID:18694851

Lack of GPR88 enhances medium spiny neuron activity and alters motor- and cue-dependent behaviors.

PubMed

Quintana, Albert; Sanz, Elisenda; Wang, Wengang; Storey, Granville P; Güler, Ali D; Wanat, Matthew J; Roller, Bryan A; La Torre, Anna; Amieux, Paul S; McKnight, G Stanley; Bamford, Nigel S; Palmiter, Richard D

2012-11-01

The striatum regulates motor control, reward and learning. Abnormal function of striatal GABAergic medium spiny neurons (MSNs) is believed to contribute to the deficits in these processes that are observed in many neuropsychiatric diseases. The orphan G protein-coupled receptor GPR88 is robustly expressed in MSNs and is regulated by neuropharmacological drugs, but its contribution to MSN physiology and behavior is unclear. We found that, in the absence of GPR88, MSNs showed increased glutamatergic excitation and reduced GABAergic inhibition, which promoted enhanced firing rates in vivo, resulting in hyperactivity, poor motor coordination and impaired cue-based learning in mice. Targeted viral expression of GPR88 in MSNs rescued the molecular and electrophysiological properties and normalized behavior, suggesting that aberrant MSN activation in the absence of GPR88 underlies behavioral deficits and its dysfunction may contribute to behaviors observed in neuropsychiatric disease.

Memantine and Kynurenic Acid: Current Neuropharmacological Aspects

PubMed Central

Majláth, Zsófia; Török, Nóra; Toldi, József; Vécsei, László

2016-01-01

Glutamatergic neurotransmission, of special importance in the human brain, is implicated in key brain functions such as synaptic plasticity and memory. The excessive activation of N-methyl- D-aspartate (NMDA) receptors may result in excitotoxic neuronal damage; this process has been implicated in the pathomechanism of different neurodegenerative disorders, such as Alzheimer’s disease (AD). Memantine is an uncompetitive antagonist of NMDA receptors with a favorable pharmacokinetic profile, and is therefore clinically well tolerated. Memantine is approved for the treatment of AD, but may additionally be beneficial for other dementia forms and pain conditions. Kynurenic acid (KYNA) is an endogenous antagonist of NMDA receptors which has been demonstrated under experimental conditions to be neuroprotective. The development of a well-tolerated NMDA antagonist may offer a novel therapeutic option for the treatment of neurodegenerative disease and pain syndromes. KYNA may be a valuable candidate for future drug development. PMID:26564141

Neuropharmacological effects of essential oil from the leaves of Croton conduplicatus Kunth and possible mechanisms of action involved.

PubMed

Oliveira Júnior, Raimundo Gonçalves de; Ferraz, Christiane Adrielly Alves; Silva, Juliane Cabral; de Andrade Teles, Roxana Braga; Silva, Mariana Gama; Diniz, Tâmara Coimbra; Dos Santos, Uiliane Soares; de Souza, Ana Valéria Vieira; Nunes, Carlos Eduardo Pereira; Salvador, Marcos José; Lorenzo, Vitor Prates; Quintans Júnior, Lucindo José; Almeida, Jackson Roberto Guedes da Silva

2018-07-15

Croton conduplicatus Kunth (Euphorbiaceae) is a Brazilian aromatic medicinal plant, widely known as "quebra-faca". In folk medicine, its leaves and stem-barks are used as a natural analgesic for the treatment of headaches. In this study, we describe for the first time the neuropharmacological potential of the essential oil obtained from the leaves of Croton conduplicatus (EO) in experimental models of pain, anxiety and insomnia. The mechanisms of action involved in these activities were also investigated. Different experimental models were used to evaluate the antinociceptive (acetic acid, formalin-induced nociception and hot plate tests), anxiolytic (elevated plus maze and hole board tests) and sedative (thiopental-induced sleeping time) effects of EO in mice. EO was evaluated in three different doses (25, 50 and 100 mg/kg, i.p.) and compared with positive and negative controls in all experimental protocols. When appropriate, animals were pretreated with pharmacological antagonists (naloxone, atropine and flumazenil) in order to evaluate the mechanisms of action involved. A docking study also was performed to identify possible targets involved. EO (25, 50 and 100 mg/kg, i.p.) demonstrated a significant antinociceptive activity in all experimental models. Pretreatment with naloxone or atropine reversed the antinociceptive response (p < 0.05), suggesting the involvement of opioid and muscarinic receptors, respectively. A docking study was performed with the major components identified in EO (1,8 cineole - 21.42%, spathulenol - 15.47%, p-cymene - 12.41% and caryophyllene oxide - 12.15%), demonstrating favorable interaction profile with different subtypes of muscarinic (M2, M3 and M4) and opioids (delta and mu) receptors. EO also showed anxiolytic (mainly at doses of 25 and 50 mg/kg, i.p.) and sedative (only at the dose of 100 mg/kg, i.p.) effects in mice. These pharmacological responses were reversed by flumazenil (p < 0.05), indicating possible involvement of GABA A receptors. Our findings support the traditional use of this plant as a natural analgesic and suggest that EO is a multi-target natural product, presenting not only antinociceptive effect but also anxiolytic and sedative activities depending on the dose used. Copyright © 2018 Elsevier B.V. All rights reserved.

Interaction of organic cation transporter 3 (SLC22A3) and amphetamine

PubMed Central

Zhu, Hao-Jie; Appel, David I.; Gründemann, Dirk; Markowitz, John S.

2013-01-01

The organic cation transporter (OCT) 3 is widely expressed in various organs in humans, and involved in the disposition of many exogenous and endogenous compounds. Several lines of evidence have suggested that OCT3 expressed in the brain plays an important role in the regulation of neurotransmission. Relative to wild-type (WT) animals, Oct3 knockout (KO) mice have displayed altered behavioral and neurochemical responses to psychostimulants such as amphetamine (AMPH) and methamphetamine. In the present study, both in vitro and in vivo approaches were utilized to explore potential mechanisms underlying the disparate neuropharmacological effects observed following AMPH exposure in Oct3 KO mice. In vitro uptake studies conducted in OCT3 transfected cells indicated that dextroamphetamine (d-AMPH) is not a substrate of OCT3. However, OCT3 was determined to be a high-capacity and low-affinity transporter for the neurotransmitters dopamine (DA), norepinephrine (NE), and serotonin (5-HT). Inhibition studies demonstrated that d-AMPH exerts relatively weak inhibitory effects on the OCT3-mediated uptake of DA, NE, 5-HT, and the model OCT3 substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide. The IC50 values were determined to be 41.5 ± 7.5 and 24.1 ± 7.0 μM for inhibiting DA and 5-HT uptake, respectively, while 50% inhibition of NE and 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide uptake was not achieved by even the highest concentration of d-AMPH applied (100 μM). Furthermore, the disposition of d-AMPH in various tissues including the brain, liver, heart, kidney, muscle, intestine, spleen, testis, uterus, and plasma were determined in both male and female Oct3 KO and WT mice. No significant difference was observed between either genotypes or sex in all tested organs and tissues. Our findings suggest that OCT3 is not a prominent factor influencing the disposition of d-AMPH. Additionally, based upon the inhibitory potency observed in vitro, d-AMPH is unlikely to inhibit the uptake of monoamines mediated by OCT3 in the brain. Differentiated neuropharmacological effects of AMPHs noted between Oct3 KO and WT mice appear to be due to the absence of Oct3 mediated uptake of neurotransmitters in the KO mice. PMID:20402963

Interaction of organic cation transporter 3 (SLC22A3) and amphetamine.

PubMed

Zhu, Hao-Jie; Appel, David I; Gründemann, Dirk; Markowitz, John S

2010-07-01

The organic cation transporter (OCT) 3 is widely expressed in various organs in humans, and involved in the disposition of many exogenous and endogenous compounds. Several lines of evidence have suggested that OCT3 expressed in the brain plays an important role in the regulation of neurotransmission. Relative to wild-type (WT) animals, Oct3 knockout (KO) mice have displayed altered behavioral and neurochemical responses to psychostimulants such as amphetamine (AMPH) and methamphetamine. In the present study, both in vitro and in vivo approaches were utilized to explore potential mechanisms underlying the disparate neuropharmacological effects observed following AMPH exposure in Oct3 KO mice. In vitro uptake studies conducted in OCT3 transfected cells indicated that dextroamphetamine (d-AMPH) is not a substrate of OCT3. However, OCT3 was determined to be a high-capacity and low-affinity transporter for the neurotransmitters dopamine (DA), norepinephrine (NE), and serotonin (5-HT). Inhibition studies demonstrated that d-AMPH exerts relatively weak inhibitory effects on the OCT3-mediated uptake of DA, NE, 5-HT, and the model OCT3 substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide. The IC(50) values were determined to be 41.5 +/- 7.5 and 24.1 +/- 7.0 microM for inhibiting DA and 5-HT uptake, respectively, while 50% inhibition of NE and 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide uptake was not achieved by even the highest concentration of d-AMPH applied (100 microM). Furthermore, the disposition of d-AMPH in various tissues including the brain, liver, heart, kidney, muscle, intestine, spleen, testis, uterus, and plasma were determined in both male and female Oct3 KO and WT mice. No significant difference was observed between either genotypes or sex in all tested organs and tissues. Our findings suggest that OCT3 is not a prominent factor influencing the disposition of d-AMPH. Additionally, based upon the inhibitory potency observed in vitro, d-AMPH is unlikely to inhibit the uptake of monoamines mediated by OCT3 in the brain. Differentiated neuropharmacological effects of AMPHs noted between Oct3 KO and WT mice appear to be due to the absence of Oct3 mediated uptake of neurotransmitters in the KO mice.

Monitoring nitric oxide (NO) in rat locus coeruleus: differential effects of NO synthase inhibitors.

PubMed

Desvignes, C; Robert, F; Vachette, C; Chouvet, G; Cespuglio, R; Renaud, B; Lambás-Señas, L

1997-04-14

A porphyrinic microsensor combined with in vivo voltammetry was used to monitor extracellular nitric oxide (NO) in the locus coeruleus (LC) of anaesthetized rats. Administration of N omega-nitro-L-arginine p-nitro-anilide (100 mg/kg, i.p) or 7-nitro indazole (30 mg/kg, i.p.), which both inhibit preferentially neuronal NO synthase (NOS), induced a marked decrease in the NO oxidation peak height. On the other hand, N omega-nitro-L-arginine methyl ester (L-NAME) (200 mg/kg, i.p.), a less selective NOS inhibitor, failed to decrease the NO signal. Moreover, intra LC administration of NMDA, known to activate LC noradrenergic neurones, increased the NO signal. This study demonstrates the usefulness of in vivo voltammetry to monitor basal levels of NO and their changes in the LC. Differential effects of NOS inhibitors show that their central activity need to be assessed through in situ measurement of NO before using these inhibitors as neuropharmacological tools.

Neuropharmacological Review of the Nootropic Herb Bacopa monnieri

PubMed Central

Borowski, Thomas

2013-01-01

Abstract This review synthesizes behavioral research with neuromolecular mechanisms putatively involved with the low-toxicity cognitive enhancing action of Bacopa monnieri (BM), a medicinal Ayurvedic herb. BM is traditionally used for various ailments, but is best known as a neural tonic and memory enhancer. Numerous animal and in vitro studies have been conducted, with many evidencing potential medicinal properties. Several randomized, double-blind, placebo-controlled trials have substantiated BM's nootropic utility in humans. There is also evidence for potential attenuation of dementia, Parkinson's disease, and epilepsy. Current evidence suggests BM acts via the following mechanisms—anti-oxidant neuroprotection (via redox and enzyme induction), acetylcholinesterase inhibition and/or choline acetyltransferase activation, β-amyloid reduction, increased cerebral blood flow, and neurotransmitter modulation (acetylcholine [ACh], 5-hydroxytryptamine [5-HT], dopamine [DA]). BM appears to exhibit low toxicity in model organisms and humans; however, long-term studies of toxicity in humans have yet to be conducted. This review will integrate molecular neuroscience with behavioral research. PMID:23772955

Neuropharmacological review of the nootropic herb Bacopa monnieri.

PubMed

Aguiar, Sebastian; Borowski, Thomas

2013-08-01

This review synthesizes behavioral research with neuromolecular mechanisms putatively involved with the low-toxicity cognitive enhancing action of Bacopa monnieri (BM), a medicinal Ayurvedic herb. BM is traditionally used for various ailments, but is best known as a neural tonic and memory enhancer. Numerous animal and in vitro studies have been conducted, with many evidencing potential medicinal properties. Several randomized, double-blind, placebo-controlled trials have substantiated BM's nootropic utility in humans. There is also evidence for potential attenuation of dementia, Parkinson's disease, and epilepsy. Current evidence suggests BM acts via the following mechanisms-anti-oxidant neuroprotection (via redox and enzyme induction), acetylcholinesterase inhibition and/or choline acetyltransferase activation, β-amyloid reduction, increased cerebral blood flow, and neurotransmitter modulation (acetylcholine [ACh], 5-hydroxytryptamine [5-HT], dopamine [DA]). BM appears to exhibit low toxicity in model organisms and humans; however, long-term studies of toxicity in humans have yet to be conducted. This review will integrate molecular neuroscience with behavioral research.

Analysis of opioid efficacy, tolerance, addiction and dependence from cell culture to human

PubMed Central

Morgan, Michael M; Christie, MacDonald J

2011-01-01

Opioid agonists are the most effective treatment for pain, but their use is limited by side effects, tolerance and fears of addiction and dependence. A major goal of opioid research is to develop agonists that have high analgesic efficacy and a low profile for side effects, tolerance, addiction and dependence. Unfortunately, there is a serious lack of experimental data comparing the degree to which different opioids produce these effects in humans. In contrast, a wide range of experimental techniques from heterologous expression systems to behaviour assessment in whole animals have been developed to study these problems. The objective of this review is to describe and evaluate these techniques as they are used to study opioid efficacy, tolerance, addiction and dependence. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21434879

Neuropharmacology of the essential oil of bergamot.

PubMed

Bagetta, Giacinto; Morrone, Luigi Antonio; Rombolà, Laura; Amantea, Diana; Russo, Rossella; Berliocchi, Laura; Sakurada, Shinobu; Sakurada, Tsukasa; Rotiroti, Domenicantonio; Corasaniti, Maria Tiziana

2010-09-01

Bergamot (Citrus bergamia, Risso) is a fruit most knowledgeable for its essential oil (BEO) used in aromatherapy to minimize symptoms of stress-induced anxiety and mild mood disorders and cancer pain though the rational basis for such applications awaits to be discovered. The behavioural and EEG spectrum power effects of BEO correlate well with its exocytotic and carrier-mediated release of discrete amino acids endowed with neurotransmitter function in the mammalian hippocampus supporting the deduction that BEO is able to interfere with normal and pathological synaptic plasticity. The observed neuroprotection in the course of experimental brain ischemia and pain does support this view. In conclusion, the data yielded so far contribute to our understanding of the mode of action of this phytocomplex on nerve tissue under normal and pathological experimental conditions and provide a rational basis for the practical use of BEO in complementary medicine. The opening of a wide venue for future research and translation into clinical settings is also envisaged. Copyright (c) 2010 Elsevier B.V. All rights reserved.

Phytochemistry and pharmacology of ornamental gingers, Hedychium coronarium and Alpinia purpurata: a review.

PubMed

Chan, Eric Wei Chiang; Wong, Siu Kuin

2015-11-01

In this review, the phytochemistry and pharmacology of two ornamental gingers, Hedychium coronarium (butterfly ginger) and Alpinia purpurata (red ginger), are updated, and their botany and uses are described. Flowers of H. coronarium are large, showy, white, yellow or white with a yellow centre and highly fragrant. Inflorescences of A. purpurata are erect spikes with attractive red or pink bracts. Phytochemical investigations on the rhizomes of H. coronarium generated research interest globally. This resulted in the isolation of 53 labdane-type diterpenes, with little work done on the leaves and flowers. Pharmacological properties of H. coronarium included antioxidant, antibacterial, antifungal, cytotoxic, chemopreventive, anti-allergic, larvicidal, anthelminthic, analgesic, anti-inflammatory, anti-urolithiatic, anti-angiogenic, neuro-pharmacological, fibrinogenolytic, coagulant and hepatoprotective activities. On the contrary, little is known on the phytochemistry of A. purpurata with pharmacological properties of antioxidant, antibacterial, larvicidal, cytotoxic and vasodilator activities reported in the leaves and rhizomes. There is much disparity in terms of research effort within and between these two ornamental gingers.

Validation of long-term primary neuronal cultures and network activity through the integration of reversibly bonded microbioreactors and MEA substrates.

PubMed

Biffi, Emilia; Menegon, Andrea; Piraino, Francesco; Pedrocchi, Alessandra; Fiore, Gianfranco B; Rasponi, Marco

2012-01-01

In vitro recording of neuronal electrical activity is a widely used technique to understand brain functions and to study the effect of drugs on the central nervous system. The integration of microfluidic devices with microelectrode arrays (MEAs) enables the recording of networks activity in a controlled microenvironment. In this work, an integrated microfluidic system for neuronal cultures was developed, reversibly coupling a PDMS microfluidic device with a commercial flat MEA through magnetic forces. Neurons from mouse embryos were cultured in a 100 µm channel and their activity was followed up to 18 days in vitro. The maturation of the networks and their morphological and functional characteristics were comparable with those of networks cultured in macro-environments and described in literature. In this work, we successfully demonstrated the ability of long-term culturing of primary neuronal cells in a reversible bonded microfluidic device (based on magnetism) that will be fundamental for neuropharmacological studies. Copyright © 2011 Wiley Periodicals, Inc.

Neuropharmacological Potential of Gastrodia elata Blume and Its Components

PubMed Central

Jang, Jung-Hee; Son, Yeonghoon; Kang, Seong Soo; Bae, Chun-Sik; Kim, Jong-Choon; Kim, Sung-Ho; Shin, Taekyun; Moon, Changjong

2015-01-01

Research has been conducted in various fields in an attempt to develop new therapeutic agents for incurable neurodegenerative diseases. Gastrodia elata Blume (GE), a traditional herbal medicine, has been used in neurological disorders as an anticonvulsant, analgesic, and sedative medication. Several neurodegenerative models are characterized by oxidative stress and inflammation in the brain, which lead to cell death via multiple extracellular and intracellular signaling pathways. The blockade of certain signaling cascades may represent a compensatory therapy for injured brain tissue. Antioxidative and anti-inflammatory compounds isolated from natural resources have been investigated, as have various synthetic chemicals. Specifically, GE rhizome extract and its components have been shown to protect neuronal cells and recover brain function in various preclinical brain injury models by inhibiting oxidative stress and inflammatory responses. The present review discusses the neuroprotective potential of GE and its components and the related mechanisms; we also provide possible preventive and therapeutic strategies for neurodegenerative disorders using herbal resources. PMID:26543487

Novel Therapeutic GPCRs for Psychiatric Disorders

PubMed Central

Komatsu, Hidetoshi

2015-01-01

G protein-coupled receptors (GPCRs) are the most common targets of the neuropharmacological drugs in the central nervous system (CNS). GPCRs are activated by manifold neurotransmitters, and their activation in turn evokes slow synaptic transmission. They are deeply involved in multiple neurological and psychiatric disorders such as Parkinson’s disease and schizophrenia. In the brain, the striatum is strongly innervated by the ventral tegmental area (VTA) and plays a central role in manifestation of psychiatric disorders. Recently, anatomical and comprehensive transcriptome analysis of the non-odorant GPCR superfamily revealed that the orphan GPCRs GPR88, GPR6, and GPR52, as well as dopamine D1 and D2 receptors and the adenosine A2a receptor, are the most highly enriched in the rodent striatum. Genetically engineered animal models and molecular biological studies have suggested that these striatally enriched GPCRs have a potential to be therapeutic psychiatric receptors. This review summarizes the current understanding of the therapeutic GPCR candidates for psychiatric disorders. PMID:26101869

Novel Therapeutic GPCRs for Psychiatric Disorders.

PubMed

Komatsu, Hidetoshi

2015-06-19

G protein-coupled receptors (GPCRs) are the most common targets of the neuropharmacological drugs in the central nervous system (CNS). GPCRs are activated by manifold neurotransmitters, and their activation in turn evokes slow synaptic transmission. They are deeply involved in multiple neurological and psychiatric disorders such as Parkinson's disease and schizophrenia. In the brain, the striatum is strongly innervated by the ventral tegmental area (VTA) and plays a central role in manifestation of psychiatric disorders. Recently, anatomical and comprehensive transcriptome analysis of the non-odorant GPCR superfamily revealed that the orphan GPCRs GPR88, GPR6, and GPR52, as well as dopamine D1 and D2 receptors and the adenosine A2a receptor, are the most highly enriched in the rodent striatum. Genetically engineered animal models and molecular biological studies have suggested that these striatally enriched GPCRs have a potential to be therapeutic psychiatric receptors. This review summarizes the current understanding of the therapeutic GPCR candidates for psychiatric disorders.

Inside-out neuropharmacology of nicotinic drugs

PubMed Central

Henderson, Brandon J.; Lester, Henry A.

2015-01-01

Upregulation of neuronal nicotinic acetylcholine receptors (AChRs) is a venerable result of chronic exposure to nicotine; but it is one of several consequences of pharmacological chaperoning by nicotine and by some other nicotinic ligands, especially agonists. Nicotinic ligands permeate through cell membranes, bind to immature AChR oligomers, elicit incompletely understood conformational reorganizations, increase the interaction between adjacent AChR subunits, and enhance the maturation process toward stable AChR pentamers. These changes and stabilizations in turn lead to increases in both anterograde and retrograde traffic within the early secretory pathway. In addition to the eventual upregulation of AChRs at the plasma membrane, other effects of pharmacological chaperoning include modifications to endoplasmic reticulum stress and to the unfolded protein response. Because these processes depend on pharmacological chaperoning within intracellular organelles, we group them as “inside-out pharmacology”. This term contrasts with the better-known, acute, “outside-in” effects of activating and desensitizing plasma membrane AChRs. We review current knowledge concerning the mechanisms and consequences of inside-out pharmacology. PMID:25660637

Different Classes of Glutamate Receptors Mediate Distinct Behaviors in a Single Brainstem Nucleus

NASA Astrophysics Data System (ADS)

Dye, John; Heiligenberg, Walter; Keller, Clifford H.; Kawasaki, Masashi

1989-11-01

We have taken advantage of the increasing understanding of glutamate neuropharmacology to probe mechanisms of well-defined vertebrate behaviors. Here we report a set of experiments that suggests distinct roles for two major classes of glutamate receptors in a discrete premotor nucleus of the brainstem. The medullary pacemaker nucleus of weakly electric fish is an endogenous oscillator that controls the electric organ discharge (EOD). Its regular frequency of firing is modulated during several distinct behaviors. The pacemaker nucleus continues firing regularly when isolated in vitro, and modulatory behaviors can be reproduced by stimulating the descending input pathway. Glutamate agonists applied to the pacemaker in vitro produced increases in frequency, while glutamate antagonists selectively blocked stimulus-induced modulations. Experiments with glutamate antagonists in the intact animal resulted in specific effects on two well-characterized behaviors. Our data indicate that these behaviors are separately mediated in the pacemaker by receptors displaying characteristics of the kainate/quisqualate and N-methyl-D-aspartate subtypes of glutamate receptor, respectively.

Undergraduate Neuropharmacology: A Model for Delivering College-Level Neuroscience to High School Students in situ.

PubMed

Martin-Morris, Linda E; Buckland, Helen T; Popa, Simina M; Cunningham, Susanna L

2015-01-01

Our university course for non-majors (Biology 100) on the neurobiology of drug addiction was recently retooled for delivery at high schools around the state of Washington in order to engage younger students in the study of psychoactive drugs. Many of these students are earning both high school and university credits (dual-enrollment). This paper outlines the course design principles we used to ensure that high school students are earning valid college credits. We present an analysis of learning gains experienced by both university and high school students as measured by before and after course knowledge surveys. We also describe how assessment strategies used for on-campus students have been transferred to our high school partner teachers and how generous interchange and observation ensure that the high school students are engaging deeply in their study of neuroscience. Indeed, many have had a transformative experience that inspires them to contemplate the field of neuroscience as they transition into university study.

Neuropharmacology of brain-stimulation-evoked aggression.

PubMed

Siegel, A; Roeling, T A; Gregg, T R; Kruk, M R

1999-01-01

Evidence is reviewed concerning the brain areas and neurotransmitters involved in aggressive behavior in the cat and rodent. In the cat, two distinct neural circuits involving the hypothalamus and PAG subserve two different kinds of aggression: defensive rage and predatory (quiet-biting) attack. The roles played by the neurotransmitters serotonin, GABA, glutamate, opioids, cholecystokinin, substance P, norepinephrine, dopamine, and acetylcholine in the modulation and expression of aggression are discussed. For the rat, a single area, largely coincident with the intermediate hypothalamic area, is crucial for the expression of attack; variations in the rat attack response in natural settings are due largely to environmental variables. Experimental evidence emphasizing the roles of serotonin and GABA in modulating hypothalamically evoked attack in the rat is discussed. It is concluded that significant progress has been made concerning our knowledge of the circuitry underlying the neural basis of aggression. Although new and important insights have been made concerning neurotransmitter regulation of aggressive behavior, wide gaps in our knowledge remain.

Gold and its relationship to neurological/glandular conditions.

PubMed

Richards, Douglas G; McMillin, David L; Mein, Eric A; Nelson, Carl D

2002-01-01

Despite increasing sales of gold supplements, and claims of benefits for neurological and glandular conditions, gold has received little attention in modern medical literature except as a drug for rheumatoid arthritis. Historically, however, gold had a reputation as a "nervine," a therapy for nervous disorders. A review of the historical literature shows gold in use during the 19th century for conditions including depression, epilepsy, migraine, and glandular problems such as amenorrhea and impotence. The most notable use of gold was in a treatment for alcoholism developed by Keeley (1897). In the modern medical literature, gold-containing medicines for rheumatoid arthritis are known to have occasional neurotoxic adverse effects. There are also a few studies suggesting a role for gold as a naturally occurring trace element in the reproductive glands. One small recent study demonstrated a possible positive effect of gold on cognitive ability. There is a need for more experimental and clinical research of the neuropharmacology and neurochemistry of gold, and for the exploration of gold's possible role as a trace element.

Drug-Gut Microbiota Interactions: Implications for Neuropharmacology.

PubMed

Walsh, Jacinta; Griffin, Brendan T; Clarke, Gerard; Hyland, Niall P

2018-05-21

The fate and activity of drugs are frequently dictated not only by the host per se but also by the microorganisms present in the gastrointestinal tract. The gut microbiome is known to, both directly and indirectly, affect drug metabolism. More evidence now hints at the impact that drugs can have on the function and composition of the gut microbiome. Both microbiota-mediated alterations in drug metabolism and drug-mediated alterations in the gut microbiome can have beneficial or detrimental effects on the host. Greater insights into the mechanisms driving these reciprocal drug-gut microbiota interactions are needed, to guide the development of microbiome-targeted dietary or pharmacological interventions, with the potential to enhance drug efficacy or reduce drug side-effects. In this review, we explore the relationship between drugs and the gut microbiome, with a specific focus on potential mechanisms underpinning the drug-mediated alterations on the gut microbiome and the potential implications for psychoactive drugs. This article is protected by copyright. All rights reserved.

Determination of the neuropharmacological drug nodakenin in rat plasma and brain tissues by liquid chromatography tandem mass spectrometry: Application to pharmacokinetic studies.

PubMed

Song, Yingshi; Yan, Huiyu; Xu, Jingbo; Ma, Hongxi

2017-09-01

A rapid and sensitive liquid chromatography tandem mass spectrometry detection using selected reaction monitoring in positive ionization mode was developed and validated for the quantification of nodakenin in rat plasma and brain. Pareruptorin A was used as internal standard. A single step liquid-liquid extraction was used for plasma and brain sample preparation. The method was validated with respect to selectivity, precision, accuracy, linearity, limit of quantification, recovery, matrix effect and stability. Lower limit of quantification of nodakenin was 2.0 ng/mL in plasma and brain tissue homogenates. Linear calibration curves were obtained over concentration ranges of 2.0-1000 ng/mL in plasma and brain tissue homogenates for nodakenin. Intra-day and inter-day precisions (relative standard deviation, RSD) were <15% in both biological media. This assay was successfully applied to plasma and brain pharmacokinetic studies of nodakenin in rats after intravenous administration. Copyright © 2017 John Wiley & Sons, Ltd.

Effects of activation and blockade of dopamine receptors on the extinction of a passive avoidance reaction in mice with a depressive-like state.

PubMed

Dubrovina, N I; Zinov'eva, D V

2010-01-01

Learning and extinction of a conditioned passive avoidance reaction resulting from neuropharmacological actions on dopamine D(1) and D(2) receptors were demonstrated to be specific in intact mice and in mice with a depressive-like state. Learning was degraded only after administration of the D(2) receptor antagonist sulpiride and was independent of the initial functional state of the mice. In intact mice, activation of D(2) receptors with quinpirole led to a deficit of extinction, consisting of a reduction in the ability to acquire new inhibitory learning in conditions associated with the disappearance of the expected punishment. In mice with the "behavioral despair" reaction, characterized by delayed extinction, activation of D(1) receptors with SKF38393 normalized this process, while the D(2) agonist was ineffective. A positive effect consisting of accelerated extinction of the memory of fear of the dark ("dangerous") sector of the experimental chamber was also seen on blockade of both types of dopamine receptor.

Neuropsychopharmacology of auditory hallucinations: insights from pharmacological functional MRI and perspectives for future research.

PubMed

Johnsen, Erik; Hugdahl, Kenneth; Fusar-Poli, Paolo; Kroken, Rune A; Kompus, Kristiina

2013-01-01

Experiencing auditory verbal hallucinations is a prominent symptom in schizophrenia that also occurs in subjects at enhanced risk for psychosis and in the general population. Drug treatment of auditory hallucinations is challenging, because the current understanding is limited with respect to the neural mechanisms involved, as well as how CNS drugs, such as antipsychotics, influence the subjective experience and neurophysiology of hallucinations. In this article, the authors review studies of the effect of antipsychotic medication on brain activation as measured with functional MRI in patients with auditory verbal hallucinations. First, the authors examine the neural correlates of ongoing auditory hallucinations. Then, the authors critically discuss studies addressing the antipsychotic effect on the neural correlates of complex cognitive tasks. Current evidence suggests that blood oxygen level-dependant effects of antipsychotic drugs reflect specific, regional effects but studies on the neuropharmacology of auditory hallucinations are scarce. Future directions for pharmacological neuroimaging of auditory hallucinations are discussed.

Antioxidant, Antinociceptive and CNS Activities of Viscum orientale and High Sensitive Quantification of Bioactive Polyphenols by UPLC

PubMed Central

Khatun, Amina; Rahman, Mahmudur; Rahman, Md. Mahfizur; Hossain, Hemayet; Jahan, Ismet A.; Nesa, Mst. Luthfun

2016-01-01

Viscum orientale Willd. (Loranthaceae) has long been used in traditional medicine to treat pain, neuropharmacological disorders and various forms of tumor but not yet been reported. The aim of this study is to rationalize the traditional medicinal use of this plant by evaluating the methanol extract of V. orientale leaves (MEVOL) for anti-nociceptive, CNS depressant and antioxidant activities and to quantify the bioactive polyphenols present in this plant. Five polyphenolic compounds namely gallic acid, vanillic acid, caffeic acid, ellagic acid, and quercetin (17.54, 8.99, 99.61, 4523.31, and 100.15 mg/100 g of dry weight, respectively) have been identified in MEVOL using Ultra Performance Liquid Chromatography. Qualitative antioxidant activity determined by Thin Layer Chromatography indicated the presence of antioxidants. In quantitative antioxidant test using 2,2-diphenyl 1-picrylhydrazyl, MEVOL exhibited strong free antioxidant activity in a dose dependant manner (IC50 = 6.63 μg/ml) compared with ascorbic acid (IC50 = 1.91 μg/ml) and butylatedhydroxyanisole (IC50 = 2.27 μg/ml) controls. Total phenolic content determined using Folin Ciocaltu reagent was found to be 73.4 mg gallic acid equivalent/g of extract, while flavonoid content estimated using aluminum chloride colorimetric method was 170.7 mg quercetin equivalent/g of extract. Anti-nociceptive activity of MEVOL measured using acetic acid and formalin induced pain models in mice was significant (p < 0.001). MEVOL showed 65.6 and 88.8% writhing inhibition at 300 and 500 mg/kg body weight, respectively, comparing with standard diclofenac-Na (75.2% inhibition) at 25 mg/kg body weight in acetic acid induced pain model. In formalin induced pain model, paw licking was inhibited 45.93 and 56.4% in early phase and 55.66 and 72.64% in late phase at 300 and 500 mg/kg body weight, respectively, while diclofenac-Na inhibited 60.47 and 61.32% in early and late phase at 10 mg/kg body weight, respectively. In neuropharmacological activity test, overall behavioral test significantly reinforced CNS depressant activity. Spontaneous motor activities were reduced (p < 0.05) in both hole cross and open field tests compared with diazepam. Antioxidant activity of MEVOL is likely due to the phenolic and flavonoid compounds present within the leaf tissues. This study reveals significant in vivo anti-nociceptive and CNS depressant activities which justifies traditional medicinal applications of V. orientale. PMID:27445814

Ethnobotany, phytochemistry and neuropharmacological effects of Petiveria alliacea L. (Phytolaccaceae): A review.

PubMed

Luz, Diandra Araújo; Pinheiro, Alana Miranda; Silva, Mallone Lopes; Monteiro, Marta Chagas; Prediger, Rui Daniel; Ferraz Maia, Cristiane Socorro; Fontes-Júnior, Enéas Andrade

2016-06-05

Petiveria alliacea L. commonly grows in the tropical regions of the Americas such as the Amazon forest, Central America, Caribbean islands and Mexico, as well as specific regions of Africa. Popularly known by several different names including 'mucuracaá', 'guiné' and 'pipi', P. alliacea has been used in traditional medicine for the treatment of various central nervous system (CNS) disorders, such as anxiety, pain, memory deficits and seizures, as well as for its anaesthetic and sedative properties. Furthermore, the use of this species for religious ceremonies has been reported since the era of slavery in the Americas. Therefore, the present review aims to provide a critical and comprehensive overview of the ethnobotany, phytochemistry and pharmacological properties of P. alliacea, focusing on CNS pharmacological effects, in order to identify scientific lacunae and to open new perspectives for future research. A literature search was performed on P. alliacea using ethnobotanical textbooks, published articles in peer-reviewed journals, unpublished materials, government survey reports and scientific databases such as PubMed, Scopus, Web of Science, Science Direct and Google Scholar. The Plant List, International Plant Name Index and Kew Botanical Garden Plant name databases were used to validate the scientific names. Crude extracts, fractions and phytochemical constituents isolated from various parts of P. alliacea show a wide spectrum of neuropharmacological activities including anxiolytic, antidepressant, antinociceptive and anti-seizure, and as cognitive enhancers. Phytochemistry studies of P. alliacea indicate that this plant contains a diversity of biologically active compounds, with qualitative and quantitative variations of the major compounds depending on the region of collection and the harvest season, such as essential oil (Petiverina), saponinic glycosides, isoarborinol-triterpene, isoarborinol-acetate, isoarborinol-cinnamate, steroids, alkaloids, flavonoids and tannins. Root chemical analyses have revealed coumarins, benzyl-hydroxy-ethyl-trisulphide, benzaldehyde, benzoic acid, dibenzyl trisulphide, potassium nitrate, b-sitosterol, isoarborinol, isoarborinol-acetate, isoarborinol-cinnamate, polyphenols, trithiolaniacine, glucose and glycine. Many traditional uses of P. alliacea have now been validated by modern pharmacology research. The available data reviewed here support the emergence of P. alliacea as a potential source for the treatment of different CNS disorders including anxiety, depression, pain, epilepsy and memory impairments. However, further studies are certainly required to improve the knowledge about the mechanisms of action, toxicity and efficacy of the plant as well as about its bioactive compounds before it can be approved in terms of its safety for therapeutic applications. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Neuropharmacology of purinergic receptors in human submucous plexus: Involvement of P2X₁, P2X₂, P2X₃ channels, P2Y and A₃ metabotropic receptors in neurotransmission.

PubMed

Liñán-Rico, A; Wunderlich, J E; Enneking, J T; Tso, D R; Grants, I; Williams, K C; Otey, A; Michel, K; Schemann, M; Needleman, B; Harzman, A; Christofi, F L

2015-08-01

The role of purinergic signaling in human ENS is not well understood. We sought to further characterize the neuropharmacology of purinergic receptors in human ENS and test the hypothesis that endogenous purines are critical regulators of neurotransmission. LSCM-Fluo-4/(Ca(2+))-imaging of postsynaptic Ca(2+) transients (PSCaTs) was used as a reporter of synaptic transmission evoked by fiber tract electrical stimulation in human SMP surgical preparations. Pharmacological analysis of purinergic signaling was done in 1,556 neurons (identified by HuC/D-immunoreactivity) in 235 ganglia from 107 patients; P2XR-immunoreactivity was evaluated in 19 patients. Real-time MSORT (Di-8-ANEPPS) imaging tested effects of adenosine on fast excitatory synaptic potentials (fEPSPs). Synaptic transmission is sensitive to pharmacological manipulations that alter accumulation of extracellular purines: Apyrase blocks PSCaTs in a majority of neurons. An ecto-NTPDase-inhibitor 6-N,N-diethyl-D-β,γ-dibromomethyleneATP or adenosine deaminase augments PSCaTs. Blockade of reuptake/deamination of eADO inhibits PSCaTs. Adenosine inhibits fEPSPs and PSCaTs (IC50 = 25 µM), sensitive to MRS1220-antagonism (A3AR). A P2Y agonist ADPβS inhibits PSCaTs (IC50 = 111 nM) in neurons without stimulatory ADPbS responses (EC50 = 960 nM). ATP or a P2X1,2,2/3 (α,β-MeATP) agonist evokes fast, slow, biphasic Ca(2+) transients or Ca(2+) oscillations (ATP,EC50 = 400 mM). PSCaTs are sensitive to P2X1 antagonist NF279. Low (20 nM) or high (5 µM) concentrations of P2X antagonist TNP-ATP block PSCaTs in different neurons; proportions of neurons with P2XR-immunoreactivity follow the order P2X2 > P2X1 > P2X3; P2X1 + P2X2 and P2X3 + P2X2 are co-localized. RT-PCR identified mRNA-transcripts for P2X1-7, P2Y1,2,12-14R. Purines are critical regulators of neurotransmission in human ENS. Purinergic signaling involves P2X1, P2X2, P2X3 channels, P2X1 + P2X2 co-localization and inhibitory P2Y or A3 receptors. These are potential novel therapeutic targets for neurogastroenterology. Published by Elsevier Ltd.

Neuropharmacological Manipulation of Restrained and Free-flying Honey Bees, Apis mellifera.

PubMed

Søvik, Eirik; Plath, Jenny A; Devaud, Jean-Marc; Barron, Andrew B

2016-11-26

Honey bees demonstrate astonishing learning abilities and advanced social behavior and communication. In addition, their brain is small, easy to visualize and to study. Therefore, bees have long been a favored model amongst neurobiologists and neuroethologists for studying the neural basis of social and natural behavior. It is important, however, that the experimental techniques used to study bees do not interfere with the behaviors being studied. Because of this, it has been necessary to develop a range of techniques for pharmacological manipulation of honey bees. In this paper we demonstrate methods for treating restrained or free-flying honey bees with a wide range of pharmacological agents. These include both noninvasive methods such as oral and topical treatments, as well as more invasive methods that allow for precise drug delivery in either systemic or localized fashion. Finally, we discuss the advantages and disadvantages of each method and describe common hurdles and how to best overcome them. We conclude with a discussion on the importance of adapting the experimental method to the biological questions rather than the other way around.

Pharmacological Enhancement of Memory and Executive Functioning in Laboratory Animals

PubMed Central

Floresco, Stan B; Jentsch, James D

2011-01-01

Investigating how different pharmacological compounds may enhance learning, memory, and higher-order cognitive functions in laboratory animals is the first critical step toward the development of cognitive enhancers that may be used to ameliorate impairments in these functions in patients suffering from neuropsychiatric disorders. Rather than focus on one aspect of cognition, or class of drug, in this review we provide a broad overview of how distinct classes of pharmacological compounds may enhance different types of memory and executive functioning, particularly those mediated by the prefrontal cortex. These include recognition memory, attention, working memory, and different components of behavioral flexibility. A key emphasis is placed on comparing and contrasting the effects of certain drugs on different cognitive and mnemonic functions, highlighting methodological issues associated with this type of research, tasks used to investigate these functions, and avenues for future research. Viewed collectively, studies of the neuropharmacological basis of cognition in rodents and non-human primates have identified targets that will hopefully open new avenues for the treatment of cognitive disabilities in persons affected by mental disorders. PMID:20844477

Neurochemical background and approaches in the understanding of motion sickness

NASA Technical Reports Server (NTRS)

Kohl, R. L.

1982-01-01

The problems and nature of space motion sickness were defined. The neurochemical and neurophysiological bases of vestibular system function and of the expression of motion sickness wre reviewed. Emphasis was given to the elucidation of the neuropharmacological mechanisms underlying the effects of scopolamine and amphetamine on motion sickness. Characterization of the ascending reticular activating system and the limbic system provided clues to the etiology of the side effects of scopolamine. The interrelationship between central cholinergic pathways and the peripheral (autonomic) expression of motion sickness was described. A correlation between the stress of excessive motion and a variety of hormonal responses to that stress was also detailed. The cholinergic system is involved in the efferent modulation of the vestibular hair cells, as an afferent modulator of the vestibular nuclei, in the activation of cortical and limbic structures, in the expression of motion sickness symptoms and most likely underscores a number of the hormonal changes that occur in stressful motion environments. The role of lecithin in the regulation of the levels of neurotransmitters was characterized as a possible means by which cholinergic neurochemistry can be modulated.

Neuroleptics and learning: effects of haloperidol, molindone, mesoridazine and thioridazine on the behavior of pigeons under a repeated acquisition procedure.

PubMed

Poling, A; Cleary, J; Berens, K; Thompson, T

1990-12-01

The purpose of the present study was to examine the effects of haloperidol (0.3-10 mg/kg), molindone (0.3-5.6 mg/kg), mesoridazine (0.3-10) and thioridazine (0.3-25 mg/kg) on the behavior of pigeons exposed to a repeated acquisition procedure. At sufficiently high doses, each of these neuroleptics increased error rates (interfered with learning) and reduced rate of responding. When the drugs were compared on the basis of absolute doses administered, haloperidol disrupted behavior at doses considerably lower than the other drugs. If, however, chlorpromazine equivalent doses were examined, haloperidol was the least disruptive of the four drugs. Comparing the degree of behavioral disruption produced by the four drugs with their relative neuroreceptor affinities for dopamine D-2, cholinergic muscarinic, histamine H1, alpha-1 adrenergic and alpha-2 adrenergic receptors suggests that behavioral disruption cannot be attributed in any simple way to dopamine or acetylcholine receptor blockade. The relationship between the behavioral effects of neuroleptics and their simple neuropharmacological actions must be considered as highly tentative.

Rotifer neuropharmacology--III. Adrenergic drug effects on Brachionus plicatilis.

PubMed

Keshmirian, J; Nogrady, T

1987-01-01

Norepinephrine (NE) induces three pharmacological effects in Brachionus plicatilis. As a result of excitation the rate of ciliary motion and swimming increases, and the animals flip their foot constantly at a rapid rate. This rapid foot flipping was used as a specific model to measure adrenergic effects in B. plicatilis. Phenylephrine induces the same effect at identical efficacy, while isoproterenol and salbutamol, two beta-agonists, show one-half and one-tenth NE efficacy. The beta blocker propranolol and the alpha blocker tolazoline both antagonize foot flipping induced by NE. However, propranolol shows antagonism because it causes foot paralysis by itself. Timolol, another beta blocker but without the membrane effect of propranolol, does not antagonize the alpha receptor mediated NE effect, nor does it cause foot paralysis. Propranolol, timolol and tolazoline also show agonist activity, inducing foot flipping. NE does not antagonize the foot paralysis induced by propranolol, only its anesthetic effect by delaying its onset. These results indicate that the foot flipping induced by NE is a receptor-mediated alpha adrenergic effect, while the foot paralysis is caused by membrane phenomena.

Compartmentalized Platforms for Neuro-pharmacological Research

PubMed Central

Jadhav, Amol D.; Wei, Li; Shi, Peng

2016-01-01

Dissociated primary neuronal cell culture remains an indispensable approach for neurobiology research in order to investigate basic mechanisms underlying diverse neuronal functions, drug screening and pharmacological investigation. Compartmentalization, a widely adopted technique since its emergence in 1970s enables spatial segregation of neuronal segments and detailed investigation that is otherwise limited with traditional culture methods. Although these compartmental chambers (e.g. Campenot chamber) have been proven valuable for the investigation of Peripheral Nervous System (PNS) neurons and to some extent within Central Nervous System (CNS) neurons, their utility has remained limited given the arduous manufacturing process, incompatibility with high-resolution optical imaging and limited throughput. The development in the area of microfabrication and microfluidics has enabled creation of next generation compartmentalized devices that are cheap, easy to manufacture, require reduced sample volumes, enable precise control over the cellular microenvironment both spatially as well as temporally, and permit highthroughput testing. In this review we briefly evaluate the various compartmentalization tools used for neurobiological research, and highlight application of the emerging microfluidic platforms towards in vitro single cell neurobiology. PMID:26813122

A systematic review of the neurobiological aspects of memory in the aging process

PubMed Central

de Oliveira, Eduardo Moreira; Kissaki, Priscilla Tiemi; Ordonez, Tiago Nascimento; Lima-Silva, Thaís Bento

2011-01-01

A systematic review of the neuroanatomical literature was performed to determine the neuropharmacological aspects most relevant to the study of memory processes. Articles were retrieved using the search terms "biology of memory", "memory and aging", "memory impairment", "elderly and memory," and their equivalents in Portuguese. Of the studies surveyed, five studies dealt with epidemiological and demographic issues, 12 were clinical trials i.e. were based on testing and implementation of instruments in human subjects, 33 studies were basic research involving studies of mice, rats and non-human primates, and biochemical and in vitro trials and finally, 52 studies were literature reviews or book chapters which in our view, fell into this category. Conclusions The work sought to highlight which neural networks are most involved in processing information, as well as their location within brain regions and the way in which neurotransmitters interact with each other for the formation of these memories. Moreover, it was shown how memory changes during the normal human aging process, both positively and negatively, by analyzing the morphological alterations that occur in the brain of aging individuals. PMID:29213758

Molecular recognition of ketamine by a subset of olfactory G protein–coupled receptors

PubMed Central

Saven, Jeffery G.; Matsunami, Hiroaki; Eckenhoff, Roderic G.

2015-01-01

Ketamine elicits various neuropharmacological effects, including sedation, analgesia, general anesthesia, and antidepressant activity. Through an in vitro screen, we identified four mouse olfactory receptors (ORs) that responded to ketamine. In addition to their presence in the olfactory epithelium, these G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptors (GPCRs) are distributed throughout the central nervous system. To better understand the molecular basis of the interactions between ketamine and ORs, we used sequence comparison and molecular modeling to design mutations that (i) increased, reduced, or abolished ketamine responsiveness in responding receptors, and (ii) rendered non-responding receptors responsive to ketamine. We showed that olfactory sensory neurons (OSNs) that expressed distinct ORs responded to ketamine in vivo, suggesting that ORs may serve as functional targets for ketamine. The ability to both abolish and introduce responsiveness to ketamine in GPCRs enabled us to identify and confirm distinct interaction loci in the binding site, which suggested a signature ketamine-binding pocket that may guide exploration of additional receptors for this general anesthetic drug. PMID:25829447

GABAA-benzodiazepine-chloride receptor-targeted therapy for tinnitus control: preliminary report.

PubMed

Shulman, Abraham; Strashun, Arnold M; Goldstein, Barbara A

2002-01-01

Our goal was to attempt to establish neuropharmacological tinnitus control (i.e., relief) with medication directed to restoration of a deficiency in the gamma-aminobutyric acid-benzodiazepine-chloride receptor in tinnitus patients with a diagnosis of a predominantly central type tinnitus. Thirty tinnitus patients completed a medical audiological tinnitus patient protocol and brain magnetic resonance imaging and single-photon emission computed tomography of brain. Treatment with GABAergic and benzodiazepine medication continued for 4-6 weeks. A maintenance dose was continued when tinnitus control was positive. Intake and outcome questionnaires were completed. Of 30 patients, 21 completed the trial (70%). Tinnitus control lasting from 4-6 weeks to 3 years was reported by 19 of the 21 (90%). The trial was not completed by 9 of the 30 (30%). No patient experienced an increase in tinnitus intensity or annoyance. Sequential brain single-photon emission computed tomography in 10 patients revealed objective evidence of increased brain perfusion. Patients with a predominantly central type tinnitus experience significant tinnitus control with medication directed to the gamma-aminobutyric acid-benzodiazepine-chloride receptor.

Current state of the use of neuroimaging techniques to understand and alter appetite control in humans.

PubMed

Spetter, Maartje S

2018-06-20

It is in the brain where the decision is made what and how much to eat. In the last decades neuroimaging research has contributed extensively to new knowledge about appetite control by revealing the underlying brain processes. Interestingly, there is the fast growing idea of using these methods to develop new treatments for obesity and eating disorders. In this review, we summarize the findings of the importance of the use of neuropharmacology and neuroimaging techniques in understanding and modifying appetite control. Appetite control is a complex interplay between homeostatic, hedonic, and cognitive processes. Administration of the neuropeptides insulin and oxytocin curb food intake and alter brain responses in reward and cognitive control areas. Additionally, these areas can be targeted for neuromodulation or neurofeedback to reduce food cravings and increase self-control to alter food intake. The recent findings reveal the potential of intranasal administration of hormones or modifying appetite control brain networks to reduce food consumption in volunteers with overweight and obesity or individuals with an eating disorder. Although long-term clinical studies are still needed.

A review on ethnobotany, phytochemistry and pharmacology of Fumaria indica (Fumitory)

PubMed Central

Gupta, Prakash Chandra; Sharma, Nisha; Rao, Ch V

2012-01-01

Fumaria indica (Hausskn.) Pugsley (Fumariaceae), known as “Fumitory”, is an annual herb found as a common weed all over the plains of India and Pakistan. The whole plant is widely used in traditional and folkloric systems of medicine. In traditional systems of medicine, the plant is reputed for its anthelmintic, diuretic, diaphoretic, laxative, cholagogue, stomachic and sedative activities and is used to purify blood and in liver obstruction in ethnopharmacology. The whole plant is ascribed to possess medicinal virtues in Ayurvedic and Unani systems of medicine and is also used in preparation of important Ayurvedic medicinal preparations and polyherbal liver formulations. The review reveals that phytochemical constituents of wide range have been separated from the plants and it possesses important pharmacological activities like smooth muscle relaxant, spasmogenic and spasmolytic, analgesic, anti-inflammatory, neuropharmacological and antibacterial activities. The separation of hepatoprotective and antifungal constituents from this plant was also reported newly. This review highlights the traditional, ethnobotanical, phytochemical, pharmacological information available on Fumaria indica, which might be helpful for scientists and researchers to find out new chemical entities responsible for its claimed traditional uses. PMID:23569991

Muscarinic agonists for the treatment of cognition in schizophrenia.

PubMed

Sellin, Angela K; Shad, Mujeeb; Tamminga, Carol

2008-11-01

It is widely accepted that cholinergic activity at muscarinic receptors is required to maintain cognitive functions, including learning and memory. Memory domains are especially impaired in schizophrenia, which may explain difficulties in psychosocial rehabilitation of individuals with this illness. However, little is known about the mechanism of this impairment. To understand our current knowledge, we reviewed the literature since 1990 via a PubMed search for the terms "muscarinic", "schizophrenia", "cognition", "memory", "learning", and "agonist" in combination. We found 89 basic science/laboratory studies, case reports/series, case-control studies, cross-sectional studies, standardized controlled animal trials, standardized controlled human trials, and reviews. Although further research is required to fully understand the neuropharmacology of the cholinergic system in cognitive function in schizophrenia, we have examined the data currently available. In general, these data suggest that agonist activity at acetylcholine muscarinic type 1 (M1) receptors would enhance memory and learning in schizophrenia. We present an overview of likely side effects of muscarinic agonists. We outline the anticholinergic activity of several available antipsychotics and review the available M1 muscarinic agonists.

Squalenoyl adenosine nanoparticles provide neuroprotection after stroke and spinal cord injury

NASA Astrophysics Data System (ADS)

Gaudin, Alice; Yemisci, Müge; Eroglu, Hakan; Lepetre-Mouelhi, Sinda; Turkoglu, Omer Faruk; Dönmez-Demir, Buket; Caban, Seçil; Sargon, Mustafa Fevzi; Garcia-Argote, Sébastien; Pieters, Grégory; Loreau, Olivier; Rousseau, Bernard; Tagit, Oya; Hildebrandt, Niko; Le Dantec, Yannick; Mougin, Julie; Valetti, Sabrina; Chacun, Hélène; Nicolas, Valérie; Desmaële, Didier; Andrieux, Karine; Capan, Yilmaz; Dalkara, Turgay; Couvreur, Patrick

2014-12-01

There is an urgent need to develop new therapeutic approaches for the treatment of severe neurological trauma, such as stroke and spinal cord injuries. However, many drugs with potential neuropharmacological activity, such as adenosine, are inefficient upon systemic administration because of their fast metabolization and rapid clearance from the bloodstream. Here, we show that conjugation of adenosine to the lipid squalene and the subsequent formation of nanoassemblies allows prolonged circulation of this nucleoside, providing neuroprotection in mouse stroke and rat spinal cord injury models. The animals receiving systemic administration of squalenoyl adenosine nanoassemblies showed a significant improvement of their neurologic deficit score in the case of cerebral ischaemia, and an early motor recovery of the hindlimbs in the case of spinal cord injury. Moreover, in vitro and in vivo studies demonstrated that the nanoassemblies were able to extend adenosine circulation and its interaction with the neurovascular unit. This Article shows, for the first time, that a hydrophilic and rapidly metabolized molecule such as adenosine may become pharmacologically efficient owing to a single conjugation with the lipid squalene.

Neuropharmacology of Purinergic Receptors in Human Submucous Plexus: Involvement of P2X1, P2X2, P2X3 Channels, P2Y and A3 Metabotropic Receptors in Neurotransmission

PubMed Central

Liñán-Rico, A.; Wunderlich, JE.; Enneking, JT.; Tso, DR.; Grants, I.; Williams, KC.; Otey, A.; Michel, K.; Schemann, M.; Needleman, B.; Harzman, A.; Christofi, FL.

2015-01-01

Rationale The role of purinergic signaling in the human ENS is not well understood. We sought to further characterize the neuropharmacology of purinergic receptors in human ENS and test the hypothesis that endogenous purines are critical regulators of neurotransmission. Experimental Approach LSCM-Fluo-4-(Ca2+)-imaging of postsynaptic Ca2+ transients (PSCaTs) was used as a reporter of neural activity. Synaptic transmission was evoked by fiber tract electrical stimulation in human SMP surgical preparations. Pharmacological analysis of purinergic signaling was done in 1,556 neurons from 234 separate ganglia 107 patients; immunochemical labeling for P2XRs of neurons in ganglia from 19 patients. Real-time MSORT (Di-8-ANEPPS) imaging was used to test effects of adenosine on fast excitatory synaptic potentials (fEPSPs). Results Synaptic transmission is sensitive to pharmacological manipulations that alter accumulation of extracellular purines. Apyrase blocks PSCaTs in a majority of neurons. An ecto-NTPDase-inhibitor 6-N,N-diethyl-D-β,γ-dibromomethyleneATP or adenosine deaminase augments PSCaTs. Blockade of reuptake/deamination of eADO inhibits PSCaTs. Adenosine inhibits fEPSPs and PSCaTs (IC50=25μM), sensitive to MRS1220-antagonism (A3AR). A P2Y agonist ADPβS inhibits PSCaTs (IC50=111nM) in neurons without stimulatory ADPβS responses (EC50=960nM). ATP or a P2X1,2,2/3 (α,β-MeATP) agonist evokes fast, slow, biphasic Ca2+ transients or Ca2+ oscillations (EC50=400μM). PSCaTs are sensitive to P2X1 antagonist NF279. Low (20nM) or high (5μM) concentrations of P2X antagonist TNP-ATP block PSCaTs in different neurons; proportions of neurons with P2XR-ir follow the order P2X2>P2X1≫P2X3; P2X1+ P2X2 and P2X3+P2X2 are co-localized. RT-PCR identified mRNA-transcripts for P2X1-7,P2Y1,2,12-14R. Responsive neurons were also identified by HuC/D-ir. Conclusions Purines are critical regulators of neurotransmission in the human enteric nervous system. Purinergic signaling involves P2X1, P2X2, P2X3 channels, P2X1+P2X2 co-localization and inhibitory P2Y or A3 receptors. These are potential novel therapeutic targets for neurogastroenterology. PMID:25724083

Evaluation of multiple comparison correction procedures in drug assessment studies using LORETA maps.

PubMed

Alonso, Joan Francesc; Romero, Sergio; Mañanas, Miguel Ángel; Rojas, Mónica; Riba, Jordi; Barbanoj, Manel José

2015-10-01

The identification of the brain regions involved in the neuropharmacological action is a potential procedure for drug development. These regions are commonly determined by the voxels showing significant statistical differences after comparing placebo-induced effects with drug-elicited effects. LORETA is an electroencephalography (EEG) source imaging technique frequently used to identify brain structures affected by the drug. The aim of the present study was to evaluate different methods for the correction of multiple comparisons in the LORETA maps. These methods which have been commonly used in neuroimaging and also simulated studies have been applied on a real case of pharmaco-EEG study where the effects of increasing benzodiazepine doses on the central nervous system measured by LORETA were investigated. Data consisted of EEG recordings obtained from nine volunteers who received single oral doses of alprazolam 0.25, 0.5, and 1 mg, and placebo in a randomized crossover double-blind design. The identification of active regions was highly dependent on the selected multiple test correction procedure. The combined criteria approach known as cluster mass was useful to reveal that increasing drug doses led to higher intensity and spread of the pharmacologically induced changes in intracerebral current density.

A specific role for hippocampal mossy fiber's zinc in rapid storage of emotional memories

PubMed Central

Ceccom, Johnatan; Halley, Hélène; Daumas, Stéphanie; Lassalle, Jean Michel

2014-01-01

We investigated the specific role of zinc present in large amounts in the synaptic vesicles of mossy fibers and coreleased with glutamate in the CA3 region. In previous studies, we have shown that blockade of zinc after release has no effect on the consolidation of spatial learning, while zinc is required for the consolidation of contextual fear conditioning. Although both are hippocampo-dependent processes, fear conditioning to the context implies a strong emotional burden. To verify the hypothesis that zinc could play a specific role in enabling sustainable memorization of a single event with a strong emotional component, we used a neuropharmacological approach combining a glutamate receptor antagonist with different zinc chelators. Results show that zinc is mandatory to allow the consolidation of one-shot memory, thus being the key element allowing the hippocampus submitted to a strong emotional charge to switch from the cognitive mode to a flashbulb memory mode. Individual differences in learning abilities have been known for a long time to be totally or partially compensated by distributed learning practice. Here we show that contextual fear conditioning impairments due to zinc blockade can be efficiently reduced by distributed learning practice. PMID:24741109

Deanol in Gilles de la Tourette Syndrome: a preliminary investigation.

PubMed

Pinta, E R

1977-03-01

On the basis of its pharmacologic action Deanol (dimethyl aminoethanol) was hypothesized to be of benefit in the Gilles de la Tourette Syndrome. In one case report the addition of Deanol to perphenazine did not result in an improvement of uncontrollable movements or involuntary speech utterances. Gilles de la Tourette Syndrome is a condition combining organic and psychogenic features existing in the interface between two etiologies. Classically the disease begins in childhood and is characterized by the appearance of sudden involuntary movements, involuntary speech utterances frequently consisting of curse words (coprolalia), and imitative phenomena such as echolalia and echopraxia. Neurotic symptomatology such as anxiety and obsessive thinking have also been reported. This condition is regarded neuropharmacologically as a dopaminergic state that responds to drugs with antidopaminergic activity e.g. the phenothiazines and butyrophenones. Deanol (dimethyl aminoethanol) is a putative cholinergic agonist and has reported effectiveness in conditions where there is a predominance of dopaminergic versus cholinergic activity, e.g. levodopa-induced dyskinesias, neuroleptic induced tardive dyskinesia, and Huntington's chorea. Because of its effectiveness in dopaminergic states it was hypothesized that Deanol could also be of benefit in the Gilles de la Tourette Syndrome.

The catecholaminergic-cholinergic balance hypothesis of bipolar disorder revisited

PubMed Central

van Enkhuizen, Jordy; Janowsky, David S; Olivier, Berend; Minassian, Arpi; Perry, William; Young, Jared W; Geyer, Mark A

2014-01-01

Bipolar disorder is a unique illness characterized by fluctuations between mood states of depression and mania. Originally, an adrenergic-cholinergic balance hypothesis was postulated to underlie these different affective states. In this review, we update this hypothesis with recent findings from human and animal studies, suggesting that a catecholaminergic-cholinergic hypothesis may be more relevant. Evidence from neuroimaging studies, neuropharmacological interventions, and genetic associations support the notion that increased cholinergic functioning underlies depression, whereas increased activations of the catecholamines (dopamine and norepinephrine) underlie mania. Elevated functional acetylcholine during depression may affect both muscarinic and nicotinic acetylcholine receptors in a compensatory fashion. Increased functional dopamine and norepinephrine during mania on the other hand may affect receptor expression and functioning of dopamine reuptake transporters. Despite increasing evidence supporting this hypothesis, a relationship between these two neurotransmitter systems that could explain cycling between states of depression and mania is missing. Future studies should focus on the influence of environmental stimuli and genetic susceptibilities that may affect the catecholaminergic-cholinergic balance underlying cycling between the affective states. Overall, observations from recent studies add important data to this revised balance theory of bipolar disorder, renewing interest in this field of research. PMID:25107282

The crossed phrenic phenomenon

PubMed Central

Ghali, Michael George Zaki

2017-01-01

The cervical spine is the most common site of traumatic vertebral column injuries. Respiratory insufficiency constitutes a significant proportion of the morbidity burden and is the most common cause of mortality in these patients. In seeking to enhance our capacity to treat specifically the respiratory dysfunction following spinal cord injury, investigators have studied the “crossed phrenic phenomenon”, wherein contraction of a hemidiaphragm paralyzed by a complete hemisection of the ipsilateral cervical spinal cord above the phrenic nucleus can be induced by respiratory stressors and recovers spontaneously over time. Strengthening of latent contralateral projections to the phrenic nucleus and sprouting of new descending axons have been proposed as mechanisms contributing to the observed recovery. We have recently demonstrated recovery of spontaneous crossed phrenic activity occurring over minutes to hours in C1-hemisected unanesthetized decerebrate rats. The specific neurochemical and molecular pathways underlying crossed phrenic activity following injury require further clarification. A thorough understanding of these is necessary in order to develop targeted therapies for respiratory neurorehabilitation following spinal trauma. Animal studies provide preliminary evidence for the utility of neuropharmacological manipulation of serotonergic and adenosinergic pathways, nerve grafts, olfactory ensheathing cells, intraspinal microstimulation and a possible role for dorsal rhizotomy in recovering phrenic activity following spinal cord injury PMID:28761411

Anxiogenic-like effects of chronic nicotine exposure in zebrafish.

PubMed

Stewart, Adam Michael; Grossman, Leah; Collier, Adam D; Echevarria, David J; Kalueff, Allan V

2015-12-01

Nicotine is one of the most widely used and abused legal drugs. Although its pharmacological profile has been extensively investigated in humans and rodents, nicotine CNS action remains poorly understood. The importance of finding evolutionarily conserved signaling pathways, and the need to apply high-throughput in vivo screens for CNS drug discovery, necessitate novel efficient experimental models for nicotine research. Zebrafish (Danio rerio) are rapidly emerging as an excellent organism for studying drug abuse, neuropharmacology and toxicology and have recently been applied to testing nicotine. Anxiolytic, rewarding and memory-modulating effects of acute nicotine treatment in zebrafish are consistently reported in the literature. However, while nicotine abuse is more relevant to long-term exposure models, little is known about chronic effects of nicotine on zebrafish behavior. In the present study, chronic 4-day exposure to 1-2mg/L nicotine mildly increased adult zebrafish shoaling but did not alter baseline cortisol levels. We also found that chronic exposure to nicotine evokes robust anxiogenic behavioral responses in zebrafish tested in the novel tank test paradigm. Generally paralleling clinical and rodent data on anxiogenic effects of chronic nicotine, our study supports the developing utility of zebrafish for nicotine research. Copyright © 2015 Elsevier Inc. All rights reserved.

Scientific Research and Corporate Influence: Smoking, Mental Illness, and the Tobacco Industry

PubMed Central

Hirshbein, Laura

2012-01-01

Mentally ill individuals have always smoked at high rates and continue to do so, despite public health efforts to encourage smoking cessation. In the last half century, the tobacco industry became interested in this connection, and conducted and supported psychiatric and basic science research on the mental health implications of smoking, long before most mental health professionals outside the industry investigated this issue. Initially, representatives of tobacco industry research organizations supported genetics and psychosomatic research to try to disprove findings that smoking causes lung cancer. Tobacco industry research leaders engaged with investigators because of shared priorities and interests in the brain effects of nicotine. By the 1980s, collaborative funding programs and individual company research and development teams engaged in intramural and extramural basic science studies on the neuropharmacology of nicotine. When mental health researchers outside the industry became interested in the issue of the mentally ill and smoking in the mid-1990s, they increasingly explained it in terms of a disease of nicotine addiction. Both the idea that smoking/nicotine does something positive for the mentally ill and the conclusion that it is the result of nicotine dependence have the potential to support corporate agendas (tobacco or pharmaceutical). PMID:21596723

Remarkable Phenytoin Sensitivity in 4 Children with SCN8A-related Epilepsy: A Molecular Neuropharmacological Approach.

PubMed

Boerma, Ragna S; Braun, Kees P; van den Broek, Marcel P H; van de Broek, Maarten P H; van Berkestijn, Frederique M C; Swinkels, Marielle E; Hagebeuk, Eveline O; Lindhout, Dick; van Kempen, Marjan; Boon, Maartje; Nicolai, Joost; de Kovel, Carolien G; Brilstra, Eva H; Koeleman, Bobby P C

2016-01-01

Mutations in SCN8A are associated with epilepsy and intellectual disability. SCN8A encodes for sodium channel Nav1.6, which is located in the brain. Gain-of-function missense mutations in SCN8A are thought to lead to increased firing of excitatory neurons containing Nav1.6, and therefore to lead to increased seizure susceptibility. We hypothesized that sodium channel blockers could have a beneficial effect in patients with SCN8A-related epilepsy by blocking the overactive Nav1.6 and thereby counteracting the effect of the mutation. Herein, we describe 4 patients with a missense SCN8A mutation and epilepsy who all show a remarkably good response on high doses of phenytoin and loss of seizure control when phenytoin medication was reduced, while side effects were relatively mild. In 2 patients, repeated withdrawal of phenytoin led to the reoccurrence of seizures. Based on the findings in these patients and the underlying molecular mechanism we consider treatment with (high-dose) phenytoin as a possible treatment option in patients with difficult-to-control seizures due to an SCN8A mutation.

Speech and swallowing disorders in Parkinson disease.

PubMed

Sapir, Shimon; Ramig, Lorraine; Fox, Cynthia

2008-06-01

To review recent research and clinical studies pertaining to the nature, diagnosis, and treatment of speech and swallowing disorders in Parkinson disease. Although some studies indicate improvement in voice and speech with dopamine therapy and deep brain stimulation of the subthalamic nucleus, others show minimal or adverse effects. Repetitive transcranial magnetic stimulation of the mouth motor cortex and injection of collagen in the vocal folds have preliminary data supporting improvement in phonation in people with Parkinson disease. Treatments focusing on vocal loudness, specifically LSVT LOUD (Lee Silverman Voice Treatment), have been effective for the treatment of speech disorders in Parkinson disease. Changes in brain activity due to LSVT LOUD provide preliminary evidence for neural plasticity. Computer-based technology makes the Lee Silverman Voice Treatment available to a large number of users. A rat model for studying neuropharmacologic effects on vocalization in Parkinson disease has been developed. New diagnostic methods of speech and swallowing are also available as the result of recent studies. Speech rehabilitation with the LSVT LOUD is highly efficacious and scientifically tested. There is a need for more studies to improve understanding, diagnosis, prevention, and treatment of speech and swallowing disorders in Parkinson disease.

A new extracellular multirecording system for electrophysiological studies: application to hippocampal organotypic cultures.

PubMed

Stoppini, L; Duport, S; Corrèges, P

1997-03-01

The present paper describes a new multirecording device which performs continuous electrophysiological studies on organotypic cultures. This device is formed by a card (Physiocard) carrying the culture which is inserted into an electronic module. Electrical activities are recorded by an array of 30 biocompatible microelectrodes which are adjusted into close contact with the upper surface of the slice culture. The microelectrode array is integrated into the card enabling electrical stimulation and recording of neurons over periods ranging from several hours to a few days outside a Faraday cage. Neuronal responses are recorded and analyzed by a dedicated electronic and acquisition chain. A perfusion chamber is contained in the card, allowing continuous perfusion in sterile conditions. Electrophysiological extracellular recordings and some drugs' effects obtained with this system in hippocampal slice cultures were identical to conventional electrophysiological set-up results with tetrodotoxin, bicuculline, kainate, dexamethasone and NBQX. The Physiocard system allows new insights for studies on nervous tissue and allows sophisticated approaches to be used quicker and more easily. It could be used for various neurophysiological studies or screening tests such as neural network mapping, nervous recovery, epilepsy, neurotoxicity or neuropharmacology.

Pharmacological imaging as a tool to visualise dopaminergic neurotoxicity.

PubMed

Schrantee, A; Reneman, L

2014-09-01

Dopamine abnormalities underlie a wide variety of psychopathologies, including ADHD and schizophrenia. A new imaging technique, pharmacological magnetic resonance imaging (phMRI), is a promising non-invasive technique to visualize the dopaminergic system in the brain. In this review we explore the clinical potential of phMRI in detecting dopamine dysfunction or neurotoxicity, assess its strengths and weaknesses and identify directions for future research. Preclinically, phMRI is able to detect severe dopaminergic abnormalities quite similar to conventional techniques such as PET and SPECT. phMRI benefits from its high spatial resolution and the possibility to visualize both local and downstream effects of dopaminergic neurotransmission. In addition, it allows for repeated measurements and assessments in vulnerable populations. The major challenge is the complex interpretation of phMRI results. Future studies in patients with dopaminergic abnormalities need to confirm the currently reviewed preclinical findings to validate the technique in a clinical setting. Eventually, based on the current review we expect that phMRI can be of use in a clinical setting involving vulnerable populations (such as children and adolescents) for diagnosis and monitoring treatment efficacy. This article is part of the Special Issue Section entitled 'Neuroimaging in Neuropharmacology'. Copyright © 2013 Elsevier Ltd. All rights reserved.

Experimental neuropharmacology of Gelsemium sempervirens: Recent advances and debated issues.

PubMed

Bellavite, Paolo; Bonafini, Clara; Marzotto, Marta

Gelsemium sempervirens L. (Gelsemium) is traditionally used for its anxiolytic-like properties and its action mechanism in laboratory models are under scrutiny. Evidence from rodent models was reported suggesting the existence of a high sensitivity of central nervous system to anxiolytic power of Gelsemium extracts and Homeopathic dilutions. In vitro investigation of extremely low doses of this plant extract showed a modulation of gene expression of human neurocytes. These studies were criticized in a few commentaries, generated a debate in literature and were followed by further experimental studies from various laboratories. Toxic doses of Gelsemium cause neurological signs characterized by marked weakness and convulsions, while ultra-low doses or high Homeopathic dilutions counteract seizures induced by lithium and pilocarpine, decrease anxiety after stress and increases the anti-stress allopregnanolone hormone, through glycine receptors. Low (non-Homeopathic) doses of this plant or its alkaloids decrease neuropathic pain and c-Fos expression in mice brain and oxidative stress. Due to the complexity of the matter, several aspects deserve interpretation and the main controversial topics, with a focus on the issues of high dilution pharmacology, are discussed and clarified. Copyright © 2017 Transdisciplinary University, Bangalore and World Ayurveda Foundation. Published by Elsevier B.V. All rights reserved.

Inside-out neuropharmacology of nicotinic drugs.

PubMed

Henderson, Brandon J; Lester, Henry A

2015-09-01

Upregulation of neuronal nicotinic acetylcholine receptors (AChRs) is a venerable result of chronic exposure to nicotine; but it is one of several consequences of pharmacological chaperoning by nicotine and by some other nicotinic ligands, especially agonists. Nicotinic ligands permeate through cell membranes, bind to immature AChR oligomers, elicit incompletely understood conformational reorganizations, increase the interaction between adjacent AChR subunits, and enhance the maturation process toward stable AChR pentamers. These changes and stabilizations in turn lead to increases in both anterograde and retrograde traffic within the early secretory pathway. In addition to the eventual upregulation of AChRs at the plasma membrane, other effects of pharmacological chaperoning include modifications to endoplasmic reticulum stress and to the unfolded protein response. Because these processes depend on pharmacological chaperoning within intracellular organelles, we group them as "inside-out pharmacology". This term contrasts with the better-known, acute, "outside-in" effects of activating and desensitizing plasma membrane AChRs. We review current knowledge concerning the mechanisms and consequences of inside-out pharmacology. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'. Copyright © 2015 Elsevier Ltd. All rights reserved.

Sertraline Induces Toxicity and Behavioral Alterations in Planarians.

PubMed

Thumé, Isabela Salvador; Frizzo, Marcos Emílio

2017-01-01

Toxicity attributed to sertraline has been demonstrated recently in different cell types and also in some organisms. We investigated the effect of sertraline on planarians, which are considered suitable for investigations in neurotoxicology and currently are widely used as an animal model in neuropharmacological studies. Planarians treated with 10  µ M sertraline showed a rapid reduction in their spontaneous movement until they became completely motionless and then showed a series of asynchronous paroxysms (seizures) followed by progressive tissue damage, beginning 48 h after the sertraline treatment, and died approximately 72 h later. Our data showed that sertraline does not cause planarian death within the range of therapeutic concentrations; however, behavioral alterations were observed with concentrations that can be considered compatible with therapeutic ones, such as a significant reduction in planarian locomotory activity at 0.4  µ M. Treatment with 4  µ M sertraline had a significant effect, reducing planarian locomotory activity and increasing the number of asynchronous paroxysms; both effects were significantly maintained even 24 h after the sertraline was withdrawn. These behavioral changes observed at low micromolar concentrations suggest that sertraline might have residual biological consequences for planarians, even after it is withdrawn.

Scientific research and corporate influence: smoking, mental illness, and the tobacco industry.

PubMed

Hirshbein, Laura

2012-07-01

Mentally ill individuals have always smoked at high rates and continue to do so, despite public health efforts to encourage smoking cessation. In the last half century, the tobacco industry became interested in this connection, and conducted and supported psychiatric and basic science research on the mental health implications of smoking, long before most mental health professionals outside the industry investigated this issue. Initially, representatives of tobacco industry research organizations supported genetics and psychosomatic research to try to disprove findings that smoking causes lung cancer. Tobacco industry research leaders engaged with investigators because of shared priorities and interests in the brain effects of nicotine. By the 1980s, collaborative funding programs and individual company research and development teams engaged in intramural and extramural basic science studies on the neuropharmacology of nicotine. When mental health researchers outside the industry became interested in the issue of the mentally ill and smoking in the mid-1990s, they increasingly explained it in terms of a disease of nicotine addiction. Both the idea that smoking/nicotine does something positive for the mentally ill and the conclusion that it is the result of nicotine dependence have the potential to support corporate agendas (tobacco or pharmaceutical).

The psychopharmacology of aggressive behavior: a translational approach: part 2: clinical studies using atypical antipsychotics, anticonvulsants, and lithium.

PubMed

Comai, Stefano; Tau, Michael; Pavlovic, Zoran; Gobbi, Gabriella

2012-04-01

Patients experiencing mental disorders are at an elevated risk for developing aggressive behavior. In the past 10 years, the psychopharmacological treatment of aggression has changed dramatically owing to the introduction of atypical antipsychotics on the market and the increased use of anticonvulsants and lithium in the treatment of aggressive patients.This review (second of 2 parts) uses a translational medicine approach to examine the neurobiology of aggression, discussing the major neurotransmitter systems implicated in its pathogenesis (serotonin, glutamate, norepinephrine, dopamine, and γ-aminobutyric acid) and the neuropharmacological rationale for using atypical antipsychotics, anticonvulsants, and lithium in the therapeutics of aggressive behavior. A critical review of all clinical trials using atypical antipsychotics (aripiprazole, clozapine, loxapine, olanzapine, quetiapine, risperidone, ziprasidone, and amisulpride), anticonvulsants (topiramate, valproate, lamotrigine, and gabapentin), and lithium are presented. Given the complex, multifaceted nature of aggression, a multifunctional combined therapy, targeting different receptors, seems to be the best strategy for treating aggressive behavior. This therapeutic strategy is supported by translational studies and a few human studies, even if additional randomized, double-blind, clinical trials are needed to confirm the clinical efficacy of this framework.

Julius Axelrod: 20 May 1912 - 29 December 2004.

PubMed

Iversen, Leslie

2006-01-01

Julie Axelrod was a laboratory technician until the age of 42, when he finally achieved his PhD and independence. He worked at the National Institutes of Health for most of his career. Among his early pioneering research achievements in applying chemical and biochemical approaches to neuroscience were the discoveries of the painkiller acetaminophen (Tylenol, Paracetamol) and the liver microsomal drug-metabolizing enzymes, and the establishment of catechol-O-methyltransferase as an important enzyme in catecholamine metabolism. He shared the Nobel Prize in Physiology or Medicine in 1970 for his discovery that the reuptake of noradrenaline (norepinephrine) into the nerve endings from which it was released represented a novel method of neurotransmitter inactivation. An important corollary was the finding that antidepressant drugs acted as inhibitors of this uptake process. Subsequent work in his laboratory on the control of melatonin biosynthesis in the pineal gland provided new insights into the way in which the nervous system controls circadian rhythms, and offered an early model system in which to study the rapid control of mammalian gene expression. Axelrod continued actively in research until shortly before his death, and trained many students who have gone on to become leaders of the new field of biochemical neuropharmacology.

Neurotensin analogs [D-TYR11] and [D-PHE11]neurotensin resist degradation by brain peptidases in vitro and in vivo.

PubMed

Checler, F; Vincent, J P; Kitabgi, P

1983-12-01

The present study was designed to compare the susceptibility of neurotensin (NT), [3H]NT, [D-Tyr11]NT and [D-Phe11]NT to degradation by 1) rat brain synaptic membranes in vitro and 2) after i.c.v. administration in the rat in vivo. Degradation was assessed by purifying the peptides using reverse phase high-performance liquid chromatography and by measuring the amount of radioactive or absorbing (OD 230) material under each peptide peak. In contrast to NT, [D-Tyr11]NT and [D-Phe11]NT were resistant to degradation by brain synaptic peptidases in vitro. Furthermore, NT was rapidly metabolized in brain tissues after i.c.v. administration, whereas [D-Tyr11]NT was metabolically stable. The present data confirm the central role of NT residue Tyr11 in the mechanisms of NT inactivation by brain synaptic peptidases. They account for the higher in vivo potency of [D-Tyr11]NT as compared with its in vitro potency. Finally, they explain, at least in part, the need to administer large doses of NT in the brain in order to observe neurobehavioral and neuropharmacological effects.

ABC transporters and cytochromes P450 in the human central nervous system: influence on brain pharmacokinetics and contribution to neurodegenerative disorders.

PubMed

Dutheil, Fabien; Jacob, Aude; Dauchy, Sandrine; Beaune, Philippe; Scherrmann, Jean-Michel; Declèves, Xavier; Loriot, Marie-Anne

2010-10-01

The identification of xenobiotic metabolizing enzymes (i.e., CYP) and transporters (i.e., ABC transporters) (XMET) in the human brain, including the BBB, raises the question whether these transporters and enzymes have specific functions in brain physiology, neuropharmacology and toxicology. Relevant literature was identified using PubMed search articles published up to March 2010. Search terms included 'ABC transporters and P450 or CYP', 'drug metabolism, effect and toxicity' and 'neurodegenerative disease (Alzheimer and Parkinson diseases)' restricted to the field of 'brain or human brain'. This review aims to provide a better understanding of XMET functions in the human brain and show their pharmacological importance for improving drug delivery and efficacy and also for managing their side effects. Finally, the impact of brain XMET activity during neurodegenerative processes is discussed, giving an opportunity to identify new markers of human brain diseases. During the last 2 decades, much evidence concerning the specific distribution patterns of XMET, their induction by xenobiotics and endobiotics and their genetic variations have made cerebral ABC transporters and CYP enzymes key elements in the way individual patients respond to centrally acting drugs.

Anaesthetic neurotoxicity and neuroplasticity: an expert group report and statement based on the BJA Salzburg Seminar

PubMed Central

Jevtovic-Todorovic, V.; Absalom, A. R.; Blomgren, K.; Brambrink, A.; Crosby, G.; Culley, D. J.; Fiskum, G.; Giffard, R. G.; Herold, K. F.; Loepke, A. W.; Ma, D.; Orser, B. A.; Planel, E.; Slikker, W.; Soriano, S. G.; Stratmann, G.; Vutskits, L.; Xie, Z.; Hemmings, H. C.

2013-01-01

Although previously considered entirely reversible, general anaesthesia is now being viewed as a potentially significant risk to cognitive performance at both extremes of age. A large body of preclinical as well as some retrospective clinical evidence suggest that exposure to general anaesthesia could be detrimental to cognitive development in young subjects, and might also contribute to accelerated cognitive decline in the elderly. A group of experts in anaesthetic neuropharmacology and neurotoxicity convened in Salzburg, Austria for the BJA Salzburg Seminar on Anaesthetic Neurotoxicity and Neuroplasticity. This focused workshop was sponsored by the British Journal of Anaesthesia to review and critically assess currently available evidence from animal and human studies, and to consider the direction of future research. It was concluded that mounting evidence from preclinical studies reveals general anaesthetics to be powerful modulators of neuronal development and function, which could contribute to detrimental behavioural outcomes. However, definitive clinical data remain elusive. Since general anaesthesia often cannot be avoided regardless of patient age, it is important to understand the complex mechanisms and effects involved in anaesthesia-induced neurotoxicity, and to develop strategies for avoiding or limiting potential brain injury through evidence-based approaches. PMID:23722106

The uncertainty processing theory of motivation.

PubMed

Anselme, Patrick

2010-04-02

Most theories describe motivation using basic terminology (drive, 'wanting', goal, pleasure, etc.) that fails to inform well about the psychological mechanisms controlling its expression. This leads to a conception of motivation as a mere psychological state 'emerging' from neurophysiological substrates. However, the involvement of motivation in a large number of behavioural parameters (triggering, intensity, duration, and directedness) and cognitive abilities (learning, memory, decision, etc.) suggest that it should be viewed as an information processing system. The uncertainty processing theory (UPT) presented here suggests that motivation is the set of cognitive processes allowing organisms to extract information from the environment by reducing uncertainty about the occurrence of psychologically significant events. This processing of information is shown to naturally result in the highlighting of specific stimuli. The UPT attempts to solve three major problems: (i) how motivations can affect behaviour and cognition so widely, (ii) how motivational specificity for objects and events can result from nonspecific neuropharmacological causal factors (such as mesolimbic dopamine), and (iii) how motivational interactions can be conceived in psychological terms, irrespective of their biological correlates. The UPT is in keeping with the conceptual tradition of the incentive salience hypothesis while trying to overcome the shortcomings inherent to this view. Copyright 2009 Elsevier B.V. All rights reserved.

The 4-aminopyridine in vitro epilepsy model analyzed with a perforated multi-electrode array.

PubMed

Gonzalez-Sulser, Alfredo; Wang, Jing; Motamedi, Gholam K; Avoli, Massimo; Vicini, Stefano; Dzakpasu, Rhonda

2011-06-01

Epileptiform discharges recorded in the 4-aminopyridine (4-AP) in vitro epilepsy model are mediated by glutamatergic and GABAergic signaling. Using a 60-channel perforated multi-electrode array (pMEA) on corticohippocampal slices from 2 to 3 week old mice we recorded interictal- and ictal-like events. When glutamatergic transmission was blocked, interictal-like events no longer initiated in the hilus or CA3/CA1 pyramidal layers but originated from the dentate gyrus granule and molecular layers. Furthermore, frequencies of interictal-like events were reduced and durations were increased in these regions while cortical discharges were completely blocked. Following GABA(A) receptor blockade interictal-like events no longer propagated to the dentate gyrus while their frequency in CA3 increased; in addition, ictal-like cortical events became shorter while increasing in frequency. Lastly, drugs that affect tonic and synaptic GABAergic conductance modulated the frequency, duration, initiation and propagation of interictal-like events. These findings confirm and expand on previous studies indicating that multiple synaptic mechanisms contribute to synchronize neuronal network activity in forebrain structures. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'. Copyright © 2010 Elsevier Ltd. All rights reserved.

Evaluation of Sedative and Hypnotic Activity of Ethanolic Extract of Scoparia dulcis Linn.

PubMed Central

Moniruzzaman, Md.; Atikur Rahman, Md.; Ferdous, Afia

2015-01-01

Scoparia dulcis Linn. (SD) is a perennial herb that has been well studied for its antioxidant, anti-inflammatory, antidiabetic, and hepatoprotective effects. However, scientific information on SD regarding the neuropharmacological effect is limited. This study evaluated the sedative and hypnotic effect of the ethanolic extract of whole plants of Scoparia dulcis (EESD). For this purpose, the whole plants of S. dulcis were extracted with ethanol following maceration process and tested for the presence of phytochemical constituents. The sedative and hypnotic activity were then investigated using hole cross, open field, hole-board, rota-rod, and thiopental sodium-induced sleeping time determination tests in mice at the doses of 50, 100, and 200 mg/kg of EESD. Diazepam at the dose of 1 mg/kg was used as a reference drug in all the experiments. We found that EESD produced a significant dose-dependent inhibition of locomotor activity of mice both in hole cross and open field tests (P < 0.05). Besides, it also decreased rota-rod performances and the number of head dips in hole-board test. Furthermore, EESD significantly decreased the induction time to sleep and prolonged the duration of sleeping, induced by thiopental sodium. Taken together, our study suggests that EESD may possess sedative principles with potent hypnotic properties. PMID:25861372

Evaluation of Sedative and Hypnotic Activity of Ethanolic Extract of Scoparia dulcis Linn.

PubMed

Moniruzzaman, Md; Atikur Rahman, Md; Ferdous, Afia

2015-01-01

Scoparia dulcis Linn. (SD) is a perennial herb that has been well studied for its antioxidant, anti-inflammatory, antidiabetic, and hepatoprotective effects. However, scientific information on SD regarding the neuropharmacological effect is limited. This study evaluated the sedative and hypnotic effect of the ethanolic extract of whole plants of Scoparia dulcis (EESD). For this purpose, the whole plants of S. dulcis were extracted with ethanol following maceration process and tested for the presence of phytochemical constituents. The sedative and hypnotic activity were then investigated using hole cross, open field, hole-board, rota-rod, and thiopental sodium-induced sleeping time determination tests in mice at the doses of 50, 100, and 200 mg/kg of EESD. Diazepam at the dose of 1 mg/kg was used as a reference drug in all the experiments. We found that EESD produced a significant dose-dependent inhibition of locomotor activity of mice both in hole cross and open field tests (P < 0.05). Besides, it also decreased rota-rod performances and the number of head dips in hole-board test. Furthermore, EESD significantly decreased the induction time to sleep and prolonged the duration of sleeping, induced by thiopental sodium. Taken together, our study suggests that EESD may possess sedative principles with potent hypnotic properties.

Bardoxolone methyl prevents obesity and hypothalamic dysfunction.

PubMed

Camer, Danielle; Yu, Yinghua; Szabo, Alexander; Wang, Hongqin; Dinh, Chi H L; Huang, Xu-Feng

2016-08-25

High-fat (HF) diet-induced obesity is associated with hypothalamic leptin resistance and low grade chronic inflammation, which largely impairs the neuroregulation of negative energy balance. Neuroregulation of negative energy balance is largely controlled by the mediobasal and paraventricular nuclei regions of the hypothalamus via leptin signal transduction. Recently, a derivative of oleanolic acid, bardoxolone methyl (BM), has been shown to have anti-inflammatory effects. We tested the hypothesis that BM would prevent HF diet-induced obesity, hypothalamic leptin resistance, and inflammation in mice fed a HF diet. Oral administration of BM via drinking water (10 mg/kg daily) for 21 weeks significantly prevented an increase in body weight, energy intake, hyperleptinemia, and peripheral fat accumulation in mice fed a HF diet. Furthermore, BM treatment prevented HF diet-induced decreases in the anorexigenic effects of peripheral leptin administration. In the mediobasal and paraventricular nuclei regions of the hypothalamus, BM administration prevented HF diet-induced impairments of the downstream protein kinase b (Akt) pathway of hypothalamic leptin signalling. BM treatment also prevented an increase in inflammatory cytokines, tumour necrosis factor alpha (TNFα) and interleukin 6 (IL-6) in these two hypothalamic regions. These results identify a potential novel neuropharmacological application for BM in preventing HF diet-induced obesity, hypothalamic leptin resistance, and inflammation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Multimodal EEG Recordings, Psychometrics and Behavioural Analysis.

PubMed

Boeijinga, Peter H

2015-01-01

High spatial and temporal resolution measurements of neuronal activity are preferably combined. In an overview on how this approach can take shape, multimodal electroencephalography (EEG) is treated in 2 main parts: by experiments without a task and in the experimentally cued working brain. It concentrates first on the alpha rhythm properties and next on data-driven search for patterns such as the default mode network. The high-resolution volumic distributions of neuronal metabolic indices result in distributed cortical regions and possibly relate to numerous nuclei, observable in a non-invasive manner in the central nervous system of humans. The second part deals with paradigms in which nowadays assessment of target-related networks can align level-dependent blood oxygenation, electrical responses and behaviour, taking the temporal resolution advantages of event-related potentials. Evidence-based electrical propagation in serial tasks during performance is now to a large extent attributed to interconnected pathways, particularly chronometry-dependent ones, throughout a chain including a dorsal stream, next ventral cortical areas taking the flow of information towards inferior temporal domains. The influence of aging is documented, and results of the first multimodal studies in neuropharmacology are consistent. Finally a scope on implementation of advanced clinical applications and personalized marker strategies in neuropsychiatry is indicated. © 2016 S. Karger AG, Basel.

The ICCAM platform study: An experimental medicine platform for evaluating new drugs for relapse prevention in addiction. Part B: fMRI description

PubMed Central

McGonigle, John; Murphy, Anna; Paterson, Louise M; Reed, Laurence J; Nestor, Liam; Nash, Jonathan; Elliott, Rebecca; Ersche, Karen D; Flechais, Remy SA; Newbould, Rexford; Orban, Csaba; Smith, Dana G; Taylor, Eleanor M; Waldman, Adam D; Robbins, Trevor W; Deakin, JF William; Nutt, David J; Lingford-Hughes, Anne R; Suckling, John

2016-01-01

Objectives: We aimed to set up a robust multi-centre clinical fMRI and neuropsychological platform to investigate the neuropharmacology of brain processes relevant to addiction – reward, impulsivity and emotional reactivity. Here we provide an overview of the fMRI battery, carried out across three centres, characterizing neuronal response to the tasks, along with exploring inter-centre differences in healthy participants. Experimental design: Three fMRI tasks were used: monetary incentive delay to probe reward sensitivity, go/no-go to probe impulsivity and an evocative images task to probe emotional reactivity. A coordinate-based activation likelihood estimation (ALE) meta-analysis was carried out for the reward and impulsivity tasks to help establish region of interest (ROI) placement. A group of healthy participants was recruited from across three centres (total n=43) to investigate inter-centre differences. Principle observations: The pattern of response observed for each of the three tasks was consistent with previous studies using similar paradigms. At the whole brain level, significant differences were not observed between centres for any task. Conclusions: In developing this platform we successfully integrated neuroimaging data from three centres, adapted validated tasks and applied whole brain and ROI approaches to explore and demonstrate their consistency across centres. PMID:27703042

Attenuation of smoke induced neuronal and physiological changes by bacoside rich extract in Wistar rats via down regulation of HO-1 and iNOS.

PubMed

Pandareesh, M D; Anand, T

2014-01-01

Bacopa monniera is well known herbal medicine for its neuropharmacological effects. It alleviates variety of disorders including neuronal and physiological changes. Crackers smoke is a potent risk factor that leads to free radical mediated oxidative stress in vivo. The aim of the current study is to evaluate the protective efficacy of B. monniera extract (BME) against crackers smoke induced neuronal and physiological changes via modulating inducible nitric oxide synthase (iNOS) and hemeoxygenase-1 (HO-1) expression in rats. Rats were exposed to smoke for 1h for a period of 3 weeks and consecutively treated with BME at three different dosages (i.e., 10, 20 and 40 mg/kg b.wt.). Our results elucidate that BME treatment ameliorates histopathalogical changes, reactive oxygen species levels, lipid peroxidation, acetylcholine esterase activity and brain neurotransmitter levels to normal. BME supplementation efficiently inhibited HO-1 expression and nitric oxide generation by down-regulating iNOS expression. Smoke induced depletion of antioxidant enzyme status, monoamine oxidase activity was also replenished by BME supplementation. Thus the present study indicates that BME ameliorates various impairments associated with neuronal and physiological changes in rats exposed to crackers smoke by its potent neuromodulatory, antioxidant and adaptogenic propensity. Copyright © 2013 Elsevier Inc. All rights reserved.

Increased serotonin axons (immunoreactive to 5-HT transporter) in postmortem brains from young autism donors.

PubMed

Azmitia, Efrain C; Singh, Jorawer S; Whitaker-Azmitia, Patricia M

2011-06-01

Imaging studies of serotonin transporter binding or tryptophan retention in autistic patients suggest that the brain serotonin system is decreased. However, treatment with drugs which increase serotonin (5-HT) levels, specific serotonin reuptake inhibitors (SSRIs), commonly produce a worsening of the symptoms. In this study we examined 5-HT axons that were immunoreactive to a serotonin transporter (5-HTT) antibody in a number of postmortem brains from autistic patients and controls with no known diagnosis who ranged in age from 2 to 29 years. Fine, highly branched, and thick straight fibers were found in forebrain pathways (e.g. medial forebrain bundle, stria terminalis and ansa lenticularis). Many immunoreactive varicose fine fibers were seen in target areas (e.g. globus pallidus, amygdala and temporal cortex). Morphometric analysis of the stained axons at all ages studied indicated that the number of serotonin axons was increased in both pathways and terminal regions in cortex from autism donors. Our findings provide morphological evidence to warrant caution when using serotonin enhancing drugs (e.g. SSRIs and receptor agonist) to treat autistic children. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'. Copyright © 2011 Elsevier Ltd. All rights reserved.

Neurocognitive rehabilitation for addiction medicine: From neurophysiological markers to cognitive rehabilitation and relapse prevention.

PubMed

Campanella, Salvatore

2016-01-01

Currently, relapse prevention remains the main challenge in addiction medicine, indicating that the established treatment methods combining psychotherapy with neuropharmacological interventions are not entirely effective. Therefore, there is a push to develop alternatives to psychotherapy- and medication-based approaches to addiction treatment. Two major cognitive factors have been identified that trigger relapse in addicted patients: attentional biases directed toward drug-related cues, which increase the urge to consume, and impaired response inhibition toward these cues, which makes it more difficult for addicted people to resist temptation. Recent studies on newly detoxified alcoholic patients have shown that by using the appropriate tasks to index these cognitive functions with event-related potentials (ERPs), it is possible to discriminate between future relapsers and nonrelapsers. These preliminary data suggest that the ERP technique has great clinical potential for preventing relapse in alcohol-dependent patients, as well as for addictive states in general. Indeed, ERPs may help to identify patients highly vulnerable to relapse and allow the development of individually adapted cognitive rehabilitation programs. The implementation of this combined approach requires an intense collaboration between psychiatry departments, clinical neurophysiology laboratories, and neuropsychological rehabilitation centers. The potential pitfalls and limitations of this approach are also discussed. © 2016 Elsevier B.V. All rights reserved.

Curcumin and its Derivatives: Their Application in Neuropharmacology and Neuroscience in the 21st Century

PubMed Central

Lee, Wing-Hin; Loo, Ching-Yee; Bebawy, Mary; Luk, Frederick; Mason, Rebecca S; Rohanizadeh, Ramin

2013-01-01

Curcumin (diferuloylmethane), a polyphenol extracted from the plant Curcuma longa, is widely used in Southeast Asia, China and India in food preparation and for medicinal purposes. Since the second half of the last century, this traditional medicine has attracted the attention of scientists from multiple disciplines to elucidate its pharmacological properties. Of significant interest is curcumin’s role to treat neurodegenerative diseases including Alzheimer’s disease (AD), and Parkinson’s disease (PD) and malignancy. These diseases all share an inflammatory basis, involving increased cellular reactive oxygen species (ROS) accumulation and oxidative damage to lipids, nucleic acids and proteins. The therapeutic benefits of curcumin for these neurodegenerative diseases appear multifactorial via regulation of transcription factors, cytokines and enzymes associated with (Nuclear factor kappa beta) NFκB activity. This review describes the historical use of curcumin in medicine, its chemistry, stability and biological activities, including curcumin's anti-cancer, anti-microbial, anti-oxidant, and anti-inflammatory properties. The review further discusses the pharmacology of curcumin and provides new perspectives on its therapeutic potential and limitations. Especially, the review focuses in detail on the effectiveness of curcumin and its mechanism of actions in treating neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases and brain malignancies. PMID:24381528

Brain-inspired cheminformatics of drug-target brain interactome, synthesis, and assay of TVP1022 derivatives.

PubMed

Romero-Durán, Francisco J; Alonso, Nerea; Yañez, Matilde; Caamaño, Olga; García-Mera, Xerardo; González-Díaz, Humberto

2016-04-01

The use of Cheminformatics tools is gaining importance in the field of translational research from Medicinal Chemistry to Neuropharmacology. In particular, we need it for the analysis of chemical information on large datasets of bioactive compounds. These compounds form large multi-target complex networks (drug-target interactome network) resulting in a very challenging data analysis problem. Artificial Neural Network (ANN) algorithms may help us predict the interactions of drugs and targets in CNS interactome. In this work, we trained different ANN models able to predict a large number of drug-target interactions. These models predict a dataset of thousands of interactions of central nervous system (CNS) drugs characterized by > 30 different experimental measures in >400 different experimental protocols for >150 molecular and cellular targets present in 11 different organisms (including human). The model was able to classify cases of non-interacting vs. interacting drug-target pairs with satisfactory performance. A second aim focus on two main directions: the synthesis and assay of new derivatives of TVP1022 (S-analogues of rasagiline) and the comparison with other rasagiline derivatives recently reported. Finally, we used the best of our models to predict drug-target interactions for the best new synthesized compound against a large number of CNS protein targets. Copyright © 2015 Elsevier Ltd. All rights reserved.

Allosteric regulation in NMDA receptors revealed by the genetically encoded photo-cross-linkers

PubMed Central

Tian, Meilin; Ye, Shixin

2016-01-01

Allostery is essential to neuronal receptor function, but its transient nature poses a challenge for characterization. The N-terminal domains (NTDs) distinct from ligand binding domains are a major locus for allosteric regulation of NMDA receptors (NMDARs), where different modulatory binding sites have been observed. The inhibitor ifenprodil, and related phenylethanoamine compounds specifically targeting GluN1/GluN2B NMDARs have neuroprotective activity. However, whether they use differential structural pathways than the endogenous inhibitor Zn2+ for regulation is unknown. We applied genetically encoded unnatural amino acids (Uaas) and monitored the functional changes in living cells with photo-cross-linkers specifically incorporated at the ifenprodil binding interface between GluN1 and GluN2B subunits. We report constraining the NTD domain movement, by a light induced crosslinking bond that introduces minimal perturbation to the ligand binding, specifically impedes the transduction of ifenprodil but not Zn2+ inhibition. Subtle distance changes reveal interfacial flexibility and NTD rearrangements in the presence of modulators. Our results present a much richer dynamic picture of allostery than conventional approaches targeting the same interface, and highlight key residues that determine functional and subtype specificity of NMDARs. The light-sensitive mutant neuronal receptors provide complementary tools to the photo-switchable ligands for opto-neuropharmacology. PMID:27713495

Stress, chemical defense agents, and cholinergic receptors. Midterm report, 1 November 1987-31 July 1989

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lane, J.D.

1989-11-30

This project is assessing the affects of exposure to a chemical defense agent on anxiety and stress, by using rat models of anxiety (conditioned emotional response (CER); conditioned suppression) and unconditioned non-specific stres (exposure to footshock). The specific experiments determined the plasticity of muscarinic cholinergic binding sites in the central nervous system. The neuroanatomical locus and neuropharmacological profile of changes in binding sites were assessed in brain areas enriched in cholinergic markers. Acetylcholine turnover was measured to determine if the receptor response is compensatory or independent. The effects of acute exposure to doses of a chemical defense agent (soman--XGD) onmore » lethality and behaviors were examined. The experiments involved training and conditioning adult rats to CER using standard operant/respondent techniques. The binding of radiolabelled ligand was studied in vitro using brain membranes and tissue sections (autoradiography). The major findings are that CER produces increases in acetylcholine turnover in brain areas involved in anxiety, and that primarily post-synaptic M1 receptors compensatorly decrease in response. These neurochemical phenomena are directly correlated with several behaviors, including onset and extinction of CER and non-specific stress. Followup experiments have been designed to test the interaction of CER, XGD and neurochemistry.« less

Facilitation of extinction and re-extinction of operant behavior in mice by chlordiazepoxide and D-cycloserine.

PubMed

Leslie, Julian C; Norwood, Kelly

2013-05-01

The aim was to compare operant extinction with re-extinction following re-acquisition and to investigate neuropharmacological mechanisms through administration of drugs potentiating GABAergic or glutamatergic systems. Groups of C57Bl/6 mice were trained to lever press for food on a fixed ratio schedule, then extinguished with or without pre-session chlordiazepoxide or post-session d-cycloserine administration (15mg/kg in each case), then retrained to lever press for food, then re-extinguished with or without pre-session chlordiazepoxide or post-session d-cycloserine. Under vehicle injections, extinction and re-extinction curves were indistinguishable, but drug treatments showed that there was less resistance to extinction in the re-extinction phase. Chlordiazepoxide facilitated extinction and re-extinction, with an earlier effect during re-extinction. d-Cycloserine also facilitated extinction and re-extinction, with some evidence of an earlier effect during re-extinction. These results replicate and extend earlier findings with operant extinction, but differ from some previous reports of d-cycloserine on re-extinction of Pavlovian conditioned fear. Implications for accounts of the similarities and differences between neural mechanisms of extinction following either Pavlovian or operant conditioning, and applications of these findings, are discussed. Copyright © 2013 Elsevier Inc. All rights reserved.

Neuropharmacology of performance monitoring.

PubMed

Jocham, Gerhard; Ullsperger, Markus

2009-01-01

Adaptive, goal-directed behavior requires that organisms evaluate their actions in terms of their outcomes. Neuroimaging studies show that unfavorable outcomes or situations with high level of conflict engage the posterior medial frontal cortex (pMFC). Recording of event-related potentials revealed that these situations are accompanied by a negative deflection, the so-called error-related negativity (ERN), which appears after an erroneous response or after negative feedback. Both activation of the pMFC and the ERN are thought to represent a signal that indicates the need for behavioral adjustment, and to recruit other brain regions that implement these adjustments. While many fMRI and EEG studies have shed light on the anatomical structures and the cognitive processes involved in performance monitoring, only very recently have researchers begun to investigate the underlying neurochemical mechanisms. Drawing on the putative involvement of dopamine (DA) neurons in coding a reward prediction error, an influential theory has ascribed a pivotal role to DA in performance monitoring. However, although important, DA is certainly not the only neuromodulator involved. Recent studies point to a role for serotonin, norepinephrine and GABA, but also for adenosine in performance monitoring. Here, we review the evidence for neurotransmitter effects on this function in humans. In this light, we critically discuss currently debated models of performance monitoring and potential alternatives.

Further analysis of the neuropharmacological profile of 9-amino-1,2,3,4-tetrahydroacridine (THA), and alleged drug for the treatment of Alzheimer's disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Drukarch, B.; Leysen, J.E.; Stoof, J.C.

1988-01-01

In a recent study the authors have documented the acetylcholinesterase and outward K+-current inhibiting activity of 9-amino-1,2,3,4-tetrahydroacridine (THA), a drug reportedly active in the treatment of Alzheimer patients. In the present study they have investigated the effects of THA on the uptake and release of radiolabeled NA, DA and 5-HT. THA concentration-dependently inhibited the uptake of these monoamines with IC-50 values of approximately 1, 7 and 2 ..mu..M respectively. Release studies of these radiolabeled monoamines from control and reserpine pretreated tissue revealed that the THA-induced uptake inhibition does not occur at the level of the axonal membrane but at themore » level of the monoaminergic storage granules. In addition the affinity of THA for alpha-1, alpha-2 and beta-adrenoceptors, for D-2 dopamine, S-la and S-2 serotonin and for muscarinic receptors was investigated. It appeared that in concentrations up to 1 ..mu..M THA did not display any affinity towards these receptors. It is concluded from these experiments that the effects of THA on monoaminergic neurotransmission might contribute to the alleged therapeutic action of THA in Alzheimer's disease. 17 references, 3 figures, 1 table.« less

Individual Differences and Social Influences on the Neurobehavioral Pharmacology of Abused Drugs

PubMed Central

Neisewander, J. L.; Kelly, T. H.

2013-01-01

The interaction of drugs with biologic targets is a critical area of research, particularly for the development of medications to treat substance use disorders. In addition to understanding these drug-target interactions, however, there is a need to understand more fully the psychosocial influences that moderate these interactions. The first section of this review introduces some examples from human behavioral pharmacology that illustrate the clinical importance of this research. The second section covers preclinical evidence to characterize some of the key individual differences that alter drug sensitivity and abuse vulnerability, related primarily to differences in response to novelty and impulsivity. Evidence is presented to indicate that critical neuropharmacological mechanisms associated with these individual differences involve integrated neurocircuits underlying stress, reward, and behavioral inhibitory processes. The third section covers social influences on drug abuse vulnerability, including effects experienced during infancy, adolescence, and young adulthood, such as maternal separation, housing conditions, and social interactions (defeat, play, and social rank). Some of the same neurocircuits involved in individual differences also are altered by social influences, although the precise neurochemical and cellular mechanisms involved remain to be elucidated fully. Finally, some speculation is offered about the implications of this research for the prevention and treatment of substance abuse. PMID:23343975

Sigma1 Pharmacology in the Context of Cancer.

PubMed

Kim, Felix J; Maher, Christina M

2017-01-01

Sigma1 (also known as sigma-1 receptor, Sig1R, σ1 receptor) is a unique pharmacologically regulated integral membrane chaperone or scaffolding protein. The majority of publications on the subject have focused on the neuropharmacology of Sigma1. However, a number of publications have also suggested a role for Sigma1 in cancer. Although there is currently no clinically used anti-cancer drug that targets Sigma1, a growing body of evidence supports the potential of Sigma1 ligands as therapeutic agents to treat cancer. In preclinical models, compounds with affinity for Sigma1 have been reported to inhibit cancer cell proliferation and survival, cell adhesion and migration, tumor growth, to alleviate cancer-associated pain, and to have immunomodulatory properties. This review will highlight that although the literature supports a role for Sigma1 in cancer, several fundamental questions regarding drug mechanism of action and the physiological relevance of aberrant SIGMAR1 transcript and Sigma1 protein expression in certain cancers remain unanswered or only partially answered. However, emerging lines of evidence suggest that Sigma1 is a component of the cancer cell support machinery, that it facilitates protein interaction networks, that it allosterically modulates the activity of its associated proteins, and that Sigma1 is a selectively multifunctional drug target.

Pharmacological enhancement of fear reduction: preclinical models

PubMed Central

Graham, Bronwyn M; Langton, Julia M; Richardson, Rick

2011-01-01

Anxiety disorders have a high prevalence, and despite the substantial advances in the psychological treatment of anxiety, relapse is still a common problem. One approach to improving existing psychological treatments for anxiety has been to develop pharmacological agents that can be used to enhance the processes underlying exposure therapy, which is the most commonly used and empirically validated psychological treatment for anxiety during which individuals are taught to appropriately inhibit fear. Animal models of exposure therapy, particularly fear extinction, have proved to be a very useful way of examining the neural and molecular correlates of fear inhibition, which has in turn led to the identification of numerous drugs that enhance these processes in rats. Several of these drugs have subsequently been tested as novel pharmacological adjuncts to exposure therapy in humans with a range of anxiety disorders. The purpose of this review is to outline the key animal models of exposure therapy and to describe how these have been used to develop potential pharmacological adjuncts for anxiety disorders. Drugs that are currently in clinical use, as well as those currently in the preclinical stages of investigation, are described. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21175588

Placebo Response is Driven by UCS Revaluation: Evidence, Neurophysiological Consequences and a Quantitative Model

PubMed Central

Puviani, Luca; Rama, Sidita

2016-01-01

Despite growing scientific interest in the placebo effect and increasing understanding of neurobiological mechanisms, theoretical modeling of the placebo response remains poorly developed. The most extensively accepted theories are expectation and conditioning, involving both conscious and unconscious information processing. However, it is not completely understood how these mechanisms can shape the placebo response. We focus here on neural processes which can account for key properties of the response to substance intake. It is shown that placebo response can be conceptualized as a reaction of a distributed neural system within the central nervous system. Such a reaction represents an integrated component of the response to open substance administration (or to substance intake) and is updated through “unconditioned stimulus (UCS) revaluation learning”. The analysis leads to a theorem, which proves the existence of two distinct quantities coded within the brain, these are the expected or prediction outcome and the reactive response. We show that the reactive response is updated automatically by implicit revaluation learning, while the expected outcome can also be modulated through conscious information processing. Conceptualizing the response to substance intake in terms of UCS revaluation learning leads to the theoretical formulation of a potential neuropharmacological treatment for increasing unlimitedly the effectiveness of a given drug. PMID:27436417

Placebo Response is Driven by UCS Revaluation: Evidence, Neurophysiological Consequences and a Quantitative Model.

PubMed

Puviani, Luca; Rama, Sidita

2016-07-20

Despite growing scientific interest in the placebo effect and increasing understanding of neurobiological mechanisms, theoretical modeling of the placebo response remains poorly developed. The most extensively accepted theories are expectation and conditioning, involving both conscious and unconscious information processing. However, it is not completely understood how these mechanisms can shape the placebo response. We focus here on neural processes which can account for key properties of the response to substance intake. It is shown that placebo response can be conceptualized as a reaction of a distributed neural system within the central nervous system. Such a reaction represents an integrated component of the response to open substance administration (or to substance intake) and is updated through "unconditioned stimulus (UCS) revaluation learning". The analysis leads to a theorem, which proves the existence of two distinct quantities coded within the brain, these are the expected or prediction outcome and the reactive response. We show that the reactive response is updated automatically by implicit revaluation learning, while the expected outcome can also be modulated through conscious information processing. Conceptualizing the response to substance intake in terms of UCS revaluation learning leads to the theoretical formulation of a potential neuropharmacological treatment for increasing unlimitedly the effectiveness of a given drug.

Depressive effects on the central nervous system and underlying mechanism of the enzymatic extract and its phlorotannin-rich fraction from Ecklonia cava edible brown seaweed.

PubMed

Cho, Suengmok; Han, Daeseok; Kim, Seon-Bong; Yoon, Minseok; Yang, Hyejin; Jin, Young-Ho; Jo, Jinho; Yong, Hyeim; Lee, Sang-Hoon; Jeon, You-Jin; Shimizu, Makoto

2012-01-01

Marine plants have been reported to possess various pharmacological properties; however, there have been few reports on their neuropharmacological effects. Terrestrial plants have depressive effects on the central nervous system (CNS) because of their polyphenols which make them effective as anticonvulsants and sleep inducers. We investigated in this study the depressive effects of the polyphenol-rich brown seaweed, Ecklonia cava (EC), on CNS. An EC enzymatic extract (ECEE) showed significant anticonvulsive (>500 mg/kg) and sleep-inducing (>500 mg/kg) effects on the respective mice seizure induced by picrotoxin and on the mice sleep induced by pentobarbital. The phlorotannin-rich fraction (PTRF) from ECEE significantly potentiated the pentobarbital-induced sleep at >50 mg/kg. PTRF had binding activity to the gamma aminobutyric acid type A (GABA(A))-benzodiazepine (BZD) receptors. The sleep-inducing effects of diazepam (DZP, a well-known GABA(A)-BZD agonist), ECEE, and PTRF were completely blocked by flumazenil, a well-known antagonist of GABA(A)-BZD receptors. These results imply that ECEE produced depressive effects on CNS by positive allosteric modulation of its phlorotannins on GABA(A)-BZD receptors like DZP. Our study proposes EC as a candidate for the effective treatment of neuropsychiatric disorders such as anxiety and insomnia.

Mu Opioid Mediated Discriminative-Stimulus Effects of Tramadol: An Individual Subjects Analysis

PubMed Central

Strickland, Justin C.; Rush, Craig R.; Stoops, William W.

2015-01-01

Drug discrimination procedures use dose-dependent generalization, substitution, and pretreatment with selective agonists and antagonists to evaluate receptor systems mediating interoceptive effects of drugs. Despite the extensive use of these techniques in the nonhuman animal literature, few studies have used human subjects. Specifically, human studies have not routinely used antagonist administration as a pharmacological tool to elucidate the mechanisms mediating the discriminative stimulus effects of drugs. This study evaluated the discriminative-stimulus effects of tramadol, an atypical analgesic with monoamine and mu opioid activity. Three human subjects first learned to discriminate 100 mg tramadol from placebo. A range of tramadol doses (25 to 150 mg) and hydromorphone (4 mg) with and without naltrexone pretreatment (50 mg) were then administered to subjects after acquiring the discrimination. Tramadol produced dose-dependent increases in drug-appropriate responding and hydromorphone partially or fully substituted for tramadol in all subjects. These effects were attenuated by naltrexone. Individual subject records indicated a relationship between mu opioid activity (i.e., miosis) and drug discrimination performance. Our findings indicate that mu opioid activity may mediate the discriminative-stimulus effects of tramadol in humans. The correspondence of generalization, substitution, and pretreatment findings with the animal literature supports the neuropharmacological specificity of the drug discrimination procedure. PMID:25664525

Studies with pyrethroids (kadethrin and deltamethrin) and lindane in ethanol sensitive (LS) and insensitive (SS) mouse strains

DOE Office of Scientific and Technical Information (OSTI.GOV)

Doherty, J.; Baker, R.C.; Deitrich, R.

1990-02-26

Ethanol (E) sensitive (LS) and insensitive (SS) mouse strains are distinguished by their sleeping time to a given dose of E and the locus for this difference is at the level of the neuron. In attempts to understand the neuropharmacological basis of insecticide action and to further define the differences in these mouse lines, LS and SS mice were dosed with type I (kadethrine, K) and II (deltamethrin, D) pyrethroids and lindane (L). These compounds were selected because their proposed modes of action are on the Na+ channel (K and D) and/or the GABA receptor ionophore (D and L). Nomore » consistent differences in the effects of K, D or L in the SS and LS mouse lines were evident. In preliminary studies both SS and LS mice dosed with 50 or 100 {mu}g/brain of L (intracerebroventricularly) but not D slept much longer (2-3X) than when dosed with E alone, an effect opposite of that predicted from L's known excitatory action. These data indicate that as far as can be distinguished by pyrethroids and L, the Na+ channel and GABA receptor/ionophore complex are similar in both the LS and SS mouse lines.« less

The ICCAM platform study: An experimental medicine platform for evaluating new drugs for relapse prevention in addiction. Part B: fMRI description.

PubMed

McGonigle, John; Murphy, Anna; Paterson, Louise M; Reed, Laurence J; Nestor, Liam; Nash, Jonathan; Elliott, Rebecca; Ersche, Karen D; Flechais, Remy Sa; Newbould, Rexford; Orban, Csaba; Smith, Dana G; Taylor, Eleanor M; Waldman, Adam D; Robbins, Trevor W; Deakin, Jf William; Nutt, David J; Lingford-Hughes, Anne R; Suckling, John

2017-01-01

We aimed to set up a robust multi-centre clinical fMRI and neuropsychological platform to investigate the neuropharmacology of brain processes relevant to addiction - reward, impulsivity and emotional reactivity. Here we provide an overview of the fMRI battery, carried out across three centres, characterizing neuronal response to the tasks, along with exploring inter-centre differences in healthy participants. Three fMRI tasks were used: monetary incentive delay to probe reward sensitivity, go/no-go to probe impulsivity and an evocative images task to probe emotional reactivity. A coordinate-based activation likelihood estimation (ALE) meta-analysis was carried out for the reward and impulsivity tasks to help establish region of interest (ROI) placement. A group of healthy participants was recruited from across three centres (total n=43) to investigate inter-centre differences. Principle observations: The pattern of response observed for each of the three tasks was consistent with previous studies using similar paradigms. At the whole brain level, significant differences were not observed between centres for any task. In developing this platform we successfully integrated neuroimaging data from three centres, adapted validated tasks and applied whole brain and ROI approaches to explore and demonstrate their consistency across centres.

The effects of chlorpromazine and lorazepam on abnormal antisaccade and no-saccade distractibility.

PubMed

Green, J F; King, D J

1998-10-15

Abnormally high levels of saccadic distractibility have been demonstrated to occur in patients with schizophrenia. Converging evidence implicates frontal cortical dysfunction as a mechanism; however, much of the neuropharmacology of saccadic distractibility has not yet been established. We measured antisaccade, no-saccade, and visually guided saccade components in healthy subjects following single doses of lorazepam 2 mg, chlorpromazine 50-100 mg, and placebo. Visual analogue rating scales (VARS) provided a subjective measure of sedation. Lorazepam, but not chlorpromazine, was shown to cause an increase in saccadic distractibility in both the antisaccade and no-saccade tasks. Peak visually guided saccade velocity was decreased by lorazepam and chlorpromazine in a dose-dependent manner, with corresponding changes seen in VARS. Lorazepam, unexpectedly, did not affect peak antisaccade velocity. The background level of antisaccade directional errors was 6.43%, which is relatively low compared to control groups in patient studies. These results support the view that abnormal saccadic distractibility in patients with schizophrenia is not due to an acute effect of antipsychotic medication. The use of benzodiazepines and the level of task practice are highlighted as possible confounding variables in patient studies. The implications of these results for the current neuropathological theories of abnormal saccadic distractibility are discussed.

Volatile substance misuse : clinical considerations, neuropsychopharmacology and potential role of pharmacotherapy in management.

PubMed

Garland, Eric L; Howard, Matthew O

2012-11-01

Volatile substance misuse is among the most prevalent and toxic forms of psychoactive drug use, and often results in highly deleterious social, psychological and medical consequences. The prevalence of this pernicious form of substance misuse owes in part to the fact that volatile substances of misuse are ubiquitous in the natural environment. Commonly misused commercial products include glue, shoe polish, nail polish remover, butane lighter fluid, gasoline and computer duster spray. National samples of volatile substance misusers tend to exhibit high rates of psychiatric problems and antisocial behaviour. In addition, cognitive impairments and affective dysregulation are often observed among these individuals. Volatile substances exert their complex neuropharmacological effects on dopaminergic, glutamatergic, GABAergic and serotoninergic receptor systems, as well as on cell membranes and ion channels. Concomitantly, pharmacotherapies for volatile substance abuse might profitably target a number of mechanisms, including reward circuitry in the brain, symptoms of craving and withdrawal, neuropsychiatric and emotional impairments that promote volatile substance abuse, and cognitive enhancement to rectify deficits in executive function. This review details the modes of use, subjective effects, epidemiology, adverse consequences, neuropsychopharmacology and drug treatment of volatile substance misuse, and discusses the potential role of novel forms of pharmacological intervention for this oft-overlooked public health threat of epidemic proportions.

Chlorogenic Acid and Mental Diseases: From Chemistry to Medicine

PubMed Central

Nabavi, Seyed Fazel; Tejada, Silvia; Setzer, William N.; Gortzi, Olga; Sureda, Antoni; Braidy, Nady; Daglia, Maria; Manayi, Azadeh; Nabavi, Seyed Mohammad

2017-01-01

Background At present, much attention has been focused on the beneficial effects of natural products on the human health due to their high efficacy and low adverse effects. Among them, polyphenolic compounds are known as one of the most important and common classes of natural products, which possess multiple range of health-promotion effects including anti-inflammatory and antioxidant activities. A plethora of scientific evidence has shown that polyphenolic compounds possess beneficial effects on the central nervous system. Methods Data were collected from Web of Science (ISI Web of Knowledge), Medline, Pubmed, Scopus, Embase, and BIOSIS Previews (from 1950 to 2015), through searching of these keywords: “chlorogenic acid and mental diseases” and “chlorogenic acid and neuroprotection”. Results Chlorogenic acid is known as one of the most common polyphenolic compounds, and is found in different types of fruits and vegetables, spices, wine, olive oil, as well as coffee. The potential neuroprotective effects of chlorogenic acid have been highlighted in several in vitro and in vivo studies. This review critically analyses the available scientific evidence regarding the neuroprotective effects of chlorogenic acid, and its neuropharmacological mechanisms of action. In addition, we also discuss its biosynthesis, sources, bioavailability and metabolism, to provide a broad perspective of the therapeutic implications of this compound in brain health and disease. Conclusion The present review showed that chlorogenic acid possesses neuroprotective effects under the both in vitro and in vivo models. PMID:27012954

Effect of Mimosa pudica (Linn.) extract on anxiety behaviour and GABAergic regulation of 5-HT neuronal activity in the mouse.

PubMed

Ayissi Mbomo, Rigobert; Gartside, Sasha; Ngo Bum, Elizabeth; Njikam, Njifutie; Okello, Ed; McQuade, Richard

2012-04-01

Mimosa pudica (Linn.) (M. pudica L.) is a plant used in some countries to treat anxiety and depression. In the present study we investigated the effects of an aqueous extract of M. pudica L. on mouse anxiety-like behaviour using the elevated T maze, and on regulation of dorsal raphe nucleus (DRN) 5-hydroxytryptamine (5-HT) neuronal activity using an in-vitro mouse brain slice preparation. Acute treatment with M. pudica L. extract had an anxiolytic effect on behaviour in the elevated T maze, specifically on inhibitory avoidance behaviour. Acute application of the extract alone had no effect on the activity of DRN 5-HT neurones. However, when co-applied with the GABA(A) receptor agonist THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), the extract enhanced the inhibitory effect of the THIP on DRN 5-HT neurones. These observed effects of M. pudica L. on both behaviour and GABA modulation of 5-HT neuronal activity are similar to the effects of diazepam, the established anxiolytic and positive modulator of the GABA(A) receptor. This study suggests that the aqueous extract of M. pudica L. contains a positive modulator of GABA(A) receptor function and provides impetus for further investigation of the neuropharmacologically active constituents of the extract.

The new chemistry of mind: a hypothesis.

PubMed

Szára, Stephen

2008-06-01

Psychopharmacology was born some 50 years ago as a relatively narrow clinical discipline with LSD-25 and chlorpromazine, among a few others, being the early prototypes. In the course of its development, psychopharmacology grew into a wider scientific discipline as psychoactive drugs were assumed to interact with biochemical processes at the synapses to influence transmission of activities among neurons in producing their effects. Thus biochemistry and neuropharmacology have been adopted as collaborative disciplines and this larger field was named neuropsychopharmacology. More recently it has been recognized that, at the clinical level, neuropsychopharmacology has also extensive contact with social issues so that there is an increasing emphasis on translational research in recent announcements from the National Institute of Mental Health in the USA to facilitate and encourage collaboration among clinicians, basic science and social science researchers. To help the process of translational research in mental health, a new organizing principle is proposed based on a novel concept of Psychonucleotides (PNs). There are two types of PNs: Simple PNs (SPN) and Complex ones (CPN) and they are seen as temporary modules mediating meaning between the linguistic and neuronal levels in the brain. As the proposed mediating takes the integrative processes of the whole brain into consideration the development of large scale neuronal theories for translational research should became easier and more comprehensive by going beyond the focus on the cognitive cortex and taking also emotional and social processes into consideration.

Recreational 3,4-methylenedioxy-N-methylamphetamine (MDMA) or 'ecstasy' and self-focused compassion: Preliminary steps in the development of a therapeutic psychopharmacology of contemplative practices.

PubMed

Kamboj, Sunjeev K; Kilford, Emma J; Minchin, Stephanie; Moss, Abigail; Lawn, Will; Das, Ravi K; Falconer, Caroline J; Gilbert, Paul; Curran, H Valerie; Freeman, Tom P

2015-09-01

3,4-methylenedioxy-N-methylamphetamine (MDMA) produces diverse pro-social effects. Cognitive training methods rooted in Eastern contemplative practices also produce these effects through the development of a compassionate mindset. Given this similarity, we propose that one potential mechanism of action of MDMA in psychotherapy is through enhancing effects on intrapersonal attitudes (i.e. pro-social attitudes towards the self). We provide a preliminary test of this idea. Recreational MDMA (ecstasy) users were tested on two occasions, having consumed or not consumed ecstasy. Self-critical and self-compassionate responses to self-threatening scenarios were assessed before (T1) and after (T2) ecstasy use (or non-use), and then after compassionate imagery (T3). Moderating roles of dispositional self-criticism and avoidant attachment were examined. Separately, compassionate imagery and ecstasy produced similar sociotropic effects, as well as increases in self-compassion and reductions in self-criticism. Higher attachment-related avoidance was associated with additive effects of compassionate imagery and ecstasy on self-compassion. Findings were in line with MDMA's neuropharmacological profile, its phenomenological effects and its proposed adjunctive use in psychotherapy. However, although conditions were balanced, the experiment was non-blind and MDMA dose/purity was not determined. Controlled studies with pharmaceutically pure MDMA are still needed to test these effects rigorously. © The Author(s) 2015.

Longitudinal muscle of the esophagus: its role in esophageal health and disease.

PubMed

Mittal, Ravinder K

2013-07-01

The muscularis propria of the esophagus is organized into circular and longitudinal muscle layers. The function of the longitudinal muscle and its role in bolus propulsion are not clear. The goal of this review is to summarize what is known of the role of the longitudinal muscle in health, as well as in sensory and motor disorders of the esophagus. Simultaneous manometry and ultrasound imaging reveal that, during peristalsis, the two muscle layers of the esophagus contract in perfect synchrony. On the contrary, during transient lower esophageal sphincter (LES) relaxation, longitudinal muscle contracts independent of the circular muscle. Recent studies have provided novel insights into the role of the longitudinal muscle in LES relaxation and descending relaxation of the esophagus. In certain diseases (e.g. some motility disorders of the esophagus), there is discoordination between the two muscle layers, which likely plays an important role in the genesis of dysphagia and delayed esophageal emptying. There is close temporal correlation between prolonged contractions of the longitudinal muscles of the esophagus and esophageal 'angina-like' pain. Novel techniques to record longitudinal muscle contraction are reviewed. Longitudinal muscles of the esophagus play a key role in the physiology and pathophysiology of esophageal sensory and motor function. Neuro-pharmacologic controls of circular and longitudinal muscle are different, which provides an opportunity for the development of novel pharmacological therapies in the treatment of esophageal sensory and motor disorders.

Evaluation of Anticonvulsant, Antidepressant-, and Anxiolytic-like Effects of an Aqueous Extract from Cultured Mycelia of the Lingzhi or Reishi Medicinal Mushroom Ganoderma lucidum (Higher Basidiomycetes) in Mice.

PubMed

Socala, Katarzyna; Nieoczym, Dorota; Grzywnowicz, Krzysztof; Stefaniuk, Dawid; Wlaz, Piotr

2015-01-01

Ganoderma lucidum is a well-known medicinal mushroom with a long history of use. This study was designed to assess the anticonvulsant potential of an aqueous extract from cultured G. lucidum mycelium in 3 acute seizure models: timed intravenous pentylenetetrazole infusion, maximal electroshock seizure threshold, and 6-Hz-induced psychomotor seizure tests in mice. Moreover, antidepressant-like and anxiolytic-like effects of G. lucidum were evaluated using the forced swim test and the elevated plus maze test in mice, respectively. No changes in seizure thresholds in the intravenous pentylenetetrazole and maximal electroshock seizure threshold tests after acute treatment with G. lucidum extract (200-600 mg/kg) was observed. However, the studied extract (100-400 mg/kg) significantly increased the threshold for psychomotor seizures in the 6-Hz seizure test. In the forced swim test, G. lucidum (100-400 mg/kg) significantly reduced the duration of immobility. No anxiolytic-like or sedative effects were reported in mice pretreated with the extract (400-600 mg/kg). G. lucidum extract (50-2400 mg/kg) did not produce toxic effects in the chimney test (motor coordination) or grip-strength test (neuromuscular strength). Further studies are required to explain the neuropharmacological effects of G. lucidum and to identify its active ingredients that may affect seizure threshold, mood, or anxiety.

Human Laboratory Paradigms in Alcohol Research

PubMed Central

Plebani, Jennifer G.; Ray, Lara A.; Morean, Meghan E.; Corbin, William R.; Mackillop, James; Amlung, Michael; King, Andrea C.

2014-01-01

Human laboratory studies have a long and rich history in the field of alcoholism. Human laboratory studies have allowed for advances in alcohol research in a variety of ways, including elucidating of the neurobehavioral mechanisms of risk, identifying phenotypically distinct sub-types of alcohol users, investigating of candidate genes underlying experimental phenotypes for alcoholism, and testing mechanisms of action of alcoholism pharmacotherapies on clinically-relevant translational phenotypes, such as persons exhibiting positive-like alcohol effects or alcohol craving. Importantly, the field of human laboratory studies in addiction has progressed rapidly over the past decade and has built upon earlier findings of alcohol's neuropharmacological effects to advancing translational research on alcoholism etiology and treatment. To that end, the new generation of human laboratory studies has focused on applying new methodologies, further refining alcoholism phenotypes, and translating these findings to studies of alcoholism genetics, medication development, and pharmacogenetics. The combination of experimental laboratory approaches with recent developments in neuroscience and pharmacology has been particularly fruitful in furthering our understanding of the impact of individual differences in alcoholism risk and in treatment response. This review of the literature focuses on human laboratory studies of subjective intoxication, alcohol craving, anxiety, and behavioral economics. Each section discusses opportunities for phenotype refinement under laboratory conditions, as well as its application to translational science of alcoholism. A summary and recommendations for future research are also provided. PMID:22309888

Serotonin 5-HT2 Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder

PubMed Central

Cunningham, Kathryn A.

2015-01-01

Cocaine exhibits prominent abuse liability, and chronic abuse can result in cocaine use disorder with significant morbidity. Major advances have been made in delineating neurobiological mechanisms of cocaine abuse; however, effective medications to treat cocaine use disorder remain to be discovered. The present review will focus on the role of serotonin (5-HT; 5-hydroxytryptamine) neurotransmission in the neuropharmacology of cocaine and related abused stimulants. Extensive research suggests that the primary contribution of 5-HT to cocaine addiction is a consequence of interactions with dopamine (DA) neurotransmission. The literature on the neurobiological and behavioral effects of cocaine is well developed, so the focus of the review will be on cocaine with inferences made about other monoamine uptake inhibitors and releasers based on mechanistic considerations. 5-HT receptors are widely expressed throughout the brain, and several different 5-HT receptor subtypes have been implicated in mediating the effects of endogenous 5-HT on DA. However, the 5-HT2A and 5-HT2C receptors in particular have been implicated as likely candidates for mediating the influence of 5-HT in cocaine abuse as well as to traits (e.g., impulsivity) that contribute to the development of cocaine use disorder and relapse in humans. Lastly, new approaches are proposed to guide targeted development of serotonergic ligands for the treatment of cocaine use disorder. PMID:25505168

Toxic essential oils. Part V: Behaviour modulating and toxic properties of thujones and thujone-containing essential oils of Salvia officinalis L., Artemisia absinthium L., Thuja occidentalis L. and Tanacetum vulgare L.

PubMed

Radulović, Niko S; Genčić, Marija S; Stojanović, Nikola M; Randjelović, Pavle J; Stojanović-Radić, Zorica Z; Stojiljković, Nenad I

2017-07-01

Neurotoxic thujones (α- and β-diastereoisomers) are common constituents of plant essential oils. In this study, we employed a statistical approach to determine the contribution of thujones to the overall observed behaviour-modulating and toxic effects of essential oils (Salvia officinalis L., Artemisia absinthium L., Thuja occidentalis L. and Tanacetum vulgare L.) containing these monoterpene ketones. The data from three in vivo neuropharmacological tests on rats (open field, light-dark, and diazepam-induced sleep), and toxicity assays (brine shrimp, and antimicrobial activity against a panel of microorganisms), together with the data from detailed chemical analyses, were subjected to a multivariate statistical treatment to reveal the possible correlation(s) between the content of essential-oil constituents and the observed effects. The results strongly imply that the toxic and behaviour-modulating activity of the oils (hundreds of constituents) should not be associated exclusively with thujones. The statistical analyses pinpointed to a number of essential-oil constituents other than thujones that demonstrated a clear correlation with either the toxicity, antimicrobial effect or the activity on CNS. Thus, in addition to the thujone content, the amount and toxicity of other constituents should be taken into consideration when making risk assessment and determining the regulatory status of plants in food and medicines. Copyright © 2017 Elsevier Ltd. All rights reserved.

Unifying Theories of Psychedelic Drug Effects

PubMed Central

Swanson, Link R.

2018-01-01

How do psychedelic drugs produce their characteristic range of acute effects in perception, emotion, cognition, and sense of self? How do these effects relate to the clinical efficacy of psychedelic-assisted therapies? Efforts to understand psychedelic phenomena date back more than a century in Western science. In this article I review theories of psychedelic drug effects and highlight key concepts which have endured over the last 125 years of psychedelic science. First, I describe the subjective phenomenology of acute psychedelic effects using the best available data. Next, I review late 19th-century and early 20th-century theories—model psychoses theory, filtration theory, and psychoanalytic theory—and highlight their shared features. I then briefly review recent findings on the neuropharmacology and neurophysiology of psychedelic drugs in humans. Finally, I describe recent theories of psychedelic drug effects which leverage 21st-century cognitive neuroscience frameworks—entropic brain theory, integrated information theory, and predictive processing—and point out key shared features that link back to earlier theories. I identify an abstract principle which cuts across many theories past and present: psychedelic drugs perturb universal brain processes that normally serve to constrain neural systems central to perception, emotion, cognition, and sense of self. I conclude that making an explicit effort to investigate the principles and mechanisms of psychedelic drug effects is a uniquely powerful way to iteratively develop and test unifying theories of brain function. PMID:29568270

Investigating ion channel conformational changes using voltage clamp fluorometry.

PubMed

Talwar, Sahil; Lynch, Joseph W

2015-11-01

Ion channels are membrane proteins whose functions are governed by conformational changes. The widespread distribution of ion channels, coupled with their involvement in most physiological and pathological processes and their importance as therapeutic targets, renders the elucidation of these conformational mechanisms highly compelling from a drug discovery perspective. Thanks to recent advances in structural biology techniques, we now have high-resolution static molecular structures for members of the major ion channel families. However, major questions remain to be resolved about the conformational states that ion channels adopt during activation, drug modulation and desensitization. Patch-clamp electrophysiology has long been used to define ion channel conformational states based on functional criteria. It achieves this by monitoring conformational changes at the channel gate and cannot detect conformational changes occurring in regions distant from the gate. Voltage clamp fluorometry involves labelling cysteines introduced into domains of interest with environmentally sensitive fluorophores and inferring structural rearrangements from voltage or ligand-induced fluorescence changes. Ion channel currents are monitored simultaneously to verify the conformational status. By defining real time conformational changes in domains distant from the gate, this technique provides unexpected new insights into ion channel structure and function. This review aims to summarise the methodology and highlight recent innovative applications of this powerful technique. This article is part of the Special Issue entitled 'Fluorescent Tools in Neuropharmacology'. Copyright © 2015 Elsevier Ltd. All rights reserved.

Functional Analysis of Dopaminergic Systems in a DYT1 Knock-in Mouse Model of Dystonia

PubMed Central

Song, Chang-Hyun; Fan, Xueliang; Exeter, Cicely J.; Hess, Ellen J.; Jinnah, H. A.

2012-01-01

The dystonias are a group of disorders characterized by involuntary twisting movements and abnormal posturing. The most common of the inherited dystonias is DYT1 dystonia, which is due to deletion of a single GAG codon (ΔE) in the TOR1A gene that encodes torsinA. Since some forms of dystonia have been linked with dysfunction of brain dopamine pathways, the integrity of these pathways was explored in a knock-in mouse model of DYT1 dystonia. In DYT1(ΔE) knock-in mice, neurochemical measures revealed only small changes in the content of dopamine or its metabolites in tissue homogenates from caudoputamen or midbrain, but microdialysis studies revealed robust decreases in baseline and amphetamine-stimulated extracellular dopamine in the caudoputamen. Quantitative stereological methods revealed no evidence for striatal or midbrain atrophy, but substantia nigra neurons immunopositive for tyrosine hydroxylase were slightly reduced in numbers and enlarged in size. Behavioral studies revealed subtle abnormalities in gross motor activity and motor coordination without overt dystonia. Neuropharmacological challenges of dopamine systems revealed normal behavioral responses to amphetamine and a minor increase in sensitivity to haloperidol. These results demonstrate that this DYT1(ΔE) knock-in mouse model of dystonia harbors neurochemical and structural changes of the dopamine pathways, as well as motor abnormalities. PMID:22659308

(S)-citalopram influences amygdala modulation in healthy subjects: a randomized placebo-controlled double-blind fMRI study using dynamic causal modeling.

PubMed

Sladky, Ronald; Spies, Marie; Hoffmann, Andre; Kranz, Georg; Hummer, Allan; Gryglewski, Gregor; Lanzenberger, Rupert; Windischberger, Christian; Kasper, Siegfried

2015-03-01

Citalopram and Escitalopram are gold standard pharmaceutical treatment options for affective, anxiety, and other psychiatric disorders. However, their neurophysiologic function on cortico-limbic circuits is incompletely characterized. Here we studied the neuropharmacological influence of Citalopram and Escitalopram on cortico-limbic regulatory processes by assessing the effective connectivity between orbitofrontal cortex (OFC) and amygdala using dynamic causal modeling (DCM) applied to functional MRI data. We investigated a cohort of 15 healthy subjects in a randomized, crossover, double-blind design after 10days of Escitalopram (10mg/d (S)-citalopram), Citalopram (10mg/d (S)-citalopram and 10mg/d (R)-citalopram), or placebo. Subjects performed an emotional face discrimination task, while undergoing functional magnetic resonance imaging (fMRI) scanning at 3 Tesla. As hypothesized, the OFC, in the context of the emotional face discrimination task, exhibited a down-regulatory effect on amygdala activation. This modulatory effect was significantly increased by (S)-citalopram, but not (R)-citalopram. For the first time, this study shows that (1) the differential effects of the two enantiomers (S)- and (R)-citalopram on cortico-limbic connections can be demonstrated by modeling effective connectivity methods, and (2) one of their mechanisms can be linked to an increased inhibition of amygdala activation by the orbitofrontal cortex. Copyright © 2014 Elsevier Inc. All rights reserved.

Neuroprotective Effects of Açaí (Euterpe oleracea Mart.) against Rotenone In Vitro Exposure.

PubMed

Machado, Alencar Kolinski; Andreazza, Ana Cristina; da Silva, Tatiane Morgana; Boligon, Aline Augusti; do Nascimento, Vanusa; Scola, Gustavo; Duong, Angela; Cadoná, Francine Carla; Ribeiro, Euler Esteves; da Cruz, Ivana Beatrice Mânica

2016-01-01

Neuropsychiatric diseases, such as bipolar disorder (BD) and schizophrenia (SCZ), have a very complex pathophysiology. Several current studies describe an association between psychiatric illness and mitochondrial dysfunction and consequent cellular modifications, including lipid, protein, and DNA damage, caused by cellular oxidative stress. Euterpe oleracea (açaí) is a powerful antioxidant fruit. Açaí is an Amazonian palm fruit primarily found in the lowlands of the Amazonian rainforest, particularly in the floodplains of the Amazon River. Given this proposed association, this study analyzed the potential in vitro neuropharmacological effect of Euterpe oleracea (açaí) extract in the modulation of mitochondrial function and oxidative metabolism. SH-SY5Y cells were treated with rotenone to induce mitochondrial complex I dysfunction and before and after we exposed the cells to açaí extract at 5  μ g/mL. Treated and untreated cells were then analyzed by spectrophotometric, fluorescent, immunological, and molecular assays. The results showed that açaí extract can potentially increase protein amount and enzyme activity of mitochondrial complex I, mainly through NDUFS7 and NDUFS8 overexpression. Açaí extract was also able to decrease cell reactive oxygen species levels and lipid peroxidation. We thus suggest açaí as a potential candidate for drug development and a possible alternative BD therapy.

Neuroprotective Effects of Açaí (Euterpe oleracea Mart.) against Rotenone In Vitro Exposure

PubMed Central

Andreazza, Ana Cristina; da Silva, Tatiane Morgana; do Nascimento, Vanusa; Duong, Angela; Ribeiro, Euler Esteves

2016-01-01

Neuropsychiatric diseases, such as bipolar disorder (BD) and schizophrenia (SCZ), have a very complex pathophysiology. Several current studies describe an association between psychiatric illness and mitochondrial dysfunction and consequent cellular modifications, including lipid, protein, and DNA damage, caused by cellular oxidative stress. Euterpe oleracea (açaí) is a powerful antioxidant fruit. Açaí is an Amazonian palm fruit primarily found in the lowlands of the Amazonian rainforest, particularly in the floodplains of the Amazon River. Given this proposed association, this study analyzed the potential in vitro neuropharmacological effect of Euterpe oleracea (açaí) extract in the modulation of mitochondrial function and oxidative metabolism. SH-SY5Y cells were treated with rotenone to induce mitochondrial complex I dysfunction and before and after we exposed the cells to açaí extract at 5 μg/mL. Treated and untreated cells were then analyzed by spectrophotometric, fluorescent, immunological, and molecular assays. The results showed that açaí extract can potentially increase protein amount and enzyme activity of mitochondrial complex I, mainly through NDUFS7 and NDUFS8 overexpression. Açaí extract was also able to decrease cell reactive oxygen species levels and lipid peroxidation. We thus suggest açaí as a potential candidate for drug development and a possible alternative BD therapy. PMID:27781077

ST09, a Novel Thioester Derivative of Tacrine, Alleviates Cognitive Deficits and Enhances Glucose Metabolism in Vascular Dementia Rats.

PubMed

Liu, Jian-Min; Wu, Peng-Fei; Rao, Jing; Zhou, Jun; Shen, Zu-Cheng; Luo, Han; Huang, Jian-Geng; Liang, Xiao; Long, Li-Hong; Xie, Qing-Guo; Jiang, Feng-Chao; Wang, Fang; Chen, Jian-Guo

2016-03-01

Chemical entities containing mercapto group have been increasingly attractive in the therapy of central nerve system (CNS) diseases. In the recent study, we screened a series of mercapto-tacrine derivatives with synergistic neuropharmacological profiles in vitro. We investigated the effect and mechanism of ST09, a thioester derivative of tacrine containing a potential mercapto group, on the vascular dementia (VaD) model of rat induced by bilateral common carotid arteries occlusion (2-VO). ST09 and its active metabolite ST10 retained excellent inhibition on acetylcholinesterase (AChE) activity. ST09 significantly attenuated the 2-VO-induced impairment in spatial acquisition performance and inhibited the 2-VO-induced rise of AChE activity. In the VaD model, ST09 attenuated the oxidative stress and decreased the apoptosis in the cortex and hippocampus. Compared with donepezil, ST09 exhibited a better effect on the regeneration of free thiols in 2-VO rats. Interestingly, ST09, not donepezil, greatly improved glucose metabolism in various brain regions of 2-VO rats using functional imaging of (18) F-labeled fluoro-deoxyglucose (FDG) positron emission tomography (PET). ST09 may serve as a more promising agent for the therapy of VaD than tacrine owing to the introduction of a potential mercapto group into the parent skeleton. © 2016 John Wiley & Sons Ltd.

The Fabric of Meaning and Subjective Effects in LSD-Induced States Depend on Serotonin 2A Receptor Activation.

PubMed

Preller, Katrin H; Herdener, Marcus; Pokorny, Thomas; Planzer, Amanda; Kraehenmann, Rainer; Stämpfli, Philipp; Liechti, Matthias E; Seifritz, Erich; Vollenweider, Franz X

2017-02-06

A core aspect of the human self is the attribution of personal relevance to everyday stimuli enabling us to experience our environment as meaningful [1]. However, abnormalities in the attribution of personal relevance to sensory experiences are also critical features of many psychiatric disorders [2, 3]. Despite their clinical relevance, the neurochemical and anatomical substrates enabling meaningful experiences are largely unknown. Therefore, we investigated the neuropharmacology of personal relevance processing in humans by combining fMRI and the administration of the mixed serotonin (5-HT) and dopamine receptor (R) agonist lysergic acid diethylamide (LSD), well known to alter the subjective meaning of percepts, with and without pretreatment with the 5-HT 2A R antagonist ketanserin. General subjective LSD effects were fully blocked by ketanserin. In addition, ketanserin inhibited the LSD-induced attribution of personal relevance to previously meaningless stimuli and modulated the processing of meaningful stimuli in cortical midline structures. These findings point to the crucial role of the 5-HT 2A R subtype and cortical midline regions in the generation and attribution of personal relevance. Our results thus increase our mechanistic understanding of personal relevance processing and reveal potential targets for the treatment of psychiatric illnesses characterized by alterations in personal relevance attribution. Copyright © 2017 Elsevier Ltd. All rights reserved.

Comparison of the Pharmacological Profiles of Selective PDE4B and PDE4D Inhibitors in the Central Nervous System

PubMed Central

Zhang, Chong; Xu, Ying; Zhang, Han-Ting; Gurney, Mark E.; O’Donnell, James M.

2017-01-01

Inhibition of cyclic AMP (cAMP)-specific phosphodiesterase 4 (PDE4) has been proposed as a potential treatment for a series of neuropsychological conditions such as depression, anxiety and memory loss. However, the specific involvement of each of the PDE4 subtypes (PDE4A, 4B and 4C) in different categories of behavior has yet to be elucidated. In the present study, we compared the possible pharmacological effects of PDE4B and PDE4D selective inhibitors, A-33 and D159687, in mediating neurological function in mice. Both compounds were equally potent in stimulating cAMP signaling in the mouse hippocampal cell line HT-22 leading to an increase in CREB phosphorylation. In contrast, A-33 and D159687 displayed distinct neuropharmacological effects in mouse behavioral tests. A-33 has an antidepressant-like profile as indicated by reduced immobility time in the forced swim and tail suspension tasks, as well as reduced latency to feed in the novelty suppressed feeding test. D159687, on the other hand, had a procognitive profile as it improved memory in the novel object recognition test but had no antidepressant or anxiolytic benefit. The present data suggests that inhibitors targeting specific subtypes of PDE4 may exhibit differential pharmacological effects and aid a more efficient pharmacotherapy towards neuropsychological conditions. PMID:28054669

Prospect theory on the brain? Toward a cognitive neuroscience of decision under risk.

PubMed

Trepel, Christopher; Fox, Craig R; Poldrack, Russell A

2005-04-01

Most decisions must be made without advance knowledge of their consequences. Economists and psychologists have devoted much attention to modeling decisions made under conditions of risk in which options can be characterized by a known probability distribution over possible outcomes. The descriptive shortcomings of classical economic models motivated the development of prospect theory (D. Kahneman, A. Tversky, Prospect theory: An analysis of decision under risk. Econometrica, 4 (1979) 263-291; A. Tversky, D. Kahneman, Advances in prospect theory: Cumulative representation of uncertainty. Journal of Risk and Uncertainty, 5 (4) (1992) 297-323) the most successful behavioral model of decision under risk. In the prospect theory, subjective value is modeled by a value function that is concave for gains, convex for losses, and steeper for losses than for gains; the impact of probabilities are characterized by a weighting function that overweights low probabilities and underweights moderate to high probabilities. We outline the possible neural bases of the components of prospect theory, surveying evidence from human imaging, lesion, and neuropharmacology studies as well as animal neurophysiology studies. These results provide preliminary suggestions concerning the neural bases of prospect theory that include a broad set of brain regions and neuromodulatory systems. These data suggest that focused studies of decision making in the context of quantitative models may provide substantial leverage towards a fuller understanding of the cognitive neuroscience of decision making.

The neuropharmacology of relapse to food seeking: methodology, main findings, and comparison with relapse to drug seeking.

PubMed

Nair, Sunila G; Adams-Deutsch, Tristan; Epstein, David H; Shaham, Yavin

2009-09-01

Relapse to old, unhealthy eating habits is a major problem in human dietary treatments. The mechanisms underlying this relapse are unknown. Surprisingly, until recently this clinical problem has not been systematically studied in animal models. Here, we review results from recent studies in which a reinstatement model (commonly used to study relapse to abused drugs) was employed to characterize the effect of pharmacological agents on relapse to food seeking induced by either food priming (non-contingent exposure to small amounts of food), cues previously associated with food, or injections of the pharmacological stressor yohimbine. We also address methodological issues related to the use of the reinstatement model to study relapse to food seeking, similarities and differences in mechanisms underlying reinstatement of food seeking versus drug seeking, and the degree to which the reinstatement procedure provides a suitable model for studying relapse in humans. We conclude by discussing implications for medication development and future research. We offer three tentative conclusions: (1)The neuronal mechanisms of food-priming- and cue-induced reinstatement are likely different from those of reinstatement induced by the pharmacological stressor yohimbine. (2)The neuronal mechanisms of reinstatement of food seeking are possibly different from those of ongoing food-reinforced operant responding. (3)The neuronal mechanisms underlying reinstatement of food seeking overlap to some degree with those of reinstatement of drug seeking.

Data collection and analysis strategies for phMRI.

PubMed

Mandeville, Joseph B; Liu, Christina H; Vanduffel, Wim; Marota, John J A; Jenkins, Bruce G

2014-09-01

Although functional MRI traditionally has been applied mainly to study changes in task-induced brain function, evolving acquisition methodologies and improved knowledge of signal mechanisms have increased the utility of this method for studying responses to pharmacological stimuli, a technique often dubbed "phMRI". The proliferation of higher magnetic field strengths and the use of exogenous contrast agent have boosted detection power, a critical factor for successful phMRI due to the restricted ability to average multiple stimuli within subjects. Receptor-based models of neurovascular coupling, including explicit pharmacological models incorporating receptor densities and affinities and data-driven models that incorporate weak biophysical constraints, have demonstrated compelling descriptions of phMRI signal induced by dopaminergic stimuli. This report describes phMRI acquisition and analysis methodologies, with an emphasis on data-driven analyses. As an example application, statistically efficient data-driven regressors were used to describe the biphasic response to the mu-opioid agonist remifentanil, and antagonism using dopaminergic and GABAergic ligands revealed modulation of the mesolimbic pathway. Results illustrate the power of phMRI as well as our incomplete understanding of mechanisms underlying the signal. Future directions are discussed for phMRI acquisitions in human studies, for evolving analysis methodologies, and for interpretative studies using the new generation of simultaneous PET/MRI scanners. This article is part of the Special Issue Section entitled 'Neuroimaging in Neuropharmacology'. Copyright © 2014 Elsevier Ltd. All rights reserved.

Reversal learning as a measure of impulsive and compulsive behavior in addictions.

PubMed

Izquierdo, Alicia; Jentsch, J David

2012-01-01

Our ability to measure the cognitive components of complex decision-making across species has greatly facilitated our understanding of its neurobiological mechanisms. One task in particular, reversal learning, has proven valuable in assessing the inhibitory processes that are central to executive control. Reversal learning measures the ability to actively suppress reward-related responding and to disengage from ongoing behavior, phenomena that are biologically and descriptively related to impulsivity and compulsivity. Consequently, reversal learning could index vulnerability for disorders characterized by impulsivity such as proclivity for initial substance abuse as well as the compulsive aspects of dependence. Though we describe common variants and similar tasks, we pay particular attention to discrimination reversal learning, its supporting neural circuitry, neuropharmacology and genetic determinants. We also review the utility of this task in measuring impulsivity and compulsivity in addictions. We restrict our review to instrumental, reward-related reversal learning studies as they are most germane to addiction. The research reviewed here suggests that discrimination reversal learning may be used as a diagnostic tool for investigating the neural mechanisms that mediate impulsive and compulsive aspects of pathological reward-seeking and -taking behaviors. Two interrelated mechanisms are posited for the neuroadaptations in addiction that often translate to poor reversal learning: frontocorticostriatal circuitry dysregulation and poor dopamine (D2 receptor) modulation of this circuitry. These data suggest new approaches to targeting inhibitory control mechanisms in addictions.

Nano-volume drop patterning for rapid on-chip neuronal connect-ability assays.

PubMed

Petrelli, Alessia; Marconi, Emanuele; Salerno, Marco; De Pietri Tonelli, Davide; Berdondini, Luca; Dante, Silvia

2013-11-21

The ability of neurons to extend projections and to form physical connections among them (i.e., "connect-ability") is altered in several neuropathologies. The quantification of these alterations is an important read-out to investigate pathogenic mechanisms and for research and development of neuropharmacological therapies, however current morphological analysis methods are very time-intensive. Here, we present and characterize a novel on-chip approach that we propose as a rapid assay. Our approach is based on the definition on a neuronal cell culture substrate of discrete patterns of adhesion protein spots (poly-d-lysine, 23 ± 5 μm in diameter) characterized by controlled inter-spot separations of increasing distance (from 40 μm to 100 μm), locally adsorbed in an adhesion-repulsive agarose layer. Under these conditions, the connect-ability of wild type primary neurons from rodents is shown to be strictly dependent on the inter-spot distance, and can be rapidly documented by simple optical read-outs. Moreover, we applied our approach to identify connect-ability defects in neurons from a mouse model of 22q11.2 deletion syndrome/DiGeorge syndrome, by comparative trials with wild type preparations. The presented results demonstrate the sensitivity and reliability of this novel on-chip-based connect-ability approach and validate the use of this method for the rapid assessment of neuronal connect-ability defects in neuropathologies.

Intrahippocampal infusion of the Ih blocker ZD7288 slows evoked theta rhythm and produces anxiolytic-like effects in the elevated plus maze.

PubMed

Yeung, Michelle; Dickson, Clayton T; Treit, Dallas

2013-04-01

Hippocampal theta rhythm has been associated with a number of behavioral processes, including learning and memory, spatial behavior, sensorimotor integration and affective responses. Suppression of hippocampal theta frequency has been shown to be a reliable neurophysiological signature of anxiolytic drug action in tests using known anxiolytic drugs (i.e., correlational evidence), but only one study to date (Yeung et al. (2012) Neuropharmacology 62:155-160) has shown that a drug with no known effect on either hippocampal theta or anxiety can in fact separately suppress hippocampal theta and anxiety in behavioral tests (i.e., prima facie evidence). Here, we attempt a further critical test of the hippocampal theta model by performing intrahippocampal administrations of the Ih blocker ZD7288, which is known to disrupt theta frequency subthreshold oscillations and resonance at the membrane level but is not known to have anxiolytic action. Intrahippocampal microinfusions of ZD7288 at high (15 µg), but not low (1 µg) doses slowed brainstem-evoked hippocampal theta responses in the urethane anesthetized rat, and more importantly, promoted anxiolytic action in freely behaving rats in the elevated plus maze. Taken together with our previous demonstration, these data provide converging, prima facie evidence of the validity of the theta suppression model. Copyright © 2012 Wiley Periodicals, Inc.

Ethylphenidate as a selective dopaminergic agonist and methylphenidate-ethanol transesterification biomarker

PubMed Central

Patrick, Kennerly S.; Corbin, Timothy R.; Murphy, Cristina E.

2014-01-01

We review the pharmaceutical science of ethylphenidate (EPH) in the contexts of drug discovery; drug interactions; biomarker for dl-methylphenidate (MPH)-ethanol exposure; potentiation of dl-MPH abuse liability; contemporary “designer drug”; pertinence to the newer transdermal and chiral switch MPH formulations; as well as problematic internal standard. d-EPH selectively targets the dopamine transporter while d-MPH exhibits equipotent actions at dopamine and norepinephrine transporters. This selectivity carries implications for the advancement of tailored attention-deficit/hyperactivity disorder (ADHD) pharmacotherapy in the era of genome-based diagnostics. Abuse of dl-MPH often involves ethanol co-abuse. Carboxylesterase 1 enantioselectively transesterifies l-MPH with ethanol to yield l-EPH accompanied by significantly increased early exposure to d-MPH and rapid potentiation of euphoria. The pharmacokinetic component of this drug interaction can largely be avoided using dexmethylphenidate (dexMPH). This notwithstanding, maximal potentiated euphoria occurs following dexMPH-ethanol. C57BL/6 mice model dl-MPH-ethanol interactions: An otherwise depressive dose of ethanol synergistically increases dl-MPH stimulation; A sub-stimulatory dose of dl-MPH potentiates a low, stimulatory dose of ethanol; Ethanol elevates blood, brain and urinary d-MPH concentrations while forming l-EPH. Integration of EPH preclinical neuropharmacology with clinical studies of MPH-ethanol interactions provides a translational approach toward advancement of ADHD personalized medicine and management of comorbid alcohol use disorder. PMID:25303048

Ethylphenidate as a selective dopaminergic agonist and methylphenidate-ethanol transesterification biomarker.

PubMed

Patrick, Kennerly S; Corbin, Timothy R; Murphy, Cristina E

2014-12-01

We review the pharmaceutical science of ethylphenidate (EPH) in the contexts of drug discovery, drug interactions, biomarker for dl-methylphenidate (MPH)-ethanol exposure, potentiation of dl-MPH abuse liability, contemporary "designer drug," pertinence to the newer transdermal and chiral switch MPH formulations, as well as problematic internal standard. d-EPH selectively targets the dopamine transporter, whereas d-MPH exhibits equipotent actions at dopamine and norepinephrine transporters. This selectivity carries implications for the advancement of tailored attention-deficit/hyperactivity disorder (ADHD) pharmacotherapy in the era of genome-based diagnostics. Abuse of dl-MPH often involves ethanol coabuse. Carboxylesterase 1 enantioselectively transesterifies l-MPH with ethanol to yield l-EPH accompanied by significantly increased early exposure to d-MPH and rapid potentiation of euphoria. The pharmacokinetic component of this drug interaction can largely be avoided using dexmethylphenidate (dexMPH). This notwithstanding, maximal potentiated euphoria occurs following dexMPH-ethanol. C57BL/6 mice model dl-MPH-ethanol interactions: an otherwise depressive dose of ethanol synergistically increases dl-MPH stimulation; a substimulatory dose of dl-MPH potentiates a low, stimulatory dose of ethanol; ethanol elevates blood, brain, and urinary d-MPH concentrations while forming l-EPH. Integration of EPH preclinical neuropharmacology with clinical studies of MPH-ethanol interactions provides a translational approach toward advancement of ADHD personalized medicine and management of comorbid alcohol use disorder. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Pharmacological management of persistent hostility and aggression in persons with schizophrenia spectrum disorders: a systematic review.

PubMed

Victoroff, Jeff; Coburn, Kerry; Reeve, Alya; Sampson, Shirlene; Shillcutt, Samuel

2014-01-01

The incidence of aggressive behaviors is higher among persons with schizophrenia spectrum disorders (SSDs) than among persons without such disorders. This phenomenon represents a risk to the well-being of patients, their families, and society. The authors undertook a systematic review of the English language literature to determine the efficacy of neuropharmacological agents for the management of hostility and aggression among persons with SSDs. The search combined findings from the Medline, EMBASE, and PsycINFO databases. Ninety-two full text articles were identified that reported relevant findings. The American Academy of Neurology criteria were used to determine levels of evidence. Paliperidone-extended release is probably effective for the management of hostility among inpatients with SSDs who have not been preselected for aggression (Level B). Clozapine is possibly more effective than haloperidol for the management of overt aggression and possibly more effective than chlorpromazine for the management of hostility among inpatients with SSDs who have not been preselected for aggression (Level C). Clozapine is also possibly more effective than olanzapine or haloperidol for reducing aggression among selected physically assaultive inpatients (Level C). Adjunctive propranolol, valproic acid, and famotidine are possibly effective for reducing some aspects of hostility or aggression among inpatients with SSDs (Level C). Paliperidone-extended release currently appears to be the agent for the management of hostility among inpatients with SSDs for which there is the strongest evidence of efficacy.

Irrational beliefs, biases and gambling: exploring the role of animal models in elucidating vulnerabilities for the development of pathological gambling.

PubMed

Cocker, P J; Winstanley, C A

2015-02-15

Gambling is a heterogeneous and complex disorder. Multiple factors may lead to problem gambling, yet one of the most important appears to be the increased presence of cognitive biases or distortions. These biases are thought to precipitate gambling as they can lead to dysfunctional decision making under risk or ambiguity. Modelling these cognitive perturbations in animals can improve our understanding of their neurobiological bases, and potentially stimulate novel treatment options. The first aim of this review is to give a broad overview of some of the cognitive biases that are most commonly associated with gambling. Secondly, we will discuss several animal models that we have developed in which rodent decision-making appears hallmarked by the same cognitive inconsistencies as human choice. In particular, we will discuss two tasks that capture elements of risk and loss averse decision making, and another in which rats appear susceptible to the 'near-miss' effect. To date, findings from both human and non-human studies suggest that these different biases are neuropharmacologically and neurostructurally dissociable, and that dopamine plays a key role in their expression. Lastly, we will briefly discuss areas in both human and animal research where limitations within the field may be hampering a more complete understanding of pathological gambling as a disorder. Copyright © 2014 Elsevier B.V. All rights reserved.

Blended learning: how can we optimise undergraduate student engagement?

PubMed

Morton, Caroline E; Saleh, Sohag N; Smith, Susan F; Hemani, Ashish; Ameen, Akram; Bennie, Taylor D; Toro-Troconis, Maria

2016-08-04

Blended learning is a combination of online and face-to-face learning and is increasingly of interest for use in undergraduate medical education. It has been used to teach clinical post-graduate students pharmacology but needs evaluation for its use in teaching pharmacology to undergraduate medical students, which represent a different group of students with different learning needs. An existing BSc-level module on neuropharmacology was redesigned using the Blended Learning Design Tool (BLEnDT), a tool which uses learning domains (psychomotor, cognitive and affective) to classify learning outcomes into those taught best by self-directed learning (online) or by collaborative learning (face-to-face). Two online courses were developed, one on Neurotransmitters and the other on Neurodegenerative Conditions. These were supported with face-to-face tutorials. Undergraduate students' engagement with blended learning was explored by the means of three focus groups, the data from which were analysed thematically. Five major themes emerged from the data 1) Purpose and Acceptability 2) Structure, Focus and Consolidation 3) Preparation and workload 4) Engagement with e-learning component 5) Future Medical Education. Blended learning was acceptable and of interest to undergraduate students learning this subject. They expressed a desire for more blended learning in their courses, but only if it was highly structured, of high quality and supported by tutorials. Students identified that the 'blend' was beneficial rather than purely online learning.

Behavioral, endocrine, and neuronal alterations in zebrafish (Danio rerio) following sub-chronic coadministration of fluoxetine and ketamine.

PubMed

Pittman, Julian; Hylton, Andrew

2015-12-01

Most existing pharmacological treatments have focused on the "monoamine hypothesis" for targeted drug design for major depressive disorder (MDD). Many of these medications have a delayed onset-of-action and limited efficacy. Antidepressants with principal targets outside the monoamine system may offer the potential for more rapid activity with improved therapeutic benefit. Growing evidence suggests that the glutamatergic system is uniquely central to the neurobiology and treatment of MDD. Ketamine (Ketalar®) is a non-competitive glutamatergic antagonist classically used to induce sedation. However, preliminary clinical evidence has been promising with regard to its rapidly acting antidepressant profile. Zebrafish (Danio rerio) have emerged as a promising new animal model to screen the effects of numerous psychotropic compounds. This study aimed to determine if a sub-chronic low (sub-anesthetic) dose of ketamine could be used to augment the antidepressant effects of the widely used antidepressant fluoxetine (Prozac®) in adult zebrafish, employing an ethanol withdrawal model. Sub-chronic exposure to dosages of 100μg/L fluoxetine and 20mg/L of ketamine reduced anxiety/depression-like behaviors, leads to upregulation of serotonin synthesis and elevated whole-body cortisol levels. These results demonstrate the utility of zebrafish as a model for neuropharmacological research, and the possible efficacy of fluoxetine and ketamine coadministration. Copyright © 2015 Elsevier Inc. All rights reserved.

Neuropharmacology of cognition and memory: a unifying theory of neuromodulator imbalance in psychiatry and amnesia.

PubMed

Vakalopoulos, Costa

2006-01-01

The case of HM, a man with intractable epilepsy who became amnesic following bilateral medial temporal lobe surgery nearly half a century ago has instigated ongoing research and theoretical speculation on the nature of memory and the role of the hippocampus. Neuropsychological testing showed that although HM had extensive anterograde memory loss he could still acquire motor and cognitive skills implicitly, but could not remember the context of this learning. This has lead to declarative and procedural descriptions of the memory process. Cholinergic and monoaminergic neurotransmitter systems have also been implicated in the memory process and anticholinergic drugs traditionally have been associated with impairment of declarative memory. The cholinergic hypothesis of Alzheimer's disease is a classic example of an application of these neuropharmacological findings. In schizophrenia, preattentive deficits have been amply demonstrated by unconscious priming studies. Memory processes are also impaired in these patients. Dopamine, glutamate and even cholinergic dysfunction has been implicated in the clinical picture of schizophrenia. The present paper will attempt to bring together both the anatomical and pharmacological data from these disparate fields of research under a cohesive theory of cognition and memory. A hypothesis is presented for an inverse relationship between monoaminergic and cholinergic systems in the modulation of implicit (unconscious) and explicit (conscious) cognitive processes. It is postulated that muscarinic cholinergic receptors and monoaminergic systems facilitate unconscious and conscious processes, respectively, and they disfacilitate conscious and unconscious processes, respectively (the purported inverse relationship). In fact, the muscarinic and monoaminergic modulations of a neural network are proposed to be finely balanced such that, if, the activity of one receptor system is modified then this by necessity has effects on the other system. It takes into account receptor subtypes and their effects mediated through excitatory and inhibitory G-protein complexes. For example, m1/D2 and D1/m4 paired receptor subtypes, colocalized on separate neurons would have opposing functional effects. A theory is then presented that the critical underlying pathophysiology of schizophrenia involves a hypofunctional muscarinic cholinergic system, which induces abnormal facilitation of monoaminergic subsystems such as dopamine (e.g., a decrease in m1R function would potentiate D2R function). This extends the idea of an inverted U function for optimal monoaminergic concentrations. Not only would this impair unconscious preattentive processes, but according to the hypothesis, explicit cognition as well including memory deficits and would underlie the mechanism of psychosis. Contrary to current thinking a different view is also presented for the role of the hippocampus in the memory process. It is postulated that long-term explicit memory traces in the neocortex are laid down by phasic coactivation of forebrain projecting monoaminergic systems above some basal firing rate, such as the rostral serotonergic raphe, which projects diffusely to the cortex and according to a modified Hebbian principle. This is the proposed principal function of the hippocampal theta rhythm. The phasic activation of the cholinergic basal forebrain is mediated by projections from a separate cortical structure, possibly the lateral prefrontal cortex. Phasic muscarinic receptor activation is proposed to strengthen implicit memory traces (at a synaptic level) in the neocortex. Thus, the latter are spared by medial temporal surgery explaining the dissociation of explicit from implicit memory.

Tracking individual membrane proteins and their biochemistry: The power of direct observation.

PubMed

Barden, Adam O; Goler, Adam S; Humphreys, Sara C; Tabatabaei, Samaneh; Lochner, Martin; Ruepp, Marc-David; Jack, Thomas; Simonin, Jonathan; Thompson, Andrew J; Jones, Jeffrey P; Brozik, James A

2015-11-01

The advent of single molecule fluorescence microscopy has allowed experimental molecular biophysics and biochemistry to transcend traditional ensemble measurements, where the behavior of individual proteins could not be precisely sampled. The recent explosion in popularity of new super-resolution and super-localization techniques coupled with technical advances in optical designs and fast highly sensitive cameras with single photon sensitivity and millisecond time resolution have made it possible to track key motions, reactions, and interactions of individual proteins with high temporal resolution and spatial resolution well beyond the diffraction limit. Within the purview of membrane proteins and ligand gated ion channels (LGICs), these outstanding advances in single molecule microscopy allow for the direct observation of discrete biochemical states and their fluctuation dynamics. Such observations are fundamentally important for understanding molecular-level mechanisms governing these systems. Examples reviewed here include the effects of allostery on the stoichiometry of ligand binding in the presence of fluorescent ligands; the observation of subdomain partitioning of membrane proteins due to microenvironment effects; and the use of single particle tracking experiments to elucidate characteristics of membrane protein diffusion and the direct measurement of thermodynamic properties, which govern the free energy landscape of protein dimerization. The review of such characteristic topics represents a snapshot of efforts to push the boundaries of fluorescence microscopy of membrane proteins to the absolute limit. This article is part of the Special Issue entitled 'Fluorescent Tools in Neuropharmacology'. Copyright © 2015 Elsevier Ltd. All rights reserved.

Blockade of NMDA receptors blocks the acquisition of cocaine conditioned approach in rats.

PubMed

Galaj, Ewa; Seepersad, Neal; Dakmak, Zena; Ranaldi, Robert

2018-01-05

Conditioned stimuli (CSs) exert motivational effects on both adaptive and pathological reward-related behaviors, including drug taking and seeking. We developed a paradigm that allows us to investigate the neuropharmacology by which previously neutral stimuli acquire the capacity to function as CSs and elicit (intravenous) cocaine conditioned approach and used this paradigm to test the role of NMDA receptor stimulation in the acquisition of cocaine conditioned approach. Rats were injected systemically with the NMDA receptor antagonist, MK-801, before the start of 4 consecutive conditioning sessions, each of which consisted of 20 randomly presented light/tone (CS) presentations paired with cocaine infusion contingent upon nose pokes. Rats later were subjected to a CS-only test. To test the role of NMDA receptor stimulation in the already established conditioned approach, rats were injected with MK-801 prior to the CS-only test that occurred after 18 CS-cocaine conditioning sessions. Blockade of NMDA receptors significantly impaired the acquisition of cocaine-conditioned approach as indicated by the emission of significantly fewer nose pokes and significantly longer latencies to nose poke during CS presentations. When MK-801 treatment was applied after the acquisition of conditioned approach responding it had no effect on these measures. These results suggest that NMDA receptor stimulation plays an important role in the acquisition of reward-related conditioned responses driven by intravenous cocaine-associated CSs. Copyright © 2017 Elsevier B.V. All rights reserved.

Neuropharmacological lesion localization in idiopathic Horner's syndrome in Golden Retrievers and dogs of other breeds.

PubMed

Simpson, Katherine M; Williams, David L; Cherubini, Giunio B

2015-01-01

To investigate whether idiopathic Horner's syndrome (HS) in Golden Retrievers is an exclusively preganglionic disorder based on denervation hypersensitivity pharmacological testing with phenylephrine. Medical records of dogs presented with HS between 2000 and 2012. Dogs presented with additional ocular or systemic signs were excluded. Clinical data examined included age, sex, duration of clinical signs, ancillary diagnostic test results, and time to mydriasis on topical ocular application of 1% phenylephrine. Lesions were diagnosed as postganglionic (mydriasis within 20 min) or preganglionic (mydriasis between 20 and 45 min). Medical records of 21 dogs of nine different breeds were included. An etiopathogenesis for Horner's syndrome was determined in five dogs, none of which were Golden Retrievers. All diagnoses correlated with pharmacological lesion localization. Ten Golden Retrievers were included (eight male and two female) with a mean age of 8.5 years (range: 4-13). Lesion localization was diagnosed as postganglionic in eight (mean: 10 min [range: 6-18]) and preganglionic in two Golden Retrievers (20 and 24 min). All cases were unilateral and had completely resolved within 15 weeks (range: 11-20). Recurrence was not reported in any of the patients. Idiopathic postganglionic HS was diagnosed in eight of 10 Golden Retrievers contradicting previous reports of a purely preganglionic localization. Etiopathogenesis of canine idiopathic HS remains to be determined; nevertheless, a vascular etiology cannot be excluded. Future studies using magnetic resonance angiography may aid in clarifying the pathogenesis. © 2013 American College of Veterinary Ophthalmologists.

Can MDMA play a role in the treatment of substance abuse?

PubMed

Jerome, Lisa; Schuster, Shira; Yazar-Klosinski, B Berra

2013-03-01

A wider array of treatments are needed for people with substance abuse disorders. Some psychedelic compounds have been assessed as potential substance abuse treatments with promising results. MDMA may also help treat substance abuse based on shared features with psychedelic compounds and recent reports indicating that MDMAassisted psychotherapy can reduce symptoms of PTSD. Narrative reports and data from early investigations found that some people reduced or eliminated their substance use after receiving MDMA, especially in a therapeutic setting. MDMA is a potent monoamine releaser with sympathomimetic effects that may indirectly activate 5-HT2A receptors. It increases interpersonal closeness and prosocial feelings, potentially through oxytocin release. Findings suggest that ecstasy, material represented as containing MDMA, is associated with deleterious long-term effects after heavy lifetime use, including fewer serotonin transporter sites and impaired verbal memory. Animal and human studies demonstrate moderate abuse liability for MDMA, and this effect may be of most concern to those treating substance abuse disorders. However, subjects who received MDMA-assisted psychotherapy in two recent clinical studies were not motivated to seek out ecstasy, and tested negative in random drug tests during follow-up in one study. MDMA could either directly treat neuropharmacological abnormalities associated with addiction, or it could indirectly assist with the therapeutic process or reduce symptoms of comorbid psychiatric conditions, providing a greater opportunity to address problematic substance use. Studies directly testing MDMA-assisted psychotherapy in people with active substance abuse disorder may be warranted.

Mechanism of PAMAM Dendrimers Internalization in Hippocampal Neurons.

PubMed

Vidal, Felipe; Vásquez, Pilar; Díaz, Carola; Nova, Daniela; Alderete, Joel; Guzmán, Leonardo

2016-10-03

Polyamidoamine (PAMAM) dendrimers are hyperbranched macromolecules which have been described as one of the most promising drug nanocarrier systems. A key process to understand is their cellular internalization mechanism because of its direct influence on their intracellular distribution, association with organelles, entry kinetics, and cargo release. Despite that internalization mechanisms of dendrimers have been studied in different cell types, in the case of neurons they are not completely described. Considering the relevance of central nervous system (CNS) diseases and neuropharmacology, the aim of this report is to describe the molecular internalization mechanism of different PAMAM-based dendrimer systems in hippocampal neurons. Four dendrimers based on fourth generation PAMAM with different surface properties were studied: unmodified G4, with a positively charged surface; PP50, with a substitution of the 50% of amino surface groups with polyethylene glycol neutral groups; PAc, with a substitution of the 30% of amino surface groups with acrylate anionic groups; and PFO, decorated with folic acid groups in a 25% of total terminal groups. Confocal images show that both G4 and PFO are able to enter the neurons, but not PP50 and PAc. Colocalization study with specific endocytosis markers and specific endocytosis inhibitor assay demonstrate that clathrin-mediated endocytosis would be the main internalization mechanism for G4, whereas clathrin- and caveolae-mediated endocytosis would be implicated in PFO internalization. These results show the existence of different internalization mechanisms for PAMAM dendrimers in neurons and the possibility to control their internalization properties with specific chemical modifications.

Neuropharmacological Properties of the Essential Oil of Bergamot for the Clinical Management of Pain-Related BPSDs.

PubMed

Scuteri, Damiana; Rombola, Laura; Tridico, Laura; Mizoguchi, Hirokazu; Watanabe, Chizuko; Sakurada, Tsukasa; Sakurada, Shinobu; Corasaniti, Maria TIziana; Bagetta, Giacinto; Morrone, Luigi Antonio

2018-03-06

1.1. Alzheimer's Disease (AD) accounts for approximately 50% of all cases of dementia and, in spite of the great effort for the development of disease-modifying drugs, a definitive treatment of cognitive impairment is not available yet. A perfect adherence to the current therapy of cognitive decline is needed for a better control of the disease and this is proven to reduce, though not completely abolish, the associated Behavioural and Psychological Symptoms of Dementia (BPSDs) from occurring. This cluster of symptoms, remarkably affecting patients' health-related quality of life (HRQL), is tightly associated to pain states. Antipsychotics are the only treatment for BPSDs. However, these drugs are more effective and safer in the short-term (6-12 weeks), they are able to manage aggression but not agitation and they cannot control pain. Aromatherapy with Melissa officinalis and Lavandula officinalis has been employed to handle BPSDs, but it has not provided strong evidence to offer relief from pain. 1.2. Bergamot Essential Oil (BEO) exerts antinociceptive activity through several pharmacological mechanisms: in particular, it is able to enhance autophagy, a process undergoing derangement in chronic pain. Thus, the sound pharmacological basis for clinical translation of aromatherapy with BEO in the treatment of BPSDs has been pointed out. 1.3. The antinociceptive effects elicited by BEO in experimental pain models make of it a possible candidate for the pharmacological management of pain-related BPSDs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Neuropharmacological effects of Phoneutria nigriventer venom on astrocytes.

PubMed

Rapôso, Catarina; Björklund, Ulrika; Kalapothakis, Evanguedes; Biber, Björn; Alice da Cruz-Höfling, Maria; Hansson, Elisabeth

2016-06-01

Bites from genus Phoneutria (Ctenidae, Araneomorpha) are the second most frequent source of spider accidents in Southeast Brazil. Severe envenoming from Phoneutria nigriventer produces vision disturbance, tremor and convulsion, suggesting that the CNS is involved; however, the mechanisms by which P. nigriventer venom (PNV) affects the CNS remain poorly understood. The present study aimed to investigate whether PNV directly impairs astrocytes. Cultured astrocytes were exposed to PNV, and intracellular Ca(2+) release and signaling were measured (Fura-2/AM), Na(+)/K(+)-ATPase and Toll-like receptor 4 (TLR4) involvement were investigated, actin filaments were stained (Alexa™ 488-conjugated phalloidin probe), the G-actin/F-actin ratio was determined, and the expression level of connexin 43 (Cx43) was assessed. Incubation in Ca(2+)-free buffer did not change the Ca(2+) responses. However, pre-incubation in thapsigargin/caffeine completely abolished these responses, suggesting that PNV-evoked Ca(2+) transients were from intracellular Ca(2+) stores. Pretreatment with a Na(+)/K(+)-ATPase antagonist (ouabain) or a TLR4 antagonist (LPS-RS) decreased or increased the Ca(2+)-evoked transients, respectively. Astrocytes showed altered actin filament structure after PNV exposure. PNV treatment increased the expression levels of Na(+)/K(+)-ATPase and Cx43 but decreased those of TLR4. The present results suggest that PNV directly affects astrocytes. Na(+)/K(+)-ATPase may thus represent a more specific drug target for controlling the neurotoxicity of PNV. Copyright © 2016 Elsevier Ltd. All rights reserved.

4-Alkylated homoibotenic acid (HIBO) analogues: versatile pharmacological agents with diverse selectivity profiles towards metabotropic and ionotropic glutamate receptor subtypes.

PubMed

Madsen, Ulf; Pickering, Darryl S; Nielsen, Birgitte; Bräuner-Osborne, Hans

2005-01-01

4-Alkylated analogues of homoibotenic acid (HIBO) have previously shown high potency and selectivity at ionotropic and metabotropic glutamic acid receptor (iGluR and mGluR) subtypes. Compounds with different selectivity profiles are valuable pharmacological tools for neuropharmacological studies, and the series of 4-alkyl-HIBO analogues have been extended in this paper in the search for versatile agents. Pharmacological characterization of five new analogues, branched and unbranched 4-alkyl-HIBO analogues, have been carried out. The present compounds are all weak antagonists at Group I mGluRs (mGluR1 and 5) presenting only small differences in potencies (Ki values ranging from 89 to 670 microM). Affinities were studied at native and cloned iGluRs, and the compounds described show preference for the AMPA receptor subtypes GluR1 and 2 over GluR3 and 4. However, compared to previous 4-alkyl-HIBO analogues, these compounds show a remarkably high affinity for the Kain preferring subtype GluR5. The observed GluR5 affinities were either similar or higher compared to their GluR1 and 2 affinity. Isopropyl-HIBO showed the highest affinity for GluR5 (Ki=0.16 microM), and represents a unique compound with high affinity towards the three subtypes GluR1, 2 and 5. In general, these compounds represent new selectivity profiles compared to previously reported Glu receptor analogues.

A microfluidic platform for controlled biochemical stimulation of twin neuronal networks.

PubMed

Biffi, Emilia; Piraino, Francesco; Pedrocchi, Alessandra; Fiore, Gianfranco B; Ferrigno, Giancarlo; Redaelli, Alberto; Menegon, Andrea; Rasponi, Marco

2012-06-01

Spatially and temporally resolved delivery of soluble factors is a key feature for pharmacological applications. In this framework, microfluidics coupled to multisite electrophysiology offers great advantages in neuropharmacology and toxicology. In this work, a microfluidic device for biochemical stimulation of neuronal networks was developed. A micro-chamber for cell culturing, previously developed and tested for long term neuronal growth by our group, was provided with a thin wall, which partially divided the cell culture region in two sub-compartments. The device was reversibly coupled to a flat micro electrode array and used to culture primary neurons in the same microenvironment. We demonstrated that the two fluidically connected compartments were able to originate two parallel neuronal networks with similar electrophysiological activity but functionally independent. Furthermore, the device allowed to connect the outlet port to a syringe pump and to transform the static culture chamber in a perfused one. At 14 days invitro, sub-networks were independently stimulated with a test molecule, tetrodotoxin, a neurotoxin known to block action potentials, by means of continuous delivery. Electrical activity recordings proved the ability of the device configuration to selectively stimulate each neuronal network individually. The proposed microfluidic approach represents an innovative methodology to perform biological, pharmacological, and electrophysiological experiments on neuronal networks. Indeed, it allows for controlled delivery of substances to cells, and it overcomes the limitations due to standard drug stimulation techniques. Finally, the twin network configuration reduces biological variability, which has important outcomes on pharmacological and drug screening.

Differential expression of IL-6/IL-6R and MAO-A regulates invasion/angiogenesis in breast cancer.

PubMed

Bharti, Rashmi; Dey, Goutam; Das, Anjan Kumar; Mandal, Mahitosh

2018-04-26

Monoamine oxidases (MAO) are mitochondrial enzymes functioning in oxidative metabolism of monoamines. The action of MAO-A has been typically described in neuro-pharmacological domains. Here, we have established a co-relation between IL-6/IL-6R and MAO-A and their regulation in hypoxia induced invasion/angiogenesis. We employed various in-vitro and in-vivo techniques and clinical samples. We studied a co-relation among MAO-A and IL-6/IL-6R and tumour angiogenesis/invasion in hypoxic environment in breast cancer model. Activation of IL-6/IL-6R and its downstream was found in hypoxic cancer cells. This elevation of IL-6/IL-6R caused sustained inhibition of MAO-A in hypoxic environment. Inhibition of IL-6R signalling or IL-6R siRNA increased MAO-A activity and inhibited tumour angiogenesis and invasion significantly in different models. Further, elevation of MAO-A with 5-azacytidine (5-Aza) modulated IL-6 mediated angiogenesis and invasive signatures including VEGF, MMPs and EMT in hypoxic breast cancer. High grade invasive ductal carcinoma (IDC) clinical specimen displayed elevated level of IL-6R and depleted MAO-A expression. Expression of VEGF and HIF-1α was unregulated and loss of E-Cadherin was observed in high grade IDC tissue specimen. Suppression of MAO-A by IL-6/IL-6R activation promotes tumour angiogenesis and invasion in hypoxic breast cancer environment.

Harnessing neuroplasticity for clinical applications

PubMed Central

Sur, Mriganka; Dobkin, Bruce H.; O'Brien, Charles; Sanger, Terence D.; Trojanowski, John Q.; Rumsey, Judith M.; Hicks, Ramona; Cameron, Judy; Chen, Daofen; Chen, Wen G.; Cohen, Leonardo G.; deCharms, Christopher; Duffy, Charles J.; Eden, Guinevere F.; Fetz, Eberhard E.; Filart, Rosemarie; Freund, Michelle; Grant, Steven J.; Haber, Suzanne; Kalivas, Peter W.; Kolb, Bryan; Kramer, Arthur F.; Lynch, Minda; Mayberg, Helen S.; McQuillen, Patrick S.; Nitkin, Ralph; Pascual-Leone, Alvaro; Reuter-Lorenz, Patricia; Schiff, Nicholas; Sharma, Anu; Shekim, Lana; Stryker, Michael; Sullivan, Edith V.; Vinogradov, Sophia

2011-01-01

Neuroplasticity can be defined as the ability of the nervous system to respond to intrinsic or extrinsic stimuli by reorganizing its structure, function and connections. Major advances in the understanding of neuroplasticity have to date yielded few established interventions. To advance the translation of neuroplasticity research towards clinical applications, the National Institutes of Health Blueprint for Neuroscience Research sponsored a workshop in 2009. Basic and clinical researchers in disciplines from central nervous system injury/stroke, mental/addictive disorders, paediatric/developmental disorders and neurodegeneration/ageing identified cardinal examples of neuroplasticity, underlying mechanisms, therapeutic implications and common denominators. Promising therapies that may enhance training-induced cognitive and motor learning, such as brain stimulation and neuropharmacological interventions, were identified, along with questions of how best to use this body of information to reduce human disability. Improved understanding of adaptive mechanisms at every level, from molecules to synapses, to networks, to behaviour, can be gained from iterative collaborations between basic and clinical researchers. Lessons can be gleaned from studying fields related to plasticity, such as development, critical periods, learning and response to disease. Improved means of assessing neuroplasticity in humans, including biomarkers for predicting and monitoring treatment response, are needed. Neuroplasticity occurs with many variations, in many forms, and in many contexts. However, common themes in plasticity that emerge across diverse central nervous system conditions include experience dependence, time sensitivity and the importance of motivation and attention. Integration of information across disciplines should enhance opportunities for the translation of neuroplasticity and circuit retraining research into effective clinical therapies. PMID:21482550

Ionic mechanisms in peripheral pain.

PubMed

Fransén, Erik

2014-01-01

Chronic pain constitutes an important and growing problem in society with large unmet needs with respect to treatment and clear implications for quality of life. Computational modeling is used to complement experimental studies to elucidate mechanisms involved in pain states. Models representing the peripheral nerve ending often address questions related to sensitization or reduction in pain detection threshold. In models of the axon or the cell body of the unmyelinated C-fiber, a large body of work concerns the role of particular sodium channels and mutations of these. Furthermore, in central structures: spinal cord or higher structures, sensitization often refers not only to enhanced synaptic efficacy but also to elevated intrinsic neuronal excitability. One of the recent developments in computational neuroscience is the emergence of computational neuropharmacology. In this area, computational modeling is used to study mechanisms of pathology with the objective of finding the means of restoring healthy function. This research has received increased attention from the pharmaceutical industry as ion channels have gained increased interest as drug targets. Computational modeling has several advantages, notably the ability to provide mechanistic links between molecular and cellular levels on the one hand and functions at the systems level on the other hand. These characteristics make computational modeling an additional tool to be used in the process of selecting pharmaceutical targets. Furthermore, large-scale simulations can provide a framework to systematically study the effects of several interacting disease parameters or effects from combinations of drugs. © 2014 Elsevier Inc. All rights reserved.

New frontiers in developmental neuropharmacology: Can long-term therapeutic effects of drugs be optimized through carefully timed early intervention?

PubMed Central

Andersen, Susan L.; Navalta, Carryl P.

2010-01-01

Our aim is to present a working model that may serve as a valuable heuristic to predict enduring effects of drugs when administered during development. Our primary tenet is that a greater understanding of neurodevelopment can lead to improved treatment that intervenes early in the progression of a given disorder and prevents symptoms from manifesting. The immature brain undergoes significant changes during the transitions between childhood, adolescence, and adulthood. Such changes in innervation, neurotransmitter levels, and their respective signaling mechanisms have profound and observable changes on typical behavior, but also increase vulnerability to psychiatric disorders when the maturational process goes awry. Given the remarkable plasticity of the immature brain to adapt to its external milieu, preventive interventions may be possible. We intend for this review to initiate a discussion of how currently used psychotropic agents can influence brain development. Drug exposure during sensitive periods may have beneficial long-term effects, but harmful delayed consequences may be possible as well. Regardless of the outcome, this information needs to be used to improve or develop alternative approaches for the treatment of childhood disorders. With this framework in mind, we present what is known about the effects of stimulants, antidepressants, and antipsychotics on brain maturation (including animal studies that use more clinically-relevant dosing paradigms or relevant animal models). We endeavor to provocatively set the stage for altering treatment approaches for improving mental health in non-adult populations. PMID:21309771

Dose-response study of N,N-dimethyltryptamine in humans. I. Neuroendocrine, autonomic, and cardiovascular effects.

PubMed

Strassman, R J; Qualls, C R

1994-02-01

To begin applying basic neuropharmacological hypotheses of hallucinogenic drug actions to humans, we generated dose-response data for intravenously administered dimethyltryptamine fumarate's (DMT) neuroendocrine, cardiovascular, autonomic, and subjective effects in a group of experienced hallucinogen users. Dimethyltryptamine, an endogenous mammalian hallucinogen and drug of abuse, was administered intravenously at 0.05, 0.1, 0.2, and 0.4 mg/kg to 11 experienced hallucinogen users, in a double-blind, saline placebo-controlled, randomized design. Treatments were separated by at least 1 week. Peak DMT blood levels and subjective effects were seen within 2 minutes after drug administration, and were negligible at 30 minutes. Dimethyltryptamine dose dependently elevated blood pressure, heart rate, pupil diameter, and rectal temperature, in addition to elevating blood concentrations of beta-endorphin, corticotropin, cortisol, and prolactin. Growth hormone blood levels rose equally in response to all doses of DMT, and melatonin levels were unaffected. Threshold doses for significant effects relative to placebo were also hallucinogenic (0.2 mg/kg and higher). Subjects with five or more exposures to 3,4-methylenedioxymethamphetamine demonstrated less robust pupil diameter effects than those with two or fewer exposures. Dimethyltryptamine can be administered safely to experienced hallucinogen users and dose-response data generated for several measures hypothesized under serotonergic modulatory control. Additional studies characterizing the specific mechanisms mediating DMT's biological effects may prove useful in psychopharmacological investigations of drug-induced and endogenous alterations in brain function.

Studies on neuropharmacological profile of ethanol extract of Moringa oleifera leaves in mice.

PubMed

Bakre, Adewale G; Aderibigbe, Adegbuyi O; Ademowo, Olusegun G

2013-10-07

Moringa oleifera (family Moringaceae), commonly called Horseradish or tree of life, is traditionally used for the treatment of epilepsy and neurologic conditions. The objective of this study is to investigate the neurobehavioural and anticonvulsant properties of the ethanol extract from the leaves of Moringa oleifera. Neurobehavioural properties were evaluated using the open field, hole board, Y-maze, elevated plus maze (EPM) and pentobarbitone-induced hypnosis. Pentylenetetrazole (leptazol), picrotoxin and strychnine induced convulsion tests were used to investigate the anti-convulsive actions of Moringa oleifera. The result showed that the extract (250-2000mg/kg) caused a significant dose-dependent decrease in rearing, grooming, head dips and locomotion (P<0.001). It also enhanced learning and memory and increased anxiogenic effect. In addition, the extract (2000mg/kg) protected mice against pentylenetetrazol induced convulsion, but has no effect on picrotoxin and strychnine induced convulsion. The effects of the extract in the various models were comparable to those of the standard drugs used except in Y-maze, EPM and picrotoxin and strychnine induced convulsion. The LD50 obtained for the acute toxicity studied using oral route of administration was >6.4g/kg. The findings from this study suggest that the ethanol extract of Moringa oleifera leaves possesses CNS depressant and anticonvulsant activities possibly mediated through the enhancement of central inhibitory mechanism involving release γ-amino butyric acid (GABA). The results partially justified the traditional use of the extract for the treatment of epilepsy. © 2013 Elsevier Ireland Ltd. All rights reserved.

The cell cycle in Alzheimer disease: a unique target for neuropharmacology.

PubMed

Webber, Kate M; Raina, Arun K; Marlatt, Michael W; Zhu, Xiongwei; Prat, María I; Morelli, Laura; Casadesus, Gemma; Perry, George; Smith, Mark A

2005-10-01

Several hypotheses have been proposed attempting to explain the pathogenesis of Alzheimer disease including, among others, theories involving amyloid deposition, tau phosphorylation, oxidative stress, metal ion dysregulation and inflammation. While there is strong evidence suggesting that each one of these proposed mechanisms contributes to disease pathogenesis, none of these mechanisms are able to account for all the physiological changes that occur during the course of the disease. For this reason, we and others have begun the search for a causative factor that predates known features found in Alzheimer disease, and that might therefore be a fundamental initiator of the pathophysiological cascade. We propose that the dysregulation of the cell cycle that occurs in neurons susceptible to degeneration in the hippocampus during Alzheimer disease is a potential causative factor that, together with oxidative stress, would initiate all known pathological events. Neuronal changes supporting alterations in cell cycle control in the etiology of Alzheimer disease include the ectopic expression of markers of the cell cycle, organelle kinesis and cytoskeletal alterations including tau phosphorylation. Such mitotic alterations are not only one of the earliest neuronal abnormalities in the disease, but as discussed herein, are also intimately linked to all of the other pathological hallmarks of Alzheimer disease including tau protein, amyloid beta protein precursor and oxidative stress, and even risk factors such as mutations in the presenilin genes. Therefore, therapeutic interventions targeted toward ameliorating mitotic changes would be predicted to have a profound and positive impact on Alzheimer disease progression.

Emerging targets for addiction neuropharmacology: From mechanisms to therapeutics.

PubMed

Ubaldi, Massimo; Cannella, Nazzareno; Ciccocioppo, Roberto

2016-01-01

Drug abuse represents a considerable burden of disease and has enormous economic impacts on societies. Over the years, few medications have been developed for clinical use. Their utilization is endowed with several limitations, including partial efficacy or significant side effects. On the other hand, the successful advancement of these compounds provides an important proof of concept for the feasibility of drug development programs in addiction. In recent years, a wealth of information has been generated on the psychological mechanisms, genetic or epigenetic predisposing factors, and neurobiological adaptations induced by drug consumption that interact with each other to contribute to disease progression. It is now clear that addiction develops through phases, from initial recreational use to excessive consumption and compulsive drug seeking, with a shift from positive to negative reinforcement driving motivated behaviors. A greater understanding of these mechanisms has opened new vistas in drug development programs. Researchers' attention has been shifted from investigation of classical targets associated with reward to biological substrates responsible for negative reinforcement, impulse loss of control, and maladaptive mechanisms resulting from protracted drug use. From this research, several new biological targets for the development of innovative therapies have started to emerge. This chapter offers an overview of targets currently under scrutiny for the development of new medications for addiction. This work is not exhaustive but rather it provides a few examples of how this research has advanced in recent years by virtue of studies carried out in our laboratory. © 2016 Elsevier B.V. All rights reserved.

New approaches to chemotherapy-induced nausea and vomiting: from neuropharmacology to clinical investigations.

PubMed

Rubenstein, Edward B; Slusher, Barbara S; Rojas, Camilo; Navari, Rudolph M

2006-01-01

Nausea and vomiting are considered to be among the most distressing consequences of cytotoxic chemotherapies. Currently, there are several novel 5-HT(3) receptor antagonists for the treatment of chemotherapy-induced nausea and vomiting (CINV), including ondansetron, granisetron, and dolasetron. These agents provide significant improvement in the management of acute emesis but are ineffective at preventing delayed emesis. In 2003, a new 5-HT(3) receptor antagonist, palonosetron HCL (Aloxi), was introduced to the U.S. market. Palonosetron was found to be effective in preventing delayed CINV. Indeed, palonosetron was the first and only 5-HT(3) receptor antagonist approved by the FDA for the prevention of both acute and delayed CINV. More recently, studies on the role of substance P in the emetic process led to the development of aprepitant (Emend) for the prevention of delayed emesis in combination with 5-HT(3) receptor antagonists. Despite these major advances, CINV remains uncontrolled in some patients. Current efforts are focused on treating refractory emesis and include both the clinical evaluation of compounds marketed for other indications and the preclinical evaluation of novel molecules targeting other transmitters in the emetic pathway. Ongoing work in pharmacogenomics has postulated several candidate genes that could be involved in emetic sensitivity and responsiveness to antiemetic therapy. Investigations into the pharmacogenomics of CINV may someday be able to aid in the identification of high risk patients and patients unlikely to respond to conventional therapies.

Alkaloids from piper: a review of its phytochemistry and pharmacology.

PubMed

Gutierrez, Rosa Martha Perez; Gonzalez, Adriana Maria Neira; Hoyo-Vadillo, Carlos

2013-02-01

Piper has been used for long timelike condiment and food, but also in traditional medicine around of the world. This work resumes the available and up to date work done on members of the Piperaceae family and their uses for therapeutic purposes. Information on Piper genus was gathered via internet using scientific databases such as Scirus, Google Scholar, CAB-abstracts, MedlinePlus, Pubmed, SciFinder, Scopus and Web of Science. The largeleafed perennial plant Piper is used for its spicy aromatic scent and flavor. It has an important presence in the cuisine of different cultures. Another quality of these plants is their known medicinal properties. It has been used as emollient, antirheumatic, diuretic, stimulant, abortifacient, anti-inflammatory, antibacterial, antifungal and antidermatophytic. A survey of the literature shows that the genus Piper is mainly known for its alkaloids with cytotoxic, chemopreventive, antimetastatic and antitumor properties in several types of cancer. Studies of its alkaloids highlight the existence of various potential leads to develop new anti-cancer agents. Modern pharmacology studies have demonstrated that its crude extracts and active compounds possess wide pharmacological activities, especially asantioxidant, anti-depressive, hepatoprotective, antimicrobial, anti-obesity, neuropharmacological, to treat cognitive disorders, anti-hyperlipidemic, anti-feedant, cardioactive, immuno-enhancing, and anti-inflamatory. All this evidence supporting its traditional uses. This review summarizes the up-to-date and comprehensive information concerning the botany, traditional use, phytochemistry and pharmacology of Piper together with its toxicology, and discusses the possible trend and scope for further research on Piper in the future.

Belief about Nicotine Modulates Subjective Craving and Insula Activity in Deprived Smokers.

PubMed

Gu, Xiaosi; Lohrenz, Terry; Salas, Ramiro; Baldwin, Philip R; Soltani, Alireza; Kirk, Ulrich; Cinciripini, Paul M; Montague, P Read

2016-01-01

Little is known about the specific neural mechanisms through which cognitive factors influence craving and associated brain responses, despite the initial success of cognitive therapies in treating drug addiction. In this study, we investigated how cognitive factors such as beliefs influence subjective craving and neural activities in nicotine-addicted individuals using model-based functional magnetic resonance imaging (fMRI) and neuropharmacology. Deprived smokers (N = 24) participated in a two-by-two balanced placebo design, which crossed beliefs about nicotine (told "nicotine" vs. told "no nicotine") with the nicotine content in a cigarette (nicotine vs. placebo) which participants smoked immediately before performing a fMRI task involving reward learning. Subjects' reported craving was measured both before smoking and after the fMRI session. We found that first, in the presence of nicotine, smokers demonstrated significantly reduced craving after smoking when told "nicotine in cigarette" but showed no change in craving when told "no nicotine." Second, neural activity in the insular cortex related to craving was only significant when smokers were told "nicotine" but not when told "no nicotine." Both effects were absent in the placebo condition. Third, insula activation related to computational learning signals was modulated by belief about nicotine regardless of nicotine's presence. These results suggest that belief about nicotine has a strong impact on subjective craving and insula responses related to both craving and learning in deprived smokers, providing insights into the complex nature of belief-drug interactions.

Belief about Nicotine Modulates Subjective Craving and Insula Activity in Deprived Smokers

PubMed Central

Gu, Xiaosi; Lohrenz, Terry; Salas, Ramiro; Baldwin, Philip R.; Soltani, Alireza; Kirk, Ulrich; Cinciripini, Paul M.; Montague, P. Read

2016-01-01

Little is known about the specific neural mechanisms through which cognitive factors influence craving and associated brain responses, despite the initial success of cognitive therapies in treating drug addiction. In this study, we investigated how cognitive factors such as beliefs influence subjective craving and neural activities in nicotine-addicted individuals using model-based functional magnetic resonance imaging (fMRI) and neuropharmacology. Deprived smokers (N = 24) participated in a two-by-two balanced placebo design, which crossed beliefs about nicotine (told “nicotine” vs. told “no nicotine”) with the nicotine content in a cigarette (nicotine vs. placebo) which participants smoked immediately before performing a fMRI task involving reward learning. Subjects’ reported craving was measured both before smoking and after the fMRI session. We found that first, in the presence of nicotine, smokers demonstrated significantly reduced craving after smoking when told “nicotine in cigarette” but showed no change in craving when told “no nicotine.” Second, neural activity in the insular cortex related to craving was only significant when smokers were told “nicotine” but not when told “no nicotine.” Both effects were absent in the placebo condition. Third, insula activation related to computational learning signals was modulated by belief about nicotine regardless of nicotine’s presence. These results suggest that belief about nicotine has a strong impact on subjective craving and insula responses related to both craving and learning in deprived smokers, providing insights into the complex nature of belief–drug interactions. PMID:27468271

Blood-brain barrier specific permeability assay reveals N-methylated tyramine derivatives in standardised leaf extracts and herbal products of Ginkgo biloba.

PubMed

Könczöl, Árpád; Rendes, Kata; Dékány, Miklós; Müller, Judit; Riethmüller, Eszter; Balogh, György Tibor

2016-11-30

The linkage between the central nervous system availability and neuropharmacological activity of the constituents of Ginkgo biloba L. extracts (GBE) is still incomplete. In this study, the in vitro blood-brain barrier (BBB) permeability profile of the standardised GBE was investigated by the parallel artificial membrane permeability assay (PAMPA). Biomarkers, such as terpene trilactones, flavonoid aglycones and ginkgotoxin exerted moderate or good BBB-permeability potential (BBB+), while glycosides and biflavones were predicted as unable to pass the BBB. N-methyltyramine (NMT) and N,N-dimethyltyramine or hordenine (Hor) were identified among BBB+ compounds, while subsequent direct HRMS analysis revealed tyramine (Tyr) and N,N,N-trimethyltyramine or candicine (Can) in GBE as trace constituents. Distribution of Tyr, NMT, Hor and Can was determined by a validated ion-exchange mechanism-based liquid chromatography-electrospray ionisation-mass spectrometry (LC-ESI-MS) method in G. biloba samples, such as herbal drugs and dietary supplements. The total content of the four tyramine derivatives in various GBEs ranged from 7.3 up to 6357μg/g dry extract with NMT and Hor as most abundant ones. Considering the pharmacological activities and the revealed fluctuation in the concentration of the analysed adrenergic protoalkaloids, the presented rapid LC-ESI-MS method is proposed for monitoring of the levels of Tyr, NMT, Hor and Can in G. biloba products. Copyright © 2016 Elsevier B.V. All rights reserved.

The age of anxiety: role of animal models of anxiolytic action in drug discovery

PubMed Central

Cryan, John F; Sweeney, Fabian F

2011-01-01

Anxiety disorders are common, serious and a growing health problem worldwide. However, the causative factors, aetiology and underlying mechanisms of anxiety disorders, as for most psychiatric disorders, remain relatively poorly understood. Animal models are an important aid in giving insight into the aetiology, neurobiology and, ultimately, the therapy of human anxiety disorders. The approach, however, is challenged with a number of complexities. In particular, the heterogeneous nature of anxiety disorders in humans coupled with the associated multifaceted and descriptive diagnostic criteria, creates challenges in both animal modelling and in clinical research. In this paper, we describe some of the more widely used approaches for assessing the anxiolytic activity of known and potential therapeutic agents. These include ethological, conflict-based, hyponeophagia, vocalization-based, physiological and cognitive-based paradigms. Developments in the characterization of translational models are also summarized, as are the challenges facing researchers in their drug discovery efforts in developing new anxiolytic drugs, not least the ever-shifting clinical conceptualization of anxiety disorders. In conclusion, to date, although animal models of anxiety have relatively good validity, anxiolytic drugs with novel mechanisms have been slow to emerge. It is clear that a better alignment of the interactions between basic and clinical scientists is needed if this is to change. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21545412

Modeling schizophrenia using hiPSC neurons

PubMed Central

Brennand, Kristen; Simone, Anthony; Jou, Jessica; Gelboin-Burkhart, Chelsea; Tran, Ngoc; Sangar, Sarah; Li, Yan; Mu, Yangling; Chen, Gong; Yu, Diana; McCarthy, Shane; Sebat, Jonathan; Gage, Fred H.

2012-01-01

SUMMARY Schizophrenia (SCZD) is a debilitating neurological disorder with a world-wide prevalence of 1%; there is a strong genetic component, with an estimated heritability of 80–85%1. Though postmortem studies have revealed reduced brain volume, cell size, spine density and abnormal neural distribution in the prefrontal cortex and hippocampus of SCZD brain tissue2 and neuropharmacological studies have implicated dopaminergic, glutamatergic and GABAergic activity in SCZD3, the cell types affected in SCZD and the molecular mechanisms underlying the disease state remain unclear. To elucidate the cellular and molecular defects of SCZD, we directly reprogrammed fibroblasts from SCZD patients into human induced pluripotent stem cells (hiPSCs) and subsequently differentiated these disorder-specific hiPSCs into neurons (SI Fig. 1). SCZD hiPSC neurons showed diminished neuronal connectivity in conjunction with decreased neurite number, PSD95-protein levels and glutamate receptor expression. Gene expression profiles of SCZD hiPSC neurons identified altered expression of many components of the cAMP and WNT signaling pathways. Key cellular and molecular elements of the SCZD phenotype were ameliorated following treatment of SCZD hiPSC neurons with the antipsychotic Loxapine. To date, hiPSC neuronal pathology has only been demonstrated in diseases characterized by both the loss of function of a single gene product and rapid disease progression in early childhood4–6. We now report hiPSC neuronal phenotypes and gene expression changes associated with SCZD, a complex genetic psychiatric disorder (SI Table 1). PMID:21490598

Charles Darwin's emotional expression "experiment" and his contribution to modern neuropharmacology.

PubMed

Snyder, Peter J; Kaufman, Rebecca; Harrison, John; Maruff, Paul

2010-04-08

In the late 1860s and early 1870s, Darwin had corresponded with the French physician and physiologist, G. B. A. Duchenne, regarding Duchenne's experimental manipulation of human facial expression of emotion, by applying Galvanic electrical stimulation directly to facial muscles. Duchenne had produced a set of over 60 photographic plates to illustrate his view that there are different muscles in the human face that are separately responsible for each individual emotion. Darwin studied this material very carefully and he received permission from Duchenne in 1871 to reproduce several of these images in The Expression of the Emotions in Man and Animals (1872). Darwin had doubted Duchenne's view that there were individual muscle groups that mediate the expression of dozens of separable emotions, and he wondered whether there might instead be a fewer set of core emotions that are expressed with great stability worldwide and across cultures. Prompted by his doubts regarding the veracity of Duchenne's model, Darwin conducted what may have been the first-ever single-blind study of the recognition of human facial expression of emotion. This single experiment was a little-known forerunner for an entire modern field of study with contemporary clinical relevance. Moreover, his specific question about cross-cultural recognition of the cardinal emotions in faces is a topic that is being actively studied (in the twenty-first century) with the hope of developing novel biomarkers to aid the discovery of new therapies for the treatment of schizophrenia, autism, and other neuropsychiatric diseases.

Accelerated habit formation following amphetamine exposure is reversed by D1, but enhanced by D2, receptor antagonists

PubMed Central

Nelson, Andrew J. D.; Killcross, Simon

2013-01-01

Repeated exposure to the psychostimulant amphetamine has been shown to disrupt goal-directed instrumental actions and promote the early and abnormal development of goal-insensitive habitual responding (Nelson and Killcross, 2006). To investigate the neuropharmacological specificity of this effect as well as restore goal-directed responding in animals with pre-training amphetamine exposure, animals were treated with the non-selective dopamine antagonist α-flupenthixol, the selective D1 antagonist SCH 23390 or the selective D2 antagonist eticlopride, prior to instrumental training (three sessions). Subsequently, the reinforcer was paired with LiCL-induced gastric-malaise and animals were given a test of goal-sensitivity both in extinction and reacquisition. The effect of these dopaminergic antagonists on the sensitivity of lever press performance to outcome devaluation was assessed in animals with pre-training exposure to amphetamine (Experiments 1A–C) or in non-sensitized animals (Experiment 2). Both α-flupenthixol and SCH23390 reversed accelerated habit formation following amphetamine sensitization. However, eticlopride appeared to enhance this effect and render instrumental performance compulsive as these animals were unable to inhibit responding both in extinction and reacquisition, even though a consumption test confirmed they had acquired an aversion to the reinforcer. These findings demonstrate that amphetamine induced-disruption of goal-directed behavior is mediated by activity at distinct dopamine receptor subtypes and may represent a putative model of the neurochemical processes involved in the loss of voluntary control over behavior. PMID:23720609

Chlorogenic Acid and Mental Diseases: From Chemistry to Medicine.

PubMed

Nabavi, Seyed Fazel; Tejada, Silvia; Setzer, William N; Gortzi, Olga; Sureda, Antoni; Braidy, Nady; Daglia, Maria; Manayi, Azadeh; Nabavi, Seyed Mohammad

2017-01-01

At present, much attention has been focused on the beneficial effects of natural products on the human health due to their high efficacy and low adverse effects. Among them, polyphenolic compounds are known as one of the most important and common classes of natural products, which possess multiple range of health-promotion effects including anti-inflammatory and antioxidant activities. A plethora of scientific evidence has shown that polyphenolic compounds possess beneficial effects on the central nervous system. Data were collected from Web of Science (ISI Web of Knowledge), Medline, Pubmed, Scopus, Embase, and BIOSIS Previews (from 1950 to 2015), through searching of these keywords: "chlorogenic acid and mental diseases" and "chlorogenic acid and neuroprotection". Chlorogenic acid is known as one of the most common polyphenolic compounds, and is found in different types of fruits and vegetables, spices, wine, olive oil, as well as coffee. The potential neuroprotective effects of chlorogenic acid have been highlighted in several in vitro and in vivo studies. This review critically analyses the available scientific evidence regarding the neuroprotective effects of chlorogenic acid, and its neuropharmacological mechanisms of action. In addition, we also discuss its biosynthesis, sources, bioavailability and metabolism, to provide a broad perspective of the therapeutic implications of this compound in brain health and disease. The present review showed that chlorogenic acid possesses neuroprotective effects under the both in vitro and in vivo models. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Pharmacodynamic Profile of Tramadol in Humans: Influence of Naltrexone Pretreatment

PubMed Central

Stoops, William W.; Lofwall, Michelle R.; Nuzzo, Paul A.; Craig, Lori B.; Siegel, Anthony J.; Walsh, Sharon L.

2012-01-01

Rationale Tramadol is a prescription analgesic that activates mu opioid and monoamine receptor systems. Tramadol is thought to have limited abuse potential compared to mu opioid agonists, but laboratory data indicate that it shares some of their pharmacodynamic effects. Objectives This study evaluated the effect of mu opioid receptor blockade with naltrexone on the pharmacodynamic action of tramadol in humans. Methods This inpatient, double-blind, randomized, within-subject study examined the effects of oral placebo, tramadol (87.5, 175 and 350 mg) and hydromorphone (4 and 16 mg; positive control) after 1 hr pretreatment with oral naltrexone (0 and 50 mg). Ten recreational opioid users completed the study. Pharmacodynamic effects were measured before and for 7 hr after initial drug administration. Results Lower doses of tramadol and hydromorphone were generally placebo-like. Hydromorphone (16 mg) produced prototypic mu opioid agonist-like effects that were blocked by naltrexone. Tramadol (350 mg) produced miosis and increased ratings of “Good Effects” and “Liking ,” but also increased ratings of “Bad Effects.” Naltrexone reversed tramadol-induced physiological effects and mydriasis emerged, but unlike results with hydromorphone, naltrexone only partially attenuated tramadol’s positive subjective effects and actually enhanced several unpleasant subjective ratings. Conclusions Naltrexone can be used to disentangle the mixed neuropharmacological actions of tramadol. High dose tramadol produces a mixed profile of effects. These data suggest that both mu and non-mu opioid actions play a role in tramadol’s subjective profile of action. PMID:22623016

Patient evaluation and general treatment planning.

PubMed

Fechtel, Scot Gerald

2006-05-01

Treating pain patients is difficult. The usual problems encountered in providing coherent and effective treatment for any chronic medical illness are compounded in painful conditions by time, society's choices, and the cultural role of the patient. Effective treatment of these patients depends on the persistence of the clinician. We must persist in requiring a complete history to understand the patient and his or her problem. We must persist in performing a thorough physical examination to uncover sufficient under-standing of the patient's physiology. We must persist in developing a comprehensive treatment plan to cover all of the intervening concerns. We must persist in following the patient in the clinic to make sure that the plan is completed and that complications that arise are dealt with efficiently. This can lead to considerable satisfaction and frustration. There remain many unanswered questions in the evaluation of pain patients and of pain itself. How accurate is physical examination in providing information about a given patient that is relevant to treating pain? Can physical examination reliably elicit a nociceptive focus for a specific individual's chronic pain experience? Is all long-term pain a smorgasbord of nociceptive, central sensitization, and neuromodulatory mechanisms? Can acute pain be more consistently aborted to minimize the development of chronic pain? Over the next few years, as our expanding knowledge of neuropharmacology, neurophysiology, and pain modulation in the CNS combines with better understanding of pain psychology and sociology, we clinicians will expect to have happier and more productive patients.

Inhibition of MDMA-induced increase in cortisol does not prevent acute impairment of verbal memory

PubMed Central

Kuypers, KPC; Torre, R; Farre, M; Pujadas, M; Ramaekers, JG

2013-01-01

Background Ecstasy use is commonly linked with memory deficits in abstinent ecstasy users. Similar impairments are being found during ecstasy intoxication after single doses of ± 3,4 metylenedioxymethamphetamine (MDMA). The concordance of memory impairments during intoxication and abstinence suggests a similar neuropharmacological mechanism underlying acute and chronic memory impairments. The mechanism underlying this impairment is to date not known. We hypothesized that cortisol might play an important role in this mechanism as cortisol, implicated in the regulation of memory performance, can be brought out of balance by stressors like MDMA. Methods In the present study, we aimed to block the MDMA-induced acute memory defect by giving participants a cortisol synthesis inhibitor (metyrapone) together with a single dose of MDMA. Seventeen polydrug MDMA users entered this placebo-controlled within subject study with four treatment conditions. The treatments consisted of MDMA (75 mg) and metyrapone (750 mg), alone and in combination, and double placebo. Pre-treatment with metyrapone or Placebo occurred 1 h prior to MDMA or Placebo administration. Memory performance was tested at peak drug concentrations by means of several memory tests. Cortisol levels were determined in blood and oral fluid; this served as a control measure to see whether manipulations were effective. Results Main findings indicated that whereas treatment with metyrapone blocked the expected MDMA-induced increase in cortisol levels in blood, it did not prevent the MDMA-induced memory deficit from happening. Conclusion We therefore conclude that MDMA-induced increments in cortisol concentrations are not related to MDMA-induced memory impairments. PMID:22946487

Cannabinoid–dopamine interactions in the physiology and physiopathology of the basal ganglia

PubMed Central

García, Concepción; Palomo‐Garo, Cristina; Gómez‐Gálvez, Yolanda

2015-01-01

Endocannabinoids and their receptors play a modulatory role in the control of dopamine transmission in the basal ganglia. However, this influence is generally indirect and exerted through the modulation of GABA and glutamate inputs received by nigrostriatal dopaminergic neurons, which lack cannabinoid CB1 receptors although they may produce endocannabinoids. Additional evidence suggests that CB2 receptors may be located in nigrostriatal dopaminergic neurons, and that certain eicosanoid‐related cannabinoids may directly activate TRPV1 receptors, which have been found in nigrostriatal dopaminergic neurons, thus allowing in both cases a direct regulation of dopamine transmission by specific cannabinoids. In addition, CB1 receptors form heteromers with dopaminergic receptors which provide another pathway to direct interactions between both systems, in this case at the postsynaptic level. Through these direct mechanisms or through indirect mechanisms involving GABA or glutamate neurons, cannabinoids may interact with dopaminergic transmission in the basal ganglia and this is likely to have important effects on dopamine‐related functions in these structures (i.e. control of movement) and, particularly, on different pathologies affecting these processes, in particular, Parkinson's disease, but also dyskinesia, dystonia and other pathological conditions. The present review will address the current literature supporting these cannabinoid–dopamine interactions at the basal ganglia, with emphasis on aspects dealing with the physiopathological consequences of these interactions. Linked Articles This article is part of a themed section on Updating Neuropathology and Neuropharmacology of Monoaminergic Systems. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.13/issuetoc PMID:26059564

Neurocircuitry of Addiction

PubMed Central

Koob, George F; Volkow, Nora D

2010-01-01

Drug addiction is a chronically relapsing disorder that has been characterized by (1) compulsion to seek and take the drug, (2) loss of control in limiting intake, and (3) emergence of a negative emotional state (eg, dysphoria, anxiety, irritability) reflecting a motivational withdrawal syndrome when access to the drug is prevented. Drug addiction has been conceptualized as a disorder that involves elements of both impulsivity and compulsivity that yield a composite addiction cycle composed of three stages: ‘binge/intoxication', ‘withdrawal/negative affect', and ‘preoccupation/anticipation' (craving). Animal and human imaging studies have revealed discrete circuits that mediate the three stages of the addiction cycle with key elements of the ventral tegmental area and ventral striatum as a focal point for the binge/intoxication stage, a key role for the extended amygdala in the withdrawal/negative affect stage, and a key role in the preoccupation/anticipation stage for a widely distributed network involving the orbitofrontal cortex–dorsal striatum, prefrontal cortex, basolateral amygdala, hippocampus, and insula involved in craving and the cingulate gyrus, dorsolateral prefrontal, and inferior frontal cortices in disrupted inhibitory control. The transition to addiction involves neuroplasticity in all of these structures that may begin with changes in the mesolimbic dopamine system and a cascade of neuroadaptations from the ventral striatum to dorsal striatum and orbitofrontal cortex and eventually dysregulation of the prefrontal cortex, cingulate gyrus, and extended amygdala. The delineation of the neurocircuitry of the evolving stages of the addiction syndrome forms a heuristic basis for the search for the molecular, genetic, and neuropharmacological neuroadaptations that are key to vulnerability for developing and maintaining addiction. PMID:19710631

Ghrelin system in alcohol-dependent subjects: role of plasma ghrelin levels in alcohol drinking and craving

PubMed Central

Leggio, Lorenzo; Ferrulli, Anna; Cardone, Silvia; Nesci, Antonio; Miceli, Antonio; Malandrino, Noemi; Capristo, Esmeralda; Canestrelli, Benedetta; Monteleone, Palmiero; Kenna, George A.; Swift, Robert M.; Addolorato, Giovanni

2016-01-01

Animal studies suggest that the gut-brain peptide ghrelin plays an important role in the neurobiology of alcohol dependence (AD). Human studies show an effect of alcohol on ghrelin levels and a correlation between ghrelin levels and alcohol craving in alcoholics. This investigation consisted of two studies. Study 1 was a 12-week study with alcohol-dependent subjects, where plasma ghrelin determinations were assessed four times (T0-T3) and related to alcohol intake and craving [Penn Alcohol Craving Score (PACS) and Obsessive Compulsive Drinking Scale (OCDS)]. Serum growth hormone (GH) levels and assessment of the nutritional/metabolic status were also performed. Study 2 was a pilot case-control study to assess ghrelin gene polymorphisms (Arg51Gln and Leu72Met) in alcohol-dependent individuals. Study 1 showed no significant differences in ghrelin levels in the whole sample, while there was a statistical difference for ghrelin between non-abstinent and abstinent subjects. Baseline ghrelin levels were significantly and positively correlated with the PACS score at T1 and with all craving scores both at T2 and T3 (PACS, OCDS, obsessive and compulsive OCDS subscores). In Study 2, although there was a higher frequency of the Leu72Met ghrelin gene polymorphism in alcohol-dependent individuals, the distribution between healthy controls and alcohol dependent individuals was not statistically significant. This investigation suggests that ghrelin is potentially able to affect alcohol-seeking behaviors, such as alcohol drinking and craving, representing a new potential neuropharmacological target for AD. PMID:21392177

UPDATE ON NEUROPHARMACOLOGICAL TREATMENTS FOR ALCOHOLISM: SCIENTIFIC BASIS AND CLINICAL FINDINGS

PubMed Central

JOHNSON, BANKOLE A.

2008-01-01

The past decade has seen an expansion of research and knowledge on pharmacotherapy for the treatment of alcohol dependence. The Food and Drug Administration (FDA)–approved medications naltrexone and acamprosate have shown mixed results in clinical trials. Oral naltrexone and naltrexone depot formulations have generally demonstrated efficacy at treating alcohol dependence, but their treatment effect size is small, and more research is needed to compare the effects of different doses on drinking outcome. Acamprosate has demonstrated efficacy for treating alcohol dependence in European trials, but with a small effect size. In U.S. trials, acamprosate has not proved to be efficacious. Research continues to explore which types of alcohol-dependent individual would benefit the most from treatment with naltrexone or acamprosate. The combination of the two medications demonstrated efficacy for treating alcohol dependence in one European study but not in a multi-site U.S. study. Another FDA-approved medication, disulfiram, is an aversive agent that does not diminish craving for alcohol. Disulfiram is most effective when given to those who are highly compliant or who are receiving their medication under supervision. Of the non-approved medications, topiramate is among the most promising, with a medium effect size in clinical trials. Another promising medication, baclofen, has shown efficacy in small trials. Serotonergic agents such as selective serotonin reuptake inhibitors and the serotonin-3 receptor antagonist, ondansetron, appear to be efficacious only among certain genetic subtypes of alcoholic. As neuroscientific research progresses, other promising medications, as well as medication combinations, for treating alcohol dependence continue to be explored. PMID:17880925

Acute Tryptophan Depletion Increases Translational Indices of Anxiety but not Fear: Serotonergic Modulation of the Bed Nucleus of the Stria Terminalis?

PubMed Central

Robinson, Oliver J; Overstreet, Cassie; Allen, Phillip S; Pine, Daniel S; Grillon, Christian

2012-01-01

Serotonin is strongly implicated in the mammalian stress response, but surprisingly little is known about its mode of action. Recent data suggest that serotonin can inhibit aversive responding in humans, but this remains underspecified. In particular, data in rodents suggest that global serotonin depletion may specifically increase long-duration bed nucleus of the stria terminalis (BNST)-mediated aversive responses (ie, anxiety), but not short-duration BNST-independent responses (ie, fear). Here, we extend these findings to humans. In a balanced, placebo-controlled crossover design, healthy volunteers (n=20) received a controlled diet with and without the serotonin precursor tryptophan (acute tryptophan depletion; ATD). Aversive states were indexed by translational acoustic startle measures. Fear and anxiety were operationally defined as the increase in startle reactivity during short- and long-duration threat periods evoked by predictable shock (fear-potentiated startle) and by the context in which the shocks were administered (anxiety-potentiated startle), respectively. ATD significantly increased long-duration anxiety-potentiated startle but had no effect on short-duration fear-potentiated startle. These results suggest that serotonin depletion in humans selectively increases anxiety but not fear. Current translational frameworks support the proposition that ATD thus disinhibits dorsal raphé-originating serotonergic control of corticotropin-releasing hormone-mediated excitation of the BNST. This generates a candidate neuropharmacological mechanism by which depleted serotonin may increase response to sustained threats, alongside clear implications for our understanding of the manifestation and treatment of mood and anxiety disorders. PMID:22491355

Longitudinal muscle dysfunction in achalasia esophagus and its relevance.

PubMed

Mittal, Ravinder K; Hong, Su Jin; Bhargava, Valmik

2013-04-01

Muscularis propria of the esophagus is organized into circular and longitudinal muscle layers. Goal of this review is to summarize the role of longitudinal muscle in physiology and pathophysiology of esophageal sensory and motor function. Simultaneous manometry and ultrasound imaging that measure circular and longitudinal muscle contraction respectively reveal that during peristalsis 2 layers of the esophagus contract in perfect synchrony. On the other hand, during transient relaxation of the lower esophageal sphincter (LES), longitudinal muscle contracts independently of circular muscle. Recent studies provide novel insights, i.e., longitudinal muscle contraction of the esophagus induces LES relaxation and possibly descending relaxation of the esophagus. In achalasia esophagus and other motility disorders there is discoordination between the 2 muscle layers. Longitudinal muscle contraction patterns are different in the recently described three types of achalasia identified by high-resolution manometry. Robust contraction of the longitudinal muscle in type II achalasia causes pan-esophageal pressurization and is the mechanism of whatever little esophageal emptying that take place in the absence of peristalsis and impaired LES relaxation. It may be that preserved longitudinal muscle contraction is also the reason for superior outcome to medical/surgical therapy in type II achalasia esophagus. Prolonged contractions of longitudinal muscles of the esophagus is a possible mechanism of heartburn and "angina like" pain seen in esophageal motility disorders and possibly achalasia esophagus. Novel techniques to record longitudinal muscle contraction are on the horizon. Neuro-pharmacologic control of circular and longitudinal muscles is different, which provides an important opportunity for the development of novel pharmacological therapies to treat sensory and motor disorders of the esophagus.

Longitudinal Muscle Dysfunction in Achalasia Esophagus and Its Relevance

PubMed Central

Hong, Su Jin; Bhargava, Valmik

2013-01-01

Muscularis propria of the esophagus is organized into circular and longitudinal muscle layers. Goal of this review is to summarize the role of longitudinal muscle in physiology and pathophysiology of esophageal sensory and motor function. Simultaneous manometry and ultrasound imaging that measure circular and longitudinal muscle contraction respectively reveal that during peristalsis 2 layers of the esophagus contract in perfect synchrony. On the other hand, during transient relaxation of the lower esophageal sphincter (LES), longitudinal muscle contracts independently of circular muscle. Recent studies provide novel insights, i.e., longitudinal muscle contraction of the esophagus induces LES relaxation and possibly descending relaxation of the esophagus. In achalasia esophagus and other motility disorders there is discoordination between the 2 muscle layers. Longitudinal muscle contraction patterns are different in the recently described three types of achalasia identified by high-resolution manometry. Robust contraction of the longitudinal muscle in type II achalasia causes pan-esophageal pressurization and is the mechanism of whatever little esophageal emptying that take place in the absence of peristalsis and impaired LES relaxation. It may be that preserved longitudinal muscle contraction is also the reason for superior outcome to medical/surgical therapy in type II achalasia esophagus. Prolonged contractions of longitudinal muscles of the esophagus is a possible mechanism of heartburn and "angina like" pain seen in esophageal motility disorders and possibly achalasia esophagus. Novel techniques to record longitudinal muscle contraction are on the horizon. Neuro-pharmacologic control of circular and longitudinal muscles is different, which provides an important opportunity for the development of novel pharmacological therapies to treat sensory and motor disorders of the esophagus. PMID:23667744

Levamisole enhances the rewarding and locomotor-activating effects of cocaine in rats.

PubMed

Tallarida, Christopher S; Tallarida, Ronald J; Rawls, Scott M

2015-04-01

The Drug Enforcement Agency estimates that 80% of cocaine seized in the United States contains the veterinary pharmaceutical levamisole (LVM). One problem with LVM is that it is producing life-threatening neutropenia in an alarming number of cocaine abusers. The neuropharmacological profile of LVM is also suggestive of an agent with modest reinforcing and stimulant effects that could enhance cocaine's addictive effects. We tested the hypothesis that LVM (ip) enhances the rewarding and locomotor stimulant effects of cocaine (ip) using rat conditioned place preference (CPP) and locomotor assays. Effects of LVM by itself were also tested. LVM (0-10 mg/kg) produced CPP at 1mg/kg (P<0.05) and locomotor activation at 5mg/kg (P < 0.05). For CPP combination experiments, a statistically inactive dose of LVM (0.1 mg/kg) was administered with a low dose of cocaine (2.5 mg/kg). Neither agent produced CPP compared to saline (P > 0.05); however, the combination of LVM and cocaine produced enhanced CPP compared to saline or either drug by itself (P < 0.01). For locomotor experiments, the same inactive dose of LVM (0.1mg/kg, ip) was administered with low (10 mg/kg) and high doses (30 mg/kg) of cocaine. LVM (0.1 mg/kg) enhanced locomotor activation produced by 10mg/kg of cocaine (P < 0.05) but not by 30 mg/kg (P>0.05). LVM can enhance rewarding and locomotor-activating effects of low doses of cocaine in rats while possessing modest activity of its own. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Nanopsychiatry--the potential role of nanotechnologies in the future of psychiatry: a systematic review.

PubMed

Fond, G; Macgregor, A; Miot, S

2013-09-01

Nanomedicine is defined as the area using nanotechnology's concepts for the benefit of human beings' health and well being. In this article, we aimed to provide an overview of areas where nanotechnology is applied and how they could be extended to care for psychiatric illnesses. The main applications of nanotechnology in psychiatry are (i) pharmacology. There are two main difficulties in neuropharmacology: drugs have to pass the blood-brain barrier and then to be internalized by targeted cells. Nanoparticles could increase drugs bioavailability and pharmacokinetics, especially improving safety and efficacy of psychotropic drugs. Liposomes, nanosomes, nanoparticle polymers, nanobubbles are some examples of this targeted drug delivery. Nanotechnologies could also add new pharmacological properties, like nanoshells and dendrimers (ii) living analysis. Nanotechnology provides technical assistance to in vivo imaging or metabolome analysis (iii) central nervous system modeling. Research teams have succeeded to modelize inorganic synapses and mimick synaptic behavior, a step essential for further creation of artificial neural systems. Some nanoparticle assemblies present the same small worlds and free-scale networks architecture as cortical neural networks. Nanotechnologies and quantum physics could be used to create models of artificial intelligence and mental illnesses. We are not about to see a concrete application of nanomedicine in daily psychiatric practice. Even if nanotechnologies are promising, their safety is still inconsistent and this must be kept in mind. However, it seems essential that psychiatrists do not forsake this area of research the perspectives of which could be decisive in the field of mental illness. Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.

Treating nausea and vomiting in palliative care: a review

PubMed Central

Glare, Paul; Miller, Jeanna; Nikolova, Tanya; Tickoo, Roma

2011-01-01

Nausea and vomiting are portrayed in the specialist palliative care literature as common and distressing symptoms affecting the majority of patients with advanced cancer and other life-limiting illnesses. However, recent surveys indicate that these symptoms may be less common and bothersome than has previously been reported. The standard palliative care approach to the assessment and treatment of nausea and vomiting is based on determining the cause and then relating this back to the “emetic pathway” before prescribing drugs such as dopamine antagonists, antihistamines, and anticholinergic agents which block neurotransmitters at different sites along the pathway. However, the evidence base for the effectiveness of this approach is meager, and may be in part because relevance of the neuropharmacology of the emetic pathway to palliative care patients is limited. Many palliative care patients are over the age of 65 years, making these agents difficult to use. Greater awareness of drug interactions and QTc prolongation are emerging concerns for all age groups. The selective serotonin receptor antagonists are the safest antiemetics, but are not used first-line in many countries because there is very little scientific rationale or clinical evidence to support their use outside the licensed indications. Cannabinoids may have an increasing role. Advances in interventional gastroenterology are increasing the options for nonpharmacological management. Despite these emerging issues, the approach to nausea and vomiting developed within palliative medicine over the past 40 years remains relevant. It advocates careful clinical evaluation of the symptom and the person suffering it, and an understanding of the clinical pharmacology of medicines that are available for palliating them. PMID:21966219

α-Iso-cubebene exerts neuroprotective effects in amyloid beta stimulated microglia activation.

PubMed

Park, Sun Young; Park, Se Jin; Park, Nan Jeong; Joo, Woo Hong; Lee, Sang-Joon; Choi, Young-Whan

2013-10-25

Schisandra chinensis is commonly used for food and as a traditional remedy for the treatment of neuronal disorders. However, it is unclear which component of S. chinensis is responsible for its neuropharmacological effects. To answer this question, we isolated α-iso-cubebene, a dibenzocyclooctadiene lignin, from S. chinensis and determined if it has any anti-neuroinflammatory and neuroprotective properties against amyloid β-induced neuroinflammation in microglia. Microglia that are stimulated by amyloid β increased their production of pro-inflammatory cytokines and chemokines, prostaglandin E2 (PGE2), nitric oxide (NO) and reactive oxygen species (ROS) and the enzymatic activity of matrix metalloproteinase 9 (MMP-9). We found this was all inhibited by α-iso-cubebene. Consistent with these results, α-iso-cubebene inhibited the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2) and MMP-9 in amyloid β-stimulated microglia. Subsequent mechanistic studies revealed that α-iso-cubebene inhibited the phosphorylation and degradation of IκB-α, the phosphorylation and transactivity of NF-κB, and the phosphorylation of MAPK in amyloid β-stimulated microglia. These results suggest that α-iso-cubebene impairs the amyloid β-induced neuroinflammatory response of microglia by inhibiting the NF-κB and MAPK signaling pathways. Importantly, α-iso-cubebene can provide critical neuroprotection for primary cortical neurons against amyloid β-stimulated microglia-mediated neurotoxicity. To the best of our knowledge, this is the first report showing that α-iso-cubebene can provide neuroprotection against, and influence neuroinflammation triggered by, amyloid β activation of microglia. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Anxiolytic-like effects of ursolic acid in mice.

PubMed

Colla, André R S; Rosa, Julia M; Cunha, Mauricio P; Rodrigues, Ana Lúcia S

2015-07-05

Ursolic acid is a pentacyclic triterpenoid that possesses several biological and neuropharmacological effects including antidepressant-like activity. Anxiety disorders represent common and disability psychiatric conditions that are often associated with depressive symptoms. This work investigated the anxiolytic-like effects of ursolic acid administration in different behavioral paradigms that evaluate anxiety in mice: open field test, elevated plus maze test, light/dark box test and marble burying test. To this end, mice were administered with ursolic acid (0.1, 1 and 10mg/kg, p.o.) or diazepam (2mg/kg, p.o.), positive control, and submitted to the behavioral tests. The results show that ursolic acid (10mg/kg) elicited an anxiolytic-like effect observed by the increased total time in the center and decreased number of rearings responses in the open field test and an increased percentage of entries and total time spent in the open arms of elevated plus maze, similarly to diazepam. No significant effects of ursolic acid were shown in the light/dark box and marble burying test. These data indicate that ursolic acid exhibits anxiolytic-like effects in the open field and elevated plus maze test, but not in the light/dark box and marble burying test, showing the relevance of testing several behavioral paradigms in the evaluation of anxiolytic-like actions. Of note, the results extend the understanding on the effects of ursolic acid in the central nervous system and suggest that it may be a novel approach for the management of anxiety-related disorders. Copyright © 2015. Published by Elsevier B.V.

Ageing in people with autistic spectrum disorder.

PubMed

Mukaetova-Ladinska, E B; Perry, E; Baron, M; Povey, C

2012-02-01

Although autism in children and in adults attracts attention with respect to clinical and research needs, autism in the older individuals has not been considered to any degree. We review the evidence for urgently addressing the question of ageing in people with autistic spectrum disorder (ASD), focusing on those with disability. Perspectives are reviewed in relation to demographics, experiences of relatives or carers, anticipated residential care needs, requirement for specifically designed cognitive assessment tools and importance of initiating new brain ageing research initiatives in this area. With escalating numbers of ASD individuals with disability reaching old age, provision of care is the paramount issue that is only beginning to be addressed in a few European communities and in the USA. How ageing affects cognition in such individuals as they reach an age no longer consistent with parental care is unknown, lacking any published evidence, and there is a clear need to design cognitive and behavioural assessment tools appropriate to ageing in ASD individuals with disability, as was the case with respect to dementia as a whole. Although there is a growing body of evidence on pathological, imaging, neuropharmacological and other key brain abnormalities in ASD, these are, to date, confined to children and young (only rarely to middle aged) adults. The need for new initiatives in research into ageing in ASD is urgent. Apart from a growing care crisis, the prospect of understanding brain ageing in this population may bring potential rewards beyond immediate clinical need given the precedent of Down syndrome. Copyright © 2011 John Wiley & Sons, Ltd.

A portable microelectrode array recording system incorporating cultured neuronal networks for neurotoxin detection.

PubMed

Pancrazio, Joseph J; Gray, Samuel A; Shubin, Yura S; Kulagina, Nadezhda; Cuttino, David S; Shaffer, Kara M; Eisemann, Kevin; Curran, Anthony; Zim, Bret; Gross, Guenter W; O'Shaughnessy, Thomas J

2003-10-01

Cultured neuronal networks, which have the capacity to respond to a wide range of neuroactive compounds, have been suggested to be useful for both screening known analytes and unknown compounds for acute neuropharmacologic effects. Extracellular recording from cultured neuronal networks provides a means for extracting physiologically relevant activity, i.e. action potential firing, in a noninvasive manner conducive for long-term measurements. Previous work from our laboratory described prototype portable systems capable of high signal-to-noise extracellular recordings from cardiac myocytes. The present work describes a portable system tailored to monitoring neuronal extracellular potentials that readily incorporates standardized microelectrode arrays developed by and in use at the University of North Texas. This system utilizes low noise amplifier and filter boards, a two-stage thermal control system with integrated fluidics and a graphical user interface for data acquisition and control implemented on a personal computer. Wherever possible, off-the-shelf components have been utilized for system design and fabrication. During use with cultured neuronal networks, the system typically exhibits input referred noise levels of only 4-6 microVRMS, such that extracellular potentials exceeding 40 microV can be readily resolved. A flow rate of up to 1 ml/min was achieved while the cell recording chamber temperature was maintained within a range of 36-37 degrees C. To demonstrate the capability of this system to resolve small extracellular potentials, pharmacological experiments with cultured neuronal networks have been performed using ion channel blockers, tetrodotoxin and tityustoxin. The implications of the experiments for neurotoxin detection are discussed.

An automatic recording system for the study of escape from fear in rats.

PubMed

Li, Ming; He, Wei

2013-11-01

Escape from fear (EFF) is an active response to a conditioned stimulus (CS) previously paired with an unconditioned fearful stimulus (US), which typically leads to the termination of the CS. In this paradigm, animals acquire two distinct associations: S-S [CS-US] and R-O [response-outcome] through Pavlovian and instrumental conditioning, respectively. The present study describes a computer controlled automatic recording system that captures the development of EFF and allows the determination of the respective roles of S-S and R-O associations in this process. We validated this system by showing that only rats subjected to a simultaneous CS-US conditioning (i.e., CS and US occur together at the beginning of each trial) acquired EFF, not those subjected to an unpaired CS-US conditioning. Paired rats had a progressively increased number of EFF and significantly shorter escape latencies than unpaired rats across the 5-trial blocks on the test day. However, during the conditioning phase, the unpaired rats emitted more 22kHz ultrasonic vocalizations, a validated measure of conditioned reactive fear responses. Our results demonstrate that the acquisition of EFF is contingent upon pairing of the CS with the US, not simply the consequence of a high level of generalized fear. Because this commercially available system is capable of examining both conditioned active and reactive fear responses in a single setup, it could be used to determine the relative roles of S-S and R-O associations in EFF, the neurobiology of conditioned active fear response and neuropharmacology of psychotherapeutic drugs. Copyright © 2013 Elsevier B.V. All rights reserved.

Translational neuropharmacology: the use of human isolated gastrointestinal tissues.

PubMed

Sanger, G J; Broad, J; Kung, V; Knowles, C H

2013-01-01

Translational sciences increasingly emphasize the measurement of functions in native human tissues. However, such studies must confront variations in patient age, gender, genetic background and disease. Here, these are discussed with reference to neuromuscular and neurosecretory functions of the human gastrointestinal (GI) tract. Tissues are obtained after informed consent, in collaboration with surgeons (surgical techniques help minimize variables) and pathologists. Given the difficulties of directly recording from human myenteric neurones (embedded between muscle layers), enteric motor nerve functions are studied by measuring muscle contractions/relaxations evoked by electrical stimulation of intrinsic nerves; responses are regionally dependent, often involving cholinergic and nitrergic phenotypes. Enteric sensory functions can be studied by evoking the peristaltic reflex, involving enteric sensory and motor nerves, but this has rarely been achieved. As submucosal neurones are more accessible (after removing the mucosa), direct neuronal recordings are possible. Neurosecretory functions are studied by measuring changes in short-circuit current across the mucosa. For all experiments, basic questions must be addressed. Because tissues are from patients, what are the controls and the influence of disease? How long does it take before function fully recovers? What is the impact of age- and gender-related differences? What is the optimal sample size? Addressing these and other questions minimizes variability and raises the scientific credibility of human tissue research. Such studies also reduce animal use. Further, the many differences between animal and human GI functions also means that human tissue research must question the ethical validity of using strains of animals with unproved translational significance. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

From basic to clinical neuropharmacology: targetophilia or pharmacodynamics?

PubMed

Green, A Richard; Aronson, Jeffrey K

2012-06-01

Historically, much drug discovery and development in psychopharmacology tended to be empirical. However, over the last 20 years it has primarily been target oriented, with synthesis and selection of compounds designed to act at a specific neurochemical site. Such compounds are then examined in functional animal models of disease. There is little evidence that this approach (which we call 'targetophilia') has enhanced the discovery process and some indications that it may have retarded it. A major problem is the weakness of many animal models in mimicking the disease and the lack of appropriate biochemical markers of drug action in animals and patients. In this review we argue that preclinical studies should be conducted as if they were clinical studies in design, analysis, and reporting, and that clinical pharmacologists should be involved at the earliest stages, to help ensure that animal models reflect as closely as possible the clinical disease. In addition, their familiarity with pharmacokinetic-pharmacodynamic integration (PK-PD) would help ensure that appropriate dosing and drug measurement techniques are applied to the discovery process, thereby producing results with relevance to therapeutics. Better integration of experimental and clinical pharmacologists early in the discovery process would allow observations in animals and patients to be quickly exchanged between the two disciplines. This non-linear approach to discovery used to be the way research proceeded, and it resulted in productivity that has never been bettered. It also follows that occasionally 'look-see' studies, a proven technique for drug discovery, deserve to be reintroduced. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

The neuropharmacology of ADHD drugs in vivo: insights on efficacy and safety.

PubMed

Heal, D J; Cheetham, S C; Smith, S L

2009-12-01

Results from in vivo techniques, especially intracerebral microdialysis in freely-moving rats, have provided insights into potential mechanisms responsible for the efficacy and safety of catecholaminergic drugs for ADHD treatment. The drugs reviewed come from distinct pharmacological classes: psychostimulant releasing agents, eg d-amphetamine; psychostimulant reuptake inhibitors, eg dl-threo-methylphenidate (dl-MPH), and non-stimulant reuptake inhibitors, eg atomoxetine. Psychostimulants, which currently deliver the best efficacy in treating ADHD, exhibit the following characteristics on extraneuronal catecholamine concentrations in rodent brain in vivo: 1) They enhance the efflux and function of both noradrenaline and dopamine in the central nervous system. 2) The increase of dopamine efflux that they produce is not limited to cortical regions. 3) They have a rapid onset of action with no ceiling on drug effect. d-Amphetamine has a mechanism independent of neuronal firing rate, displacing intraneuronal stores of catecholamines, delaying their reuptake and inhibiting catabolism by monoamine oxidase. dl-MPH has an enigmatic, extraneuronal action that is neuronal firing rate-dependent and reuptake transporter-mediated, yet paradoxically, almost as powerful as that of d-amphetamine. In safety terms, these powerful catecholaminergic effects also make the psychostimulants liable for abuse. Since efficacy and safety derive from the same pharmacological mechanisms, it has not yet been possible to separate these two components. However, the development of once-daily psychostimulant formulations and a prodrug, lisdexamfetamine, has improved patient compliance and markedly reduced scope for their diversion/abuse. This review will discuss the in vivo pharmacological profiles of approved catecholaminergic drugs for treatment of ADHD and implications for their clinical efficacy and abuse liability.

The medicinal chemistry and neuropharmacology of kratom: A preliminary discussion of a promising medicinal plant and analysis of its potential for abuse.

PubMed

Kruegel, Andrew C; Grundmann, Oliver

2017-08-19

The leaves of Mitragyna speciosa (commonly known as kratom), a tree endogenous to parts of Southeast Asia, have been used traditionally for their stimulant, mood-elevating, and analgesic effects and have recently attracted significant attention due to increased use in Western cultures as an alternative medicine. The plant's active alkaloid constituents, mitragynine and 7-hydroxymitragynine, have been shown to modulate opioid receptors, acting as partial agonists at mu-opioid receptors and competitive antagonists at kappa- and delta-opioid receptors. Furthermore, both alkaloids are G protein-biased agonists of the mu-opioid receptor and therefore, may induce less respiratory depression than classical opioid agonists. The Mitragyna alkaloids also appear to exert diverse activities at other brain receptors (including adrenergic, serotonergic, and dopaminergic receptors), which may explain the complex pharmacological profile of raw kratom extracts, although characterization of effects at these other targets remains extremely limited. Through allometric scaling, doses of pure mitragynine and 7-hydroxymitragynine used in animal studies can be related to single doses of raw kratom plant commonly consumed by humans, permitting preliminary interpretation of expected behavioral and physiological effects in man based on this preclinical data and comparison to both anecdotal human experience and multiple epidemiological surveys. Kratom exposure alone has not been causally associated with human fatalities to date. However, further research is needed to clarify the complex mechanism of action of the Mitragyna alkaloids and unlock their full therapeutic potential. Copyright © 2017 Elsevier Ltd. All rights reserved.

Ghrelin system in alcohol-dependent subjects: role of plasma ghrelin levels in alcohol drinking and craving.

PubMed

Leggio, Lorenzo; Ferrulli, Anna; Cardone, Silvia; Nesci, Antonio; Miceli, Antonio; Malandrino, Noemi; Capristo, Esmeralda; Canestrelli, Benedetta; Monteleone, Palmiero; Kenna, George A; Swift, Robert M; Addolorato, Giovanni

2012-03-01

Animal studies suggest that the gut-brain peptide ghrelin plays an important role in the neurobiology of alcohol dependence (AD). Human studies show an effect of alcohol on ghrelin levels and a correlation between ghrelin levels and alcohol craving in alcoholics. This investigation consisted of two studies. Study 1 was a 12-week study with alcohol-dependent subjects, where plasma ghrelin determinations were assessed four times (T0-T3) and related to alcohol intake and craving [Penn Alcohol Craving Score (PACS) and Obsessive Compulsive Drinking Scale (OCDS)]. Serum growth hormone levels and assessment of the nutritional/metabolic status were also performed. Study 2 was a pilot case-control study to assess ghrelin gene polymorphisms (Arg51Gln and Leu72Met) in alcohol-dependent individuals. Study 1 showed no significant differences in ghrelin levels in the whole sample, while there was a statistical difference for ghrelin between non-abstinent and abstinent subjects. Baseline ghrelin levels were significantly and positively correlated with the PACS score at T1 and with all craving scores both at T2 and T3 (PACS, OCDS, obsessive and compulsive OCDS subscores). In Study 2, although there was a higher frequency of the Leu72Met ghrelin gene polymorphism in alcohol-dependent individuals, the distribution between healthy controls and alcohol dependent individuals was not statistically significant. This investigation suggests that ghrelin is potentially able to affect alcohol-seeking behaviors, such as alcohol drinking and craving, representing a new potential neuropharmacological target for AD. © 2011 The Authors, Addiction Biology © 2011 Society for the Study of Addiction.

Psychoactive Substances Bill and Act of New Zealand: A Chance to Engage Undergraduate Scientists with Society using a Transfer Learning Paradigm.

PubMed

Gliddon, Catherine M; Cridge, Belinda

2015-01-01

Our aim was to develop a teaching paradigm that connected undergraduate's neuropharmacological/toxicological knowledge to that of government policy. One goal of undergraduate education should be to help develop scientists that can use their scientific knowledge to critique government policy. There is little research, however, on whether democratization of science occurs: nor how to achieve this. Our work focused on a semi-structured workshop designed around the Psychoactive Substances Bill (PSB). Third year science students were given a questionnaire that was designed to address whether participating in the workshop enhanced their understanding of the PSB and its relationship to their established knowledge (i.e., transfer learning). Furthermore, whether they felt that they had enough expertise to consider making a submission (i.e., societal engagement). Results showed that the students appreciated the opportunity to explore potential application of their knowledge and delve into a socio-scientific issue. However, our findings suggested they felt uncomfortable discussing their ideas outside the classroom: nor, did they identify themselves as having sufficient knowledge to contribute to a submission. In conclusion, this study highlights two points. First, that discussion based transfer learning can be used in the tertiary sector and students value the opportunity to apply their knowledge to socio-scientific issue. Second, if social participation and democratization of science is a goal, then more emphasis should be placed on how students can realistically and confidently apply their learning to change social policy. In order to achieve this, education programs need to focus on legitimate real-life processes such as the PSB for engagement.

The mouse cerebellar cortex in organotypic slice cultures: an in vitro model to analyze the consequences of mutations and pathologies on neuronal survival, development, and function.

PubMed

Lonchamp, Etienne; Dupont, Jean-Luc; Beekenkamp, Huguette; Poulain, Bernard; Bossu, Jean-Louis

2006-01-01

Thin acute slices and dissociated cell cultures taken from different parts of the brain have been widely used to examine the function of the nervous system, neuron-specific interactions, and neuronal development (specifically, neurobiology, neuropharmacology, and neurotoxicology studies). Here, we focus on an alternative in vitro model: brain-slice cultures in roller tubes, initially introduced by Beat Gähwiler for studies with rats, that we have recently adapted for studies of mouse cerebellum. Cultured cerebellar slices afford many of the advantages of dissociated cultures of neurons and thin acute slices. Organotypic slice cultures were established from newborn or 10-15-day-old mice. After 3-4 weeks in culture, the slices flattened to form a cell monolayer. The main types of cerebellar neurons could be identified with immunostaining techniques, while their electrophysiological properties could be easily characterized with the patch-clamp recording technique. When slices were taken from newborn mice and cultured for 3 weeks, aspects of the cerebellar development were displayed. A functional neuronal network was established despite the absence of mossy and climbing fibers, which are the two excitatory afferent projections to the cerebellum. When slices were made from 10-15-day-old mice, which are at a developmental stage when cerebellum organization is almost established, the structure and neuronal pathways were intact after 3-4 weeks in culture. These unique characteristics make organotypic slice cultures of mouse cerebellar cortex a valuable model for analyzing the consequences of gene mutations that profoundly alter neuronal function and compromise postnatal survival.

Dopamine precursor depletion impairs structure and efficiency of resting state brain functional networks.

PubMed

Carbonell, Felix; Nagano-Saito, Atsuko; Leyton, Marco; Cisek, Paul; Benkelfat, Chawki; He, Yong; Dagher, Alain

2014-09-01

Spatial patterns of functional connectivity derived from resting brain activity may be used to elucidate the topological properties of brain networks. Such networks are amenable to study using graph theory, which shows that they possess small world properties and can be used to differentiate healthy subjects and patient populations. Of particular interest is the possibility that some of these differences are related to alterations in the dopamine system. To investigate the role of dopamine in the topological organization of brain networks at rest, we tested the effects of reducing dopamine synthesis in 13 healthy subjects undergoing functional magnetic resonance imaging. All subjects were scanned twice, in a resting state, following ingestion of one of two amino acid drinks in a randomized, double-blind manner. One drink was a nutritionally balanced amino acid mixture, and the other was tyrosine and phenylalanine deficient. Functional connectivity between 90 cortical and subcortical regions was estimated for each individual subject under each dopaminergic condition. The lowered dopamine state caused the following network changes: reduced global and local efficiency of the whole brain network, reduced regional efficiency in limbic areas, reduced modularity of brain networks, and greater connection between the normally anti-correlated task-positive and default-mode networks. We conclude that dopamine plays a role in maintaining the efficient small-world properties and high modularity of functional brain networks, and in segregating the task-positive and default-mode networks. This article is part of the Special Issue Section entitled 'Neuroimaging in Neuropharmacology'. Copyright © 2014 Elsevier Ltd. All rights reserved.

Piracetam attenuates binge eating disorder related symptoms in rats.

PubMed

Hussain, Yusuf; Krishnamurthy, Sairam

2018-06-01

Binge eating disorder (BED) is a stress-related disorder characterized by acute episodes of excessive food intake. Piracetam, a nootropic agent has been reported to show several other neuropharmacological properties. The present study, evaluated the pharmacological effect of piracetam (200 mg/kg i.p.) on BED in female rats, induced by free access to palatable cookies for 2 h on alternate days. BED was confirmed by an increase in binge eating behavior and weight gain. BED leads to anxiety, cognitive and memory deficits, as evaluated by EPM (Elevated plus maze), OFT (open field test), and Y-maze tests. Increased levels of plasma corticosterone (CORT), glutamate in nucleus accumbens (NAC), hypothalamus (HYP) and prefrontal cortex (PFC) indicate stress and excitotoxicity. Moreover, it was observed that the levels of dopamine were higher in NAC and PFC, and less in HYP which may be responsible for motivational behavior for palatable feeding and cognitive deficits. More surprisingly, feeding behaviour regulating hormones namelyleptin was increased and ghrelin level was decreased in BED. Further, level of acetylcholine which regulates cognitive behaviour was compromised in BED. Piracetam significantly decreased binge eating behavior and associated body weight and regulated the levels of concerned neurotransmitters in respective regions. However, piracetam did not alter normal feeding behavior in the fast-refed model. Further, piracetam showed brain region-specific decrease in vascular endothelial growth factor expression. Piracetam showed anxiolytic activity and also alleviated cognitive deficit observed in BED. Hence, preclinical evidence indicates the potential use of piracetam for the treatment of BED. Copyright © 2018 Elsevier Inc. All rights reserved.

Pharmacodynamic and pharmacokinetic studies of agmatine after spinal administration in the mouse.

PubMed

Roberts, John C; Grocholski, Brent M; Kitto, Kelley F; Fairbanks, Carolyn A

2005-09-01

Agmatine is an endogenous decarboxylation product of arginine that has been previously shown to antagonize the N-methyl-d-aspartate (NMDA) receptor and inhibit nitric-oxide synthase. Many neuropharmacological studies have shown that exogenous administration of agmatine prevents or reverses biological phenomena dependent on central nervous system glutamatergic systems, including opioid-induced tolerance, opioid self-administration, and chronic pain. However, the central nervous system (CNS) pharmacokinetic profile of agmatine remains minimally defined. The present study determined the spinal cord pharmacokinetics and acute pharmacodynamics of intrathecally administered agmatine in mice. After a single bolus intrathecal injection, agmatine concentrations in spinal cord (cervical, thoracic, and lumbosacral) tissue and serum were quantified by an isocratic high-performance liquid chromatography fluorescence detection system. Agmatine persisted at near maximum concentrations in all levels of the spinal cord for several hours with a half-life of approximately 12 h. Initial agmatine concentrations in serum were 10% those in CNS. However, the serum half-life was less than 10 min after intrathecal injection of agmatine, consistent with previous preliminary pharmacokinetic reports of systemically administered agmatine. The pharmacodynamic response to agmatine in the NMDA-nociceptive behavior and thermal hyperalgesia tests was assessed. Whereas MK-801 (dizocilpine maleate) inhibits these two responses with equal potency, agmatine inhibits the thermal hyperalgesia with significantly increased potency compared with the nociceptive behavior, suggesting two sites of action. In contrast to the pharmacokinetic results, the agmatine inhibition of both behaviors had a duration of only 10 to 30 min. Collectively, these results suggest the existence of a currently undefined agmatinergic extracellular clearance process in spinal cord.

Banking for the future: an Australian experience in brain banking.

PubMed

Sarris, M; Garrick, T M; Sheedy, D; Harper, C G

2002-06-01

The New South Wales (NSW) Tissue Resource Centre (TRC) has been set up to provide Australian and international researchers with fixed and frozen brain tissue from cases that are well characterised, both clinically and pathologically, for projects related to neuropsychiatric and alcohol-related disorders. A daily review of the Department of Forensic Medicine provides initial information regarding a potential collection. If the case adheres to the strict inclusion criteria, the pathologist performing the postmortem examination is approached regarding retention of the brain tissue. The next of kin of the deceased is then contacted requesting permission to retain the brain for medical research. Cases are also obtained through donor programmes, where donors are assessed and consent to donate their brain during life. Once the brain is removed at autopsy, the brain is photographed, weighed and the volume determined, the brainstem and cerebellum are removed. The two hemispheres are divided, one hemisphere is fresh frozen and one fixed (randomised). Prior to freezing, the hemisphere is sliced into 1-cm coronal slices and a set of critical area blocks is taken. All frozen tissues are kept bagged at -80 degrees C. The other hemisphere is fixed in 15% buffered formalin for 2 weeks, embedded in agar and sliced at 3-mm intervals in the coronal plane. Tissue blocks from these slices are used for neuropathological analysis to exclude any other pathology. The TRC currently has 230 cases of both fixed and frozen material that has proven useful in a range of techniques in many research projects. These techniques include quantitative analyses of brain regions using neuropathological, neurochemical, neuropharmacological and gene expression assays.

Central nervous system effects and chemical composition of two subspecies of Agastache mexicana; an ethnomedicine of Mexico.

PubMed

Estrada-Reyes, Rosa; López-Rubalcava, C; Ferreyra-Cruz, Octavio Alberto; Dorantes-Barrón, Ana María; Heinze, G; Moreno Aguilar, Julia; Martínez-Vázquez, Mariano

2014-04-11

Agastache mexicana subspecies mexicana (Amm) and xolocotziana (Amx) are used in Mexican traditional medicine to relief cultural affiliation syndromes known as "susto" or "espanto", for "nervous" condition, and as a sleep aid. Despite its intensive use, neuropharmacological studies are scarce, and the chemical composition of the aqueous extracts has not been described. Aims of the study are: (1) To analyze the chemical composition of aqueous extracts from aerial parts of Amm and Amx. (2) To evaluate the anxiolytic-like, sedative, antidepressant-like effects. (3) Analyze the general toxic effects of different doses. Anxiolytic-like and sedative effects were measured in the avoidance exploratory behavior, burying behavior and the hole-board tests. The antidepressant-like actions were studied in the forced swimming and tail suspension tests. Finally, general activity and motor coordination disturbances were evaluated in the open field, inverted screen and rota-rod tests. The acute toxicity of Amm and Amx was determined by calculating their LD50 (mean lethal dose). The chemical analyses were performed employing chromatographic, photometric and HPLC-ESI-MS techniques. Low doses of Amm and Amx (0.1σ1.0mg/kg) induced anxiolytic-like actions; while higher doses (over 10mg/kg) induced sedation and reduced the locomotor activity, exerting a general inhibition in the central nervous system (CNS). Results support the use of Amm and Amx in traditional medicine as tranquilizers and sleep inducers. Additionally, this paper contributes to the knowledge of the chemical composition of the aqueous extracts of these plants. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

The utility of animal models to evaluate novel anti-obesity agents

PubMed Central

Vickers, Steven P; Jackson, Helen C; Cheetham, Sharon C

2011-01-01

The global incidence of obesity continues to rise and is a major driver of morbidity and mortality through cardiovascular and cerebrovascular diseases. Animal models used in the discovery of novel treatments for obesity range from straightforward measures of food intake in lean rodents to long-term studies in animals exhibiting obesity due to the continuous access to diets high in fat. The utility of these animal models can be extended to determine, for example, that weight loss is due to fat loss and/or assess whether beneficial changes in key plasma parameters (e.g. insulin) are evident. In addition, behavioural models such as the behavioural satiety sequence can be used to confirm that a drug treatment has a selective effect on food intake. Typically, animal models have excellent predictive validity whereby drug-induced weight loss in rodents subsequently translates to weight loss in man. However, despite this, at the time of writing orlistat (Europe; USA) remains the only drug currently marketed for the treatment of obesity, with sibutramine having recently been withdrawn from sale globally due to the increased incidence of serious, non-fatal cardiovascular events. While the utility of rodent models in predicting clinical weight loss is detailed, the review also discusses whether animals can be used to predict adverse events such as those seen with recent anti-obesity drugs in the clinic. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21265828

A Second-Generation Device for Automated Training and Quantitative Behavior Analyses of Molecularly-Tractable Model Organisms

PubMed Central

Blackiston, Douglas; Shomrat, Tal; Nicolas, Cindy L.; Granata, Christopher; Levin, Michael

2010-01-01

A deep understanding of cognitive processes requires functional, quantitative analyses of the steps leading from genetics and the development of nervous system structure to behavior. Molecularly-tractable model systems such as Xenopus laevis and planaria offer an unprecedented opportunity to dissect the mechanisms determining the complex structure of the brain and CNS. A standardized platform that facilitated quantitative analysis of behavior would make a significant impact on evolutionary ethology, neuropharmacology, and cognitive science. While some animal tracking systems exist, the available systems do not allow automated training (feedback to individual subjects in real time, which is necessary for operant conditioning assays). The lack of standardization in the field, and the numerous technical challenges that face the development of a versatile system with the necessary capabilities, comprise a significant barrier keeping molecular developmental biology labs from integrating behavior analysis endpoints into their pharmacological and genetic perturbations. Here we report the development of a second-generation system that is a highly flexible, powerful machine vision and environmental control platform. In order to enable multidisciplinary studies aimed at understanding the roles of genes in brain function and behavior, and aid other laboratories that do not have the facilities to undergo complex engineering development, we describe the device and the problems that it overcomes. We also present sample data using frog tadpoles and flatworms to illustrate its use. Having solved significant engineering challenges in its construction, the resulting design is a relatively inexpensive instrument of wide relevance for several fields, and will accelerate interdisciplinary discovery in pharmacology, neurobiology, regenerative medicine, and cognitive science. PMID:21179424

Predictive validity of behavioural animal models for chronic pain

PubMed Central

Berge, Odd-Geir

2011-01-01

Rodent models of chronic pain may elucidate pathophysiological mechanisms and identify potential drug targets, but whether they predict clinical efficacy of novel compounds is controversial. Several potential analgesics have failed in clinical trials, in spite of strong animal modelling support for efficacy, but there are also examples of successful modelling. Significant differences in how methods are implemented and results are reported means that a literature-based comparison between preclinical data and clinical trials will not reveal whether a particular model is generally predictive. Limited reports on negative outcomes prevents reliable estimate of specificity of any model. Animal models tend to be validated with standard analgesics and may be biased towards tractable pain mechanisms. But preclinical publications rarely contain drug exposure data, and drugs are usually given in high doses and as a single administration, which may lead to drug distribution and exposure deviating significantly from clinical conditions. The greatest challenge for predictive modelling is, however, the heterogeneity of the target patient populations, in terms of both symptoms and pharmacology, probably reflecting differences in pathophysiology. In well-controlled clinical trials, a majority of patients shows less than 50% reduction in pain. A model that responds well to current analgesics should therefore predict efficacy only in a subset of patients within a diagnostic group. It follows that successful translation requires several models for each indication, reflecting critical pathophysiological processes, combined with data linking exposure levels with effect on target. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21371010

Structured cues or modafinil for fatigue amelioration in clinicians? A double-blind, randomized controlled trial of critical clinical information recall in fatigued clinicians.

PubMed

Flindall, Ian; Leff, Daniel Richard; Goodship, Jonathan; Sugden, Colin; Darzi, Ara

2016-04-01

To evaluate the impact of modafinil on "free" and "cued" recall of clinical information in fatigued but nonsleep-deprived clinicians. Despite attempts to minimize sleep deprivation through redesign of the roster of residents and staff surgeons, evidence suggests that fatigue remains prevalent. The wake-promoting agent modafinil improves cognition in the sleep-deprived fatigued state and may improve information recall in fatigued nonsleep-deprived clinicians. Twenty-four medical undergraduates participated in a double-blind, parallel, randomized controlled trial (modafinil-200 mg:placebo). Medication was allocated 2 hours before a 90-minute fatigue-inducing, continuous performance task (dual 2-back task). A case history memorization task was then performed. Clinical information recall was assessed as "free"(no cognitive aids) and "cued"(using aid memoirs). Open and closed cues represent information of increasing specificity to aid the recall of clinical information. Fatigue was measured objectively using the psychomotor vigilance task at induction, before and after the dual 2-back task. Modafinil decreased false starts and lapses (modafinil = 0.50, placebo = 9.83, P < .05) and improved psychomotor vigilance task performance (Decreased Performance, modafinil = 0.006, placebo = 0.098, P < .05). Modafinil improved free information recall (modafinil = 137.8, placebo = 106.0, P < .01). There was no significant difference between groups in the amount of information recalled with open (modafinil = 62.3, placebo = 52.8, P = .1) and closed cues (modafinil = 80.1, placebo = 75.9, P = .3). Modafinil attenuated fatigue and improved free recall of clinical information without improving cue-based recall under the design of our experimental conditions. Memory cues to aid retrieval of clinical information are convenient interventions that could decrease fatigue-related error without adverse effects of the neuropharmacology. Copyright © 2016 Elsevier Inc. All rights reserved.

Changes in ambient temperature differentially alter the thermoregulatory, cardiac and locomotor stimulant effects of 4-methylmethcathinone (mephedrone).

PubMed

Miller, M L; Creehan, K M; Angrish, D; Barlow, D J; Houseknecht, K L; Dickerson, T J; Taffe, M A

2013-01-01

The substituted cathinone compound known as mephedrone (4-methylmethcathinone; 4-MMC) has become popular with recreational users of psychomotor-stimulant compounds. Only recently have the first preclinical studies provided information about this drug in the scientific literature; nevertheless, media reports have led to drug control actions in the UK and across several US states. Rodent studies indicate that 4-MMC exhibits neuropharmacological similarity to 3,4-methylenedioxymethamphetamine (MDMA) and prompt investigation of the thermoregulatory, cardiac and locomotor effects of 4-MMC. This study focuses on the role of ambient temperature, which has been shown to shift the effects of MDMA from hyperthermic to hypothermic. Male Sprague-Dawley rats were monitored after subcutaneous administration of 4-MMC (1.0-5.6 mg/kg) using an implantable radiotelemetry system under conditions of low (20 °C) and high (30 °C) ambient temperature. A pharmacokinetic study found a T(max) of 0.25 h and a C(max) of 1206 ng/ml after 5.6 mg/kg 4-MMC. A dose-dependent reduction of body temperature was produced by 4-MMC at 20 °C but there was no temperature change at 30 °C. Increased locomotor activity was observed after 4-MMC administration under both ambient temperatures, however, significantly more activity was observed at 30 °C. Heart rate was slowed by 1.0 and 5.6 mg/kg 4-MMC at 20°C, and was slower in the 30 °C vs. 20 °C condition across all treatments. These results show that the cathinone analog 4-MMC exhibits in vivo thermoregulatory properties that are distinct from those produced by MDMA. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Effect of ambient temperature on the thermoregulatory and locomotor stimulant effects of 4-methylmethcathinone in Wistar and Sprague-Dawley rats.

PubMed

Wright, M Jerry; Angrish, Deepshikha; Aarde, Shawn M; Barlow, Deborah J; Buczynski, Matthew W; Creehan, Kevin M; Vandewater, Sophia A; Parsons, Loren H; Houseknecht, Karen L; Dickerson, Tobin J; Taffe, Michael A

2012-01-01

The drug 4-methylmethcathinone (4-MMC; aka, mephedrone, MMCAT, "plant food", "bath salts") is a recent addition to the list of popular recreational psychomotor-stimulant compounds. Relatively little information about this drug is available in the scientific literature, but popular media reports have driven recent drug control actions in the UK and several US States. Online user reports of subjective similarity to 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") prompted the current investigation of the thermoregulatory and locomotor effects of 4-MMC. Male Wistar and Sprague-Dawley rats were monitored after subcutaneous administration of 4-MMC (1-10 mg/kg ) using an implantable radiotelemetry system under conditions of low (23°C) and high (27°C) ambient temperature. A reliable reduction of body temperature was produced by 4-MMC in Wistar rats at 23°C or 27°C with only minimal effect in Sprague-Dawley rats. Increased locomotor activity was observed after 4-MMC administration in both strains with significantly more activity produced in the Sprague-Dawley strain. The 10 mg/kg s.c. dose evoked greater increase in extracellular serotonin, compared with dopamine, in the nucleus accumbens. Follow-up studies confirmed that the degree of locomotor stimulation produced by 10 mg/kg 4-MMC was nearly identical to that produced by 1 mg/kg d-methamphetamine in each strain. Furthermore, hypothermia produced by the serotonin 1(A/7) receptor agonist 8-hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT) was similar in each strain. These results show that the cathinone analog 4-MMC exhibits thermoregulatory and locomotor properties that are distinct from those established for methamphetamine or MDMA in prior work, despite recent evidence of neuropharmacological similarity with MDMA.

Targeting Human Central Nervous System Protein Kinases: An Isoform Selective p38αMAPK Inhibitor That Attenuates Disease Progression in Alzheimer’s Disease Mouse Models

PubMed Central

2015-01-01

The first kinase inhibitor drug approval in 2001 initiated a remarkable decade of tyrosine kinase inhibitor drugs for oncology indications, but a void exists for serine/threonine protein kinase inhibitor drugs and central nervous system indications. Stress kinases are of special interest in neurological and neuropsychiatric disorders due to their involvement in synaptic dysfunction and complex disease susceptibility. Clinical and preclinical evidence implicates the stress related kinase p38αMAPK as a potential neurotherapeutic target, but isoform selective p38αMAPK inhibitor candidates are lacking and the mixed kinase inhibitor drugs that are promising in peripheral tissue disease indications have limitations for neurologic indications. Therefore, pursuit of the neurotherapeutic hypothesis requires kinase isoform selective inhibitors with appropriate neuropharmacology features. Synaptic dysfunction disorders offer a potential for enhanced pharmacological efficacy due to stress-induced activation of p38αMAPK in both neurons and glia, the interacting cellular components of the synaptic pathophysiological axis, to be modulated. We report a novel isoform selective p38αMAPK inhibitor, MW01-18-150SRM (=MW150), that is efficacious in suppression of hippocampal-dependent associative and spatial memory deficits in two distinct synaptic dysfunction mouse models. A synthetic scheme for biocompatible product and positive outcomes from pharmacological screens are presented. The high-resolution crystallographic structure of the p38αMAPK/MW150 complex documents active site binding, reveals a potential low energy conformation of the bound inhibitor, and suggests a structural explanation for MW150’s exquisite target selectivity. As far as we are aware, MW150 is without precedent as an isoform selective p38MAPK inhibitor or as a kinase inhibitor capable of modulating in vivo stress related behavior. PMID:25676389

Divergent effects of estradiol and the estrogen receptor-alpha agonist PPT on eating and activation of PVN CRH neurons in ovariectomized rats and mice.

PubMed

Thammacharoen, Sumpun; Geary, Nori; Lutz, Thomas A; Ogawa, Sonoko; Asarian, Lori

2009-05-01

Eating is modulated by estradiol in females of many species and in women. To further investigate the estrogen receptor mechanism mediating this effect, ovariectomized rats and mice were treated with estradiol benzoate or the estrogen receptor-alpha (ER-alpha)-selective agonist PPT. PPT inhibited eating in rats much more rapidly than estradiol (approximately 2-6 h versus >24 h). In contrast, the latencies to vaginal estrus after PPT and estradiol were similar (>24 h). PPT also inhibited eating within a few hours in wild-type mice, but failed to inhibit eating in transgenic mice deficient in ER-alpha (ERalphaKO mice). PPT, but not estradiol, induced the expression of c-Fos in corticotrophin-releasing hormone (CRH)-expressing cells of the paraventricular nucleus (PVN) of the hypothalamus within 90-180 min in rats. Both PPT and estradiol reduced c-Fos expression in an ER-alpha-containing area of the nucleus of the solitary tract. The anomalously rapid eating-inhibitory effect of PPT suggests that PPT's neuropharmacological effect differs from estradiol's, perhaps because PPT differentially activates membrane versus nuclear ER-alpha or because PPT activates non-ER-alpha membrane estrogen receptors in addition to ER-alpha. The failure of PPT to inhibit eating in ERalphaKO mice, however, indicates that ER-alpha is necessary for PPT's eating-inhibitory action and that any PPT-induced activation of non-ER-alpha estrogen receptors is not sufficient to inhibit eating. Finally, the rapid induction of c-Fos in CRH-expressing cells in the PVN by PPT suggests that PPT elicits a neural response that is similar to that elicited by stress or aversive emotional stimuli.

On-demand SSRI treatment of premature ejaculation: pharmacodynamic limitations for relevant ejaculation delay and consequent solutions.

PubMed

Waldinger, Marcel D; Schweitzer, Dave H; Olivier, Berend

2005-01-01

Recently, the idea has emerged that on-demand use of serotonin reuptake inhibitors (SSRIs), particularly short half-life, should be equally effective in delaying ejaculation as daily SSRI treatment of premature ejaculation. To provide evidence that SSRI-induced ejaculation delay is mainly dependent on pharmacodynamic properties of the drug and hardly on pharmacokinetic factors, and that combined SSRI administration with specific 5-hydroxytryptamine (5-HT) receptor antagonism leads acutely to stronger ejaculation delay than acute SSRI monoadministration. We performed a detailed analysis of serotonin neurotransmission and reviewed animal studies with 5-HT(1A) receptor antagonists. In addition, we critically reviewed existing on-demand SSRI treatments publications and the current debate on a definition of premature ejaculation. Intravaginal ejaculation latency time (IELT). Acute SSRI administration leads to only a mild or no increase of 5-HT neurotransmission and concomitant stimulation of postsynaptic 5-HT receptors. Existing on-demand SSRI treatment studies suffer from methodological insufficiencies, and the reported high-fold increases of ejaculation time contradict with neuropharmacological insights from serotonin metabolism. Animal studies show that SSRI coadministration with 5-HT(1A) receptor antagonists significantly increases the ejaculation time acutely compared to acute SSRI monoadministration. On-demand SSRI treatment has less ejaculation-delaying effects than daily SSRI treatment. SSRIs with a short half-life are likely leading to much less ejaculation delay than current registered SSRIs. Combined use of SSRIs with 5-HT(1A) receptor antagonists increases the likelihood of clinically relevant ejaculation delay after on-demand treatment. On-demand SSRIs with short half-life that insufficiently delay ejaculation in men with IELTs less than 1 minute should be called ejaculation-delaying drugs rather than drugs against premature ejaculation.

Differential involvement of dopamine receptors in conditioned suppression induced by cocaine.

PubMed

Grakalic, Ivana; Panlilio, Leigh V; Thorndike, Eric B; Schindler, Charles W

2007-11-14

Cocaine-paired stimuli can suppress food-reinforced operant behavior in rats, providing an animal model of conditioned drug effects. To study the neuropharmacological basis of this phenomenon, we examined the effects of various dopamine receptor antagonists on the acquisition and expression of cocaine-induced conditioned suppression in rats. Superimposed on an ongoing baseline of food-reinforced operant responding, a stimulus was paired with response-independent cocaine (3.0 mg/kg, i.v.) during each of 8 training sessions. To study acquisition, independent groups of rats were given saline, the dopamine D(1)-like receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390) (0.001-0.03 mg/kg, i.p.), or the dopamine D(2)-like receptor antagonist eticlopride (0.001-0.03 mg/kg, i.p.) prior to each training session. To study expression, independent groups of rats were trained first, then given saline, SCH 23390, eticlopride, or N-[4-(4-(2-methoxyphenyl)piperazinyl)butyl]-2-naphthamide (BP 897) (a dopamine D(3) partial receptor agonist; 0.1-1.0 mg/kg, i.p.) before test sessions in which the stimulus was presented without cocaine. Pre-treatment with either SCH 23390 or eticlopride during acquisition reduced the direct suppressant effects of cocaine, but conditioning was blocked only in rats that were treated with SCH 23390 during acquisition training. Expression of conditioning was attenuated only by eticlopride. Thus, dopamine at least partially mediates both the acquisition and expression of cocaine-induced conditioned suppression, with activation of dopamine D(1)- and D(2)-like receptors underlying these respective processes.

An Open-Source Hardware and Software System for Acquisition and Real-Time Processing of Electrophysiology during High Field MRI

PubMed Central

Purdon, Patrick L.; Millan, Hernan; Fuller, Peter L.; Bonmassar, Giorgio

2008-01-01

Simultaneous recording of electrophysiology and functional magnetic resonance imaging (fMRI) is a technique of growing importance in neuroscience. Rapidly evolving clinical and scientific requirements have created a need for hardware and software that can be customized for specific applications. Hardware may require customization to enable a variety of recording types (e.g., electroencephalogram, local field potentials, or multi-unit activity) while meeting the stringent and costly requirements of MRI safety and compatibility. Real-time signal processing tools are an enabling technology for studies of learning, attention, sleep, epilepsy, neurofeedback, and neuropharmacology, yet real-time signal processing tools are difficult to develop. We describe an open source system for simultaneous electrophysiology and fMRI featuring low-noise (< 0.6 uV p-p input noise), electromagnetic compatibility for MRI (tested up to 7 Tesla), and user-programmable real-time signal processing. The hardware distribution provides the complete specifications required to build an MRI-compatible electrophysiological data acquisition system, including circuit schematics, print circuit board (PCB) layouts, Gerber files for PCB fabrication and robotic assembly, a bill of materials with part numbers, data sheets, and vendor information, and test procedures. The software facilitates rapid implementation of real-time signal processing algorithms. This system has used in human EEG/fMRI studies at 3 and 7 Tesla examining the auditory system, visual system, sleep physiology, and anesthesia, as well as in intracranial electrophysiological studies of the non-human primate visual system during 3 Tesla fMRI, and in human hyperbaric physiology studies at depths of up to 300 feet below sea level. PMID:18761038

Memory and mood during MDMA intoxication, with and without memantine pretreatment.

PubMed

de Sousa Fernandes Perna, E B; Theunissen, E L; Kuypers, K P C; Heckman, P; de la Torre, R; Farre, M; Ramaekers, J G

2014-12-01

Previous studies have shown that single doses of MDMA can affect mood and impair memory in humans. The neuropharmacological mechanisms involved in MDMA-induced memory impairment are not clear. Memantine, an NMDA and alpha 7 nicotinic acetylcholine (ACh) receptor antagonist, was able to reverse MDMA-induced memory impairment in rats. This study investigated whether treatment with memantine can prevent MDMA-induced memory impairment in humans. 15 subjects participated in a double-blind, placebo controlled, within-subject design. Subjects received both pre-treatment (placebo/memantine 20 mg) (T1) and treatment (placebo/MDMA 75 mg) (T2) on separate test days. T1 preceded T2 by 120 min. Memory function was assessed 90 min after T2 by means of a Visual Verbal Learning Task, a Prospective Memory Task, the Sternberg Memory Task and the Abstract Visual Pattern Learning Task. Profile of Mood State and psychomotor performance were also assessed to control whether MDMA and memantine interactions would selectively pertain to memory or transfer to other domains as well. MDMA significantly impaired performance in the visual verbal learning task and abstract visual pattern learning task. Pre-treatment with memantine did not prevent MDMA-induced memory impairment in these two tasks. Both positive (vigour, arousal, elation) and negative mood effects (anxiety) were increased by MDMA. The responses were not altered by pretreatment with memantine which had no effect on memory or mood when given alone. These preliminary results suggest that memantine does not reverse MDMA-induced memory impairment and mood in humans. This article is part of the Special Issue entitled 'CNS Stimulants'. Copyright © 2014 Elsevier Ltd. All rights reserved.

Inhibition of human cytochrome P450 enzymes by Bacopa monnieri standardized extract and constituents.

PubMed

Ramasamy, Seetha; Kiew, Lik Voon; Chung, Lip Yong

2014-02-24

Bacopa monnieri and the constituents of this plant, especially bacosides, possess various neuropharmacological properties. Like drugs, some herbal extracts and the constituents of their extracts alter cytochrome P450 (CYP) enzymes, causing potential herb-drug interactions. The effects of Bacopa monnieri standardized extract and the bacosides from the extract on five major CYP isoforms in vitro were analyzed using a luminescent CYP recombinant human enzyme assay. B. monnieri extract exhibited non-competitive inhibition of CYP2C19 (IC50/Ki = 23.67/9.5 µg/mL), CYP2C9 (36.49/12.5 µg/mL), CYP1A2 (52.20/25.1 µg/mL); competitive inhibition of CYP3A4 (83.95/14.5 µg/mL) and weak inhibition of CYP2D6 (IC50 = 2061.50 µg/mL). However, the bacosides showed negligible inhibition of the same isoforms. B. monnieri, which is orally administered, has a higher concentration in the gut than the liver; therefore, this herb could exhibit stronger inhibition of intestinal CYPs than hepatic CYPs. At an estimated gut concentration of 600 µg/mL (based on a daily dosage of 300 mg/day), B. monnieri reduced the catalytic activities of CYP3A4, CYP2C9 and CYP2C19 to less than 10% compared to the total activity (without inhibitor = 100%). These findings suggest that B. monnieri extract could contribute to herb-drug interactions when orally co-administered with drugs metabolized by CYP1A2, CYP3A4, CYP2C9 and CYP2C19.

Synthetic cathinones and stereochemistry: S enantiomer of mephedrone reduces anxiety- and depressant-like effects in cocaine- or MDPV-abstinent rats.

PubMed

Philogene-Khalid, Helene L; Hicks, Callum; Reitz, Allen B; Liu-Chen, Lee-Yuan; Rawls, Scott M

2017-09-01

The neuropharmacological profile of the synthetic cathinone mephedrone (MEPH) is influenced by stereochemistry. Both MEPH enantiomers are monoamine transporter substrates, but R-MEPH is primarily responsible for rewarding effects of MEPH as it produces greater locomotor activation and intracranial self-stimulation than S-MEPH. S-MEPH is a 50-fold more potent 5-HT releaser than R-MEPH and does not place preference in rats. MEPH is also structurally similar to the cathinone derivative bupropion, an antidepressant and smoking cessation medication, suggesting MEPH has therapeutic and addictive properties. We tested the hypothesis that S-MEPH reduces anxiety- and depression-like behaviors in rats withdrawn from chronic cocaine or methylenedioxypyrovalerone (MDPV) using the elevated plus maze (EPM) and forced swim test (FST), respectively. Rats were tested 48-h after a binge-like paradigm (3×/day for 10days in 1-h intervals) of cocaine (10mg/kg), MDPV (1mg/kg) or saline. In vitro studies assessed the receptor binding and activity of S-MEPH. Rats withdrawn from chronic cocaine or MDPV displayed an increase in anxiety- and depression-like behaviors that was antagonized by treatment with S-MEPH (10, 30mg/kg). S-MEPH displayed affinity, but not agonist activity, for 5-HT 2 receptors (2A-2C) and showed negligible affinity for dopaminergic, adrenergic and nicotinic receptors. S-MEPH attenuated withdrawal behaviors following chronic cocaine or MDPV, perhaps through 5-HT release and/or 5-HT 2 receptor interactions. The present data suggest S-MEPH may be a possible structural and pharmacological template to develop maintenance therapy for acute anxiety and depression during early withdrawal from psychostimulant abuse. Copyright © 2017 Elsevier B.V. All rights reserved.

The Neurocognitive Basis for Impaired Dual-Task Performance in Senior Fallers.

PubMed

Nagamatsu, Lindsay S; Hsu, C Liang; Voss, Michelle W; Chan, Alison; Bolandzadeh, Niousha; Handy, Todd C; Graf, Peter; Beattie, B Lynn; Liu-Ambrose, Teresa

2016-01-01

Falls are a major health-care concern, and while dual-task performance is widely recognized as being impaired in those at-risk for falls, the underlying neurocognitive mechanisms remain unknown. A better understanding of the underlying mechanisms could lead to the refinement and development of behavioral, cognitive, or neuropharmacological interventions for falls prevention. Therefore, we conducted a cross-sectional study with community-dwelling older adults aged 70-80 years with a history of falls (i.e., two or more falls in the past 12 months) or no history of falls (i.e., zero falls in the past 12 months); n = 28 per group. We compared functional activation during cognitive-based dual-task performance between fallers and non-fallers using functional magnetic resonance imaging (fMRI). Executive cognitive functioning was assessed via Stroop, Trail Making, and Digit Span. Mobility was assessed via the Timed Up and Go test (TUG). We found that non-fallers exhibited significantly greater functional activation compared with fallers during dual-task performance in key regions responsible for resolving dual-task interference, including precentral, postcentral, and lingual gyri. Further, we report slower reaction times during dual-task performance in fallers and significant correlations between level of functional activation and independent measures of executive cognitive functioning and mobility. Our study is the first neuroimaging study to examine dual-task performance in fallers, and supports the notion that fallers have reduced functional brain activation compared with non-fallers. Given that dual-task performance-and the underlying neural concomitants-appears to be malleable with relevant training, our study serves as a launching point for promising strategies to reduce falls in the future.

Animal modelling of traumatic brain injury in preclinical drug development: where do we go from here?

PubMed Central

Marklund, Niklas; Hillered, Lars

2011-01-01

Traumatic brain injury (TBI) is the leading cause of death and disability in young adults. Survivors of TBI frequently suffer from long-term personality changes and deficits in cognitive and motor performance, urgently calling for novel pharmacological treatment options. To date, all clinical trials evaluating neuroprotective compounds have failed in demonstrating clinical efficacy in cohorts of severely injured TBI patients. The purpose of the present review is to describe the utility of animal models of TBI for preclinical evaluation of pharmacological compounds. No single animal model can adequately mimic all aspects of human TBI owing to the heterogeneity of clinical TBI. To successfully develop compounds for clinical TBI, a thorough evaluation in several TBI models and injury severities is crucial. Additionally, brain pharmacokinetics and the time window must be carefully evaluated. Although the search for a single-compound, ‘silver bullet’ therapy is ongoing, a combination of drugs targeting various aspects of neuroprotection, neuroinflammation and regeneration may be needed. In summary, finding drugs and prove clinical efficacy in TBI is a major challenge ahead for the research community and the drug industry. For a successful translation of basic science knowledge to the clinic to occur we believe that a further refinement of animal models and functional outcome methods is important. In the clinical setting, improved patient classification, more homogenous patient cohorts in clinical trials, standardized treatment strategies, improved central nervous system drug delivery systems and monitoring of target drug levels and drug effects is warranted. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21175576

A method to predict different mechanisms for blood-brain barrier permeability of CNS activity compounds in Chinese herbs using support vector machine.

PubMed

Jiang, Ludi; Chen, Jiahua; He, Yusu; Zhang, Yanling; Li, Gongyu

2016-02-01

The blood-brain barrier (BBB), a highly selective barrier between central nervous system (CNS) and the blood stream, restricts and regulates the penetration of compounds from the blood into the brain. Drugs that affect the CNS interact with the BBB prior to their target site, so the prediction research on BBB permeability is a fundamental and significant research direction in neuropharmacology. In this study, we combed through the available data and then with the help of support vector machine (SVM), we established an experiment process for discovering potential CNS compounds and investigating the mechanisms of BBB permeability of them to advance the research in this field four types of prediction models, referring to CNS activity, BBB permeability, passive diffusion and efflux transport, were obtained in the experiment process. The first two models were used to discover compounds which may have CNS activity and also cross the BBB at the same time; the latter two were used to elucidate the mechanism of BBB permeability of those compounds. Three optimization parameter methods, Grid Search, Genetic Algorithm (GA), and Particle Swarm Optimization (PSO), were used to optimize the SVM models. Then, four optimal models were selected with excellent evaluation indexes (the accuracy, sensitivity and specificity of each model were all above 85%). Furthermore, discrimination models were utilized to study the BBB properties of the known CNS activity compounds in Chinese herbs and this may guide the CNS drug development. With the relatively systematic and quick approach, the application rationality of traditional Chinese medicines for treating nervous system disease in the clinical practice will be improved.

Gaddum and LSD: the birth and growth of experimental and clinical neuropharmacology research on 5-HT in the UK

PubMed Central

Green, A R

2008-01-01

The vasoconstrictor substance named serotonin was identified as 5-hydroxytryptamine (5-HT) by Maurice Rapport in 1949. In 1951, Rapport gave Gaddum samples of 5-HT substance allowing him to develop a bioassay to both detect and measure the amine. Gaddum and colleagues rapidly identified 5-HT in brain and showed that lysergic acid diethylamide (LSD) antagonized its action in peripheral tissues. Gaddum accordingly postulated that 5-HT might have a role in mood regulation. This review examines the role of UK scientists in the first 20 years following these major discoveries, discussing their role in developing assays for 5-HT in the CNS, identifying the enzymes involved in the synthesis and metabolism of 5-HT and investigating the effect of drugs on brain 5-HT. It reviews studies on the effects of LSD in humans, including Gaddum's self-administration experiments. It outlines investigations on the role of 5-HT in psychiatric disorders, including studies on the effect of antidepressant drugs on the 5-HT concentration in rodent and human brain, and the attempts to examine 5-HT biochemistry in the brains of patients with depressive illness. It is clear that a rather small group of both preclinical scientists and psychiatrists in the UK made major advances in our understanding of the role of 5-HT in the brain, paving the way for much of the knowledge now taken for granted when discussing ways that 5-HT might be involved in the control of mood and the idea that therapeutic drugs used to alleviate psychiatric illness might alter the function of cerebral 5-HT. PMID:18516072

Animal models of schizophrenia

PubMed Central

Jones, CA; Watson, DJG; Fone, KCF

2011-01-01

Developing reliable, predictive animal models for complex psychiatric disorders, such as schizophrenia, is essential to increase our understanding of the neurobiological basis of the disorder and for the development of novel drugs with improved therapeutic efficacy. All available animal models of schizophrenia fit into four different induction categories: developmental, drug-induced, lesion or genetic manipulation, and the best characterized examples of each type are reviewed herein. Most rodent models have behavioural phenotype changes that resemble ‘positive-like’ symptoms of schizophrenia, probably reflecting altered mesolimbic dopamine function, but fewer models also show altered social interaction, and learning and memory impairment, analogous to negative and cognitive symptoms of schizophrenia respectively. The negative and cognitive impairments in schizophrenia are resistant to treatment with current antipsychotics, even after remission of the psychosis, which limits their therapeutic efficacy. The MATRICS initiative developed a consensus on the core cognitive deficits of schizophrenic patients, and recommended a standardized test battery to evaluate them. More recently, work has begun to identify specific rodent behavioural tasks with translational relevance to specific cognitive domains affected in schizophrenia, and where available this review focuses on reporting the effect of current and potential antipsychotics on these tasks. The review also highlights the need to develop more comprehensive animal models that more adequately replicate deficits in negative and cognitive symptoms. Increasing information on the neurochemical and structural CNS changes accompanying each model will also help assess treatments that prevent the development of schizophrenia rather than treating the symptoms, another pivotal change required to enable new more effective therapeutic strategies to be developed. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21449915

[Autism: toward a necessary cultural revolution].

PubMed

Chamak, Brigitte; Cohen, David

2003-11-01

Autism is a pervasive developmental disorder of childhood characterised by disturbances in both social interactions and communication as well as stereotyped patterns of activities and behaviour. The increase in estimates of the prevalence of autism has raised the question of an "epidemic" of autism. More active case assessment and changes in diagnostic criteria probably account in large part for such increase. Investigators have attempted to define the neural pathophysiology of autism ever since the hypothesis of "refrigerator mother" as its cause was replaced by the view that it is a developmental disorder of the immature brain. However consensus is yet to be reached concerning the brain regions implicated. Psychoanalysis, cognitive psychology, neurophysiology, neuropharmacology, and genetics propose restricted view of the major issues leaving extensive areas unexplored. Therapeutic approaches induce only partial and uncertain results. There is no cure for autism but substantial evidence indicates that early, intensive, individualised education is beneficial for children. All modern intervention programs for autism affected children share a high degree of environmental structuring and predictability and an extensive individual approach. Autism being a behaviourally defined syndrome, it gave rise to a number of controversies concerning definition, classification, etiopathogenesis and therapeutics. In the 1990s a crisis has occurred in France with a loss of confidence between parents and psychiatrists with a problem concerning the means and ways of care of the autistic individual. The aim of this paper is to point out the different questions raised by autism in order to better understand this syndrome which touches upon essential behaviour-related aspects such as self consciousness, reality perception, the functioning of the thought and communication, as well as the role of hereditary and acquired influences in normal and pathological development.

Dietary interventions designed to protect the perinatal brain from hypoxic-ischemic encephalopathy--Creatine prophylaxis and the need for multi-organ protection.

PubMed

Ellery, Stacey J; Dickinson, Hayley; McKenzie, Matthew; Walker, David W

2016-05-01

Birth asphyxia or hypoxia arises from impaired placental gas exchange during labor and remains one of the leading causes of neonatal morbidity and mortality worldwide. It is a condition that can strike in pregnancies that have been uneventful until these final moments, and leads to fundamental loss of cellular energy reserves in the newborn. The cascade of metabolic changes that occurs in the brain at birth as a result of hypoxia can lead to significant damage that evolves over several hours and days, the severity of which can be ameliorated with therapeutic cerebral hypothermia. However, this treatment is only applied to a subset of newborns that meet strict inclusion criteria and is usually administered only in facilities with a high level of medical surveillance. Hence, a number of neuropharmacological interventions have been suggested as adjunct therapies to improve the efficacy of hypothermia, which alone improves survival of the post-hypoxic infant but does not altogether prevent adverse neurological outcomes. In this review we discuss the prospect of using creatine as a dietary supplement during pregnancy and nutritional intervention that can significantly decrease the risk of brain damage in the event of severe oxygen deprivation at birth. Because brain damage can also arise secondarily to compromise of other fetal organs (e.g., heart, diaphragm, kidney), and that compromise of mitochondrial function under hypoxic conditions may be a common mechanism leading to damage of these tissues, we present data suggesting that dietary creatine supplementation during pregnancy may be an effective prophylaxis that can protect the fetus from the multi-organ consequences of severe hypoxia at birth. Copyright © 2015 Elsevier Ltd. All rights reserved.

Predictive animal models of mania: hits, misses and future directions

PubMed Central

Young, Jared W; Henry, Brook L; Geyer, Mark A

2011-01-01

Mania has long been recognized as aberrant behaviour indicative of mental illness. Manic states include a variety of complex and multifaceted symptoms that challenge clear clinical distinctions. Symptoms include over-activity, hypersexuality, irritability and reduced need for sleep, with cognitive deficits recently linked to functional outcome. Current treatments have arisen through serendipity or from other disorders. Hence, treatments are not efficacious for all patients, and there is an urgent need to develop targeted therapeutics. Part of the drug discovery process is the assessment of therapeutics in animal models. Here we review pharmacological, environmental and genetic manipulations developed to test the efficacy of therapeutics in animal models of mania. The merits of these models are discussed in terms of the manipulation used and the facet of mania measured. Moreover, the predictive validity of these models is discussed in the context of differentiating drugs that succeed or fail to meet criteria as approved mania treatments. The multifaceted symptomatology of mania has not been reflected in the majority of animal models, where locomotor activity remains the primary measure. This approach has resulted in numerous false positives for putative treatments. Recent work highlights the need to utilize multivariate strategies to enable comprehensive assessment of affective and cognitive dysfunction. Advances in therapeutic treatment may depend on novel models developed with an integrated approach that includes: (i) a comprehensive battery of tests for different aspects of mania, (ii) utilization of genetic information to establish aetiological validity and (iii) objective quantification of patient behaviour with translational cross-species paradigms. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21410454

Fluorine-18 labeled tracers for PET studies in the neurosciences

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ding, Yu-Shin; Fowler, J.S.

This chapter focuses on fluorine-18, the positron emitter with the longest half-life, the lowest positron energy and probably, the most challenging chemistry. The incorporation of F-18 into organic compounds presents many challenges, including: the need to synthesize and purify the compound within a 2--3 hour time frame; the limited number of labeled precursor molecules; the need to work on a microscale; and the need to produce radiotracers which are chemically and radiochemically pure, sterile and pyrogen-free, and suitable for intravenous injection. The PET method and F-18 labeling of organic molecules are described followed by highlights of the applications of F-18more » labeled compounds in the neurosciences and neuropharmacology. It is important to emphasize the essential and pivotal role that organic synthesis has played in the progression of the PET field over the past twenty years from one in which only a handful of institutions possessed the instrumentation and staff to carry out research to the present-day situation where there are more than 200 PET centers worldwide. During this period PET has become an important scientific tool in the neurosciences, cardiology and oncology. It is important to point out that PET is by no means a mature field. The fact that a hundreds of different F-18 labeled compounds have been developed but only a few possess the necessary selectivity and sensitivity in vivo to track a specific biochemical process illustrates this and underscores a major difficulty in radiotracer development, namely the selection of priority structures for synthesis and the complexities of the interactions between chemical compounds and living systems. New developments in rapid organic synthesis are needed in order to investigate new molecular targets and to improve the quantitative nature of PET experiments.« less

Reversal of behavioral depression by infusion of an alpha-2 adrenergic agonist into the locus coeruleus.

PubMed

Simson, P G; Weiss, J M; Hoffman, L J; Ambrose, M J

1986-04-01

This experiment demonstrated that behavioral depression produced by exposure of rats to strong uncontrollable shocks could be reversed by infusion of the alpha-2 adrenergic agonist clonidine into the region of the locus coeruleus (LC). A 20-min infusion, through bilateral cannulae, into the locus coeruleus of clonidine, piperoxane (alpha-2 antagonist) or inactive vehicle (0.85% saline), was given beginning 70 min after the animals were removed from the stress situation. The dose and volume of drug given in the infusion (0.16 microgram/microliter, 0.1 microliter/min) had been previously shown to produce effects specific to the locus coeruleus (Weiss, Simson, Hoffman, Ambrose, Cooper and Webster, 1986; Neuropharmacology 25: 367-384). At the conclusion of the infusion, active behavior of animals was measured in a 15-min swim test. Results showed that stressed animals infused with vehicle exhibited significantly less active behavior in the swim test than did non-stressed animals infused with vehicle, thereby showing the usual behavioral depression seen after exposure to an uncontrollable stress. Stressed animals infused with clonidine showed no difference in active behavior in comparison to non-stressed animals infused with vehicle and showed significantly more activity than did the stressed animals infused with vehicle. Stressed animals infused with piperoxane showed no significant difference in activity in comparison to the stressed animals infused with vehicle and were significantly less active than either the non-stressed animals infused with vehicle or the stressed animals infused with clonidine. Thus, infusion into the locus coeruleus of the alpha-2 agonist clonidine, but not the alpha-2 antagonist piperoxane, eliminated behavioral depression.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuromodulation of Prefrontal Cortex in Non-Human Primates by Dopaminergic Receptors during Rule-Guided Flexible Behavior and Cognitive Control

PubMed Central

Vijayraghavan, Susheel; Major, Alex J.; Everling, Stefan

2017-01-01

The prefrontal cortex (PFC) is indispensable for several higher-order cognitive and executive capacities of primates, including representation of salient stimuli in working memory (WM), maintenance of cognitive task set, inhibition of inappropriate responses and rule-guided flexible behavior. PFC networks are subject to robust neuromodulation from ascending catecholaminergic systems. Disruption of these systems in PFC has been implicated in cognitive deficits associated with several neuropsychiatric disorders. Over the past four decades, a considerable body of work has examined the influence of dopamine on macaque PFC activity representing spatial WM. There has also been burgeoning interest in neuromodulation of PFC circuits involved in other cognitive functions of PFC, including representation of rules to guide flexible behavior. Here, we review recent neuropharmacological investigations conducted in our laboratory and others of the role of PFC dopamine receptors in regulating rule-guided behavior in non-human primates. Employing iontophoresis, we examined the effects of local manipulation of dopaminergic subtypes on neuronal activity during performance of rule-guided pro- and antisaccades, an experimental paradigm sensitive to PFC integrity, wherein deficits in performance are reliably observed in many neuropsychiatric disorders. We found dissociable effects of dopamine receptors on neuronal activity for rule representation and oculomotor responses and discuss these findings in the context of prior studies that have examined the role of dopamine in spatial delayed response tasks, attention, target selection, abstract rules, visuomotor learning and reward. The findings we describe here highlight the common features, as well as heterogeneity and context dependence of dopaminergic neuromodulation in regulating the efficacy of cognitive functions of PFC in health and disease. PMID:29259545

An open-source hardware and software system for acquisition and real-time processing of electrophysiology during high field MRI.

PubMed

Purdon, Patrick L; Millan, Hernan; Fuller, Peter L; Bonmassar, Giorgio

2008-11-15

Simultaneous recording of electrophysiology and functional magnetic resonance imaging (fMRI) is a technique of growing importance in neuroscience. Rapidly evolving clinical and scientific requirements have created a need for hardware and software that can be customized for specific applications. Hardware may require customization to enable a variety of recording types (e.g., electroencephalogram, local field potentials, or multi-unit activity) while meeting the stringent and costly requirements of MRI safety and compatibility. Real-time signal processing tools are an enabling technology for studies of learning, attention, sleep, epilepsy, neurofeedback, and neuropharmacology, yet real-time signal processing tools are difficult to develop. We describe an open-source system for simultaneous electrophysiology and fMRI featuring low-noise (<0.6microV p-p input noise), electromagnetic compatibility for MRI (tested up to 7T), and user-programmable real-time signal processing. The hardware distribution provides the complete specifications required to build an MRI-compatible electrophysiological data acquisition system, including circuit schematics, print circuit board (PCB) layouts, Gerber files for PCB fabrication and robotic assembly, a bill of materials with part numbers, data sheets, and vendor information, and test procedures. The software facilitates rapid implementation of real-time signal processing algorithms. This system has been used in human EEG/fMRI studies at 3 and 7T examining the auditory system, visual system, sleep physiology, and anesthesia, as well as in intracranial electrophysiological studies of the non-human primate visual system during 3T fMRI, and in human hyperbaric physiology studies at depths of up to 300 feet below sea level.

A new psychoactive 5H-2,3-benzodiazepine with a unique spectrum of activity.

PubMed

Horváth, K; Andrási, F; Berzsenyi, P; Pátfalusi, M; Patthy, M; Szabó, G; Sebestyén, L; Bagdy, E; Körösi, J; Botka, P

1989-08-01

The neuropharmacological effects of 1-(4-amino-phenyl)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine (GYKI 52 322) were investigated and compared with those of chlordiazepoxide and chlorpromazine. This novel 2,3-benzodiazepine displays neuroleptic activity in the apomorphine-climbing (ED50 = 1.15 mg/kg i.p.) and swim-induced grooming (ED50 = 6.9 mg/kg i.p.) tests in mice and it inhibits the conditioned avoidance response in rats (ED50 = 8.2 mg/kg i.p. and 9.8 mg/kg p.o.). However, it does not antagonize apomorphine-evoked vomiting in dogs; or stereotypy, hypermotility and turning in rats even at as high a dose as 50 mg/kg i.p. On the other hand it is active in the hole board test in mice (MED (minimal effective dose) = 0.5 mg/kg i.p.) and in the lick conflict assay in rats (MED = 5 mg/kg i.p.), indicating anxiolytic property. It shows antiaggressive effect in the fighting mice test (ED50 = 8.1 mg/kg p.o.) and the carbachol-rage procedure in cats (active at 10 mg/kg i.p.) According to the biochemical findings, this compound does not bind to the central dopamine receptors (IC50 greater than 10(-4) mol/l), but it shows affinity to the 5-HT1 receptors (IC50 = 7.1 x 10(-6) mol/l) and inhibits brain cAMP-phosphodiesterase (IC50 = 2.4 x 10(-5) mol/l). The substance causes no elevation of dopamine turnover and serum prolactin level suggesting fewer side effects. So the term "atypical neuroleptic agent" is proposed to characterize this molecule.

A Programmable Smoke Delivery Device for PET Imaging with Cigarettes Containing 11C-nicotine

PubMed Central

Zuo, Yantao; Garg, Pradeep K; Nazih, Rachid; Garg, Sudha; Rose, Jed E; Murugesan, Thangaraju; Mukhin, Alexey G

2017-01-01

Introduction PET imaging with 11C-nicotine-loaded cigarettes is a valuable tool to directly assess fast nicotine kinetics and its neuropharmacological role in tobacco dependence. To eliminate variations among puffs inhaled by subjects, this work aimed to develop a programmable smoke delivery device (SDD) to produce highly reproducible and adjustable puffs of cigarette smoke for PET experiments. New method The SDD was built around a programmable syringe pump as a smoking machine to draw a puff of smoke from a 11C-nicotine-loaded cigarette and make it available for a subject to take the smoke into the mouth and then inhale it during PET data acquisition. Brain nicotine time activity curves and total body absorbed 11C-nicotine doses (TAD) were measured in smokers who inhaled a single puff of smoke via the SDD from a 11C-nicotine-loaded cigarette. Results Nearly identical brain nicotine kinetics were observed between participants who inhaled a puff of smoke through the SDD and those who inhaled directly from a cigarette. Comparison with existing methods This new device minimizes puff variations that exist with earlier smoke delivery apparatuses which could introduce confounding factors. Conclusions The SDD is effective in delivering 11C-nicotine from the study cigarettes. Despite a 2-sec increase in aging of smoke delivered through the SDD versus smoke taken directly from a cigarette, the difference in brain nicotine kinetics after 11C-nicotine delivery with and without use of the SDD is negligible. This refined device may be useful for future research on the deposition and pharmacokinetics of nicotine inhaled with tobacco smoke. PMID:28347784

Prevention of the degeneration of human dopaminergic neurons in an astrocyte co-culture system allowing endogenous drug metabolism

PubMed Central

Efremova, Liudmila; Schildknecht, Stefan; Adam, Martina; Pape, Regina; Gutbier, Simon; Hanf, Benjamin; Bürkle, Alexander; Leist, Marcel

2015-01-01

Background and Purpose Few neuropharmacological model systems use human neurons. Moreover, available test systems rarely reflect functional roles of co-cultured glial cells. There is no human in vitro counterpart of the widely used 1-methyl-4-phenyl-tetrahydropyridine (MPTP) mouse model of Parkinson's disease Experimental Approach We generated such a model by growing an intricate network of human dopaminergic neurons on a dense layer of astrocytes. In these co-cultures, MPTP was metabolized to 1-methyl-4-phenyl-pyridinium (MPP+) by the glial cells, and the toxic metabolite was taken up through the dopamine transporter into neurons. Cell viability was measured biochemically and by quantitative neurite imaging, siRNA techniques were also used. Key Results We initially characterized the activation of PARP. As in mouse models, MPTP exposure induced (poly-ADP-ribose) synthesis and neurodegeneration was blocked by PARP inhibitors. Several different putative neuroprotectants were then compared in mono-cultures and co-cultures. Rho kinase inhibitors worked in both models; CEP1347, ascorbic acid or a caspase inhibitor protected mono-cultures from MPP+ toxicity, but did not protect co-cultures, when used alone or in combination. Application of GSSG prevented degeneration in co-cultures, but not in mono-cultures. The surprisingly different pharmacological profiles of the models suggest that the presence of glial cells, and the in situ generation of the toxic metabolite MPP+ within the layered cultures played an important role in neuroprotection. Conclusions and Implications Our new model system is a closer model of human brain tissue than conventional cultures. Its use for screening of candidate neuroprotectants may increase the predictiveness of a test battery. PMID:25989025

Animal models to guide clinical drug development in ADHD: lost in translation?

PubMed Central

Wickens, Jeffery R; Hyland, Brian I; Tripp, Gail

2011-01-01

We review strategies for developing animal models for examining and selecting compounds with potential therapeutic benefit in attention-deficit hyperactivity disorder (ADHD). ADHD is a behavioural disorder of unknown aetiology and pathophysiology. Current understanding suggests that genetic factors play an important role in the aetiology of ADHD. The involvement of dopaminergic and noradrenergic systems in the pathophysiology of ADHD is probable. We review the clinical features of ADHD including inattention, hyperactivity and impulsivity and how these are operationalized for laboratory study. Measures of temporal discounting (but not premature responding) appear to predict known drug effects well (treatment validity). Open-field measures of overactivity commonly used do not have treatment validity in human populations. A number of animal models have been proposed that simulate the symptoms of ADHD. The most commonly used are the spontaneously hypertensive rat (SHR) and the 6-hydroxydopamine-lesioned (6-OHDA) animals. To date, however, the SHR lacks treatment validity, and the effects of drugs on symptoms of impulsivity and inattention have not been studied extensively in 6-OHDA-lesioned animals. At the present stage of development, there are no in vivo models of proven effectiveness for examining and selecting compounds with potential therapeutic benefit in ADHD. However, temporal discounting is an emerging theme in theories of ADHD, and there is good evidence of increased value of delayed reward following treatment with stimulant drugs. Therefore, operant behaviour paradigms that measure the effects of drugs in situations of delayed reinforcement, whether in normal rats or selected models, show promise for the future. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21480864

Translational approaches to obsessive-compulsive disorder: from animal models to clinical treatment

PubMed Central

Fineberg, NA; Chamberlain, SR; Hollander, E; Boulougouris, V; Robbins, TW

2011-01-01

Obsessive-compulsive disorder (OCD) is characterized by obsessions (intrusive thoughts) and compulsions (repetitive ritualistic behaviours) leading to functional impairment. Accumulating evidence links these conditions with underlying dysregulation of fronto-striatal circuitry and monoamine systems. These abnormalities represent key targets for existing and novel treatment interventions. However, the brain bases of these conditions and treatment mechanisms are still not fully elucidated. Animal models simulating the behavioural and clinical manifestations of the disorder show great potential for augmenting our understanding of the pathophysiology and treatment of OCD. This paper provides an overview of what is known about OCD from several perspectives. We begin by describing the clinical features of OCD and the criteria used to assess the validity of animal models of symptomatology; namely, face validity (phenomenological similarity between inducing conditions and specific symptoms of the human phenomenon), predictive validity (similarity in response to treatment) and construct validity (similarity in underlying physiological or psychological mechanisms). We then survey animal models of OC spectrum conditions within this framework, focusing on (i) ethological models; (ii) genetic and pharmacological models; and (iii) neurobehavioural models. We also discuss their advantages and shortcomings in relation to their capacity to identify potentially efficacious new compounds. It is of interest that there has been rather little evidence of ‘false alarms’ for therapeutic drug effects in OCD models which actually fail in the clinic. While it is more difficult to model obsessive cognition than compulsive behaviour in experimental animals, it is feasible to infer cognitive inflexibility in certain animal paradigms. Finally, key future neurobiological and treatment research areas are highlighted. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21486280

Critical thoughts on current rodent models for evaluating potential treatments of alcohol addiction and withdrawal

PubMed Central

Ripley, Tamzin L; Stephens, David N

2011-01-01

Despite years of neurobiological research that have helped to identify potential therapeutic targets, we do not have a reliable pharmacological treatment for alcoholism. There are a range of possible explanations for this failure, including arguments that alcoholism is a spectrum disorder and that different population subtypes may respond to different treatments. This view is supported by categorisations such as early- and late-onset alcoholism, whilst multifactorial genetic factors may also alter responsivity to pharmacological agents. Furthermore, experience of alcohol withdrawal may play a role in future drinking in a way that may distinguish alcoholism from other forms of addiction. Additionally, our neurobiological models, based largely upon results from rodent studies, may not mimic specific aspects of the human condition and may reflect different underlying phenomena and biological processes from the clinical pattern. As a result, potential treatments may be targeting inappropriate aspects of alcohol-related behaviours. Instead, we suggest a more profitable approach is (a) to identify well-defined intermediate behavioural phenotypes in human experimental models that reflect defined aspects of the human clinical disorder and (b) to develop animal models that are homologous with those phenotypes in terms of psychological processes and underlying neurobiological mechanisms. This review describes an array of animal models currently used in the addiction field and what they tell us about alcoholism. We will then examine how established pharmacological agents have been developed using only a limited number of these models, before describing some alternative novel approaches to achieving homology between animal and human experimental measures. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21470204

Ebselen has lithium-like effects on central 5-HT2A receptor function.

PubMed

Antoniadou, I; Kouskou, M; Arsiwala, T; Singh, N; Vasudevan, S R; Fowler, T; Cadirci, E; Churchill, G C; Sharp, T

2018-02-27

Lithium's antidepressant action may be mediated by inhibition of inositol monophosphatase (IMPase), a key enzyme in G q protein coupled receptor signalling. Recently, the antioxidant agent ebselen was identified as an IMPase inhibitor. Here we investigated both ebselen and lithium in models of the 5-HT 2A receptor, a G q protein coupled receptor implicated in lithium's actions. 5-HT 2A receptor function was modelled in mice by measuring the behavioural (head-twitches) and cortical immediate early gene (IEG; Arc, c-fos and Erg2 mRNA) responses to 5-HT 2A receptor agonist administration. Ebselen and lithium were administered either acutely or chronically prior to assessment of 5-HT 2A receptor function. Given the SSRI augmenting action of lithium and 5-HT 2A antagonists, ebselen was also tested for this action by co-administration with the SSRI citalopram in microdialysis (extracellular 5-HT) experiments. Acute and repeated administration of ebselen inhibited behavioural and IEG responses to the 5-HT 2A receptor agonist DOI. Repeated lithium also inhibited DOI-evoked behavioural and IEG responses. In comparison, a selective IMPase inhibitor (L-690,330) attenuated the behavioural response to DOI whereas glycogen synthase kinase inhibitor (AR-A014418) did not. Finally, ebselen increased regional brain 5-HT synthesis and enhanced the increase in extracellular 5-HT induced by citalopram. The current data demonstrate lithium-mimetic effects of ebselen in different experimental models of 5-HT 2A receptor function, likely mediated by IMPase inhibition. This evidence of lithium-like neuropharmacological effects of ebselen adds further support for the clinical testing of ebselen in mood disorder, including as an antidepressant augmenting agent. This article is protected by copyright. All rights reserved.

Neurophysiological mechanisms of cortical plasticity impairments in schizophrenia and modulation by the NMDA receptor agonist D-serine

PubMed Central

Kantrowitz, Joshua T.; Epstein, Michael L.; Beggel, Odeta; Rohrig, Stephanie; Lehrfeld, Jonathan M.; Revheim, Nadine; Lehrfeld, Nayla P.; Reep, Jacob; Parker, Emily; Silipo, Gail; Ahissar, Merav; Javitt, Daniel C.

2016-01-01

Schizophrenia is associated with deficits in cortical plasticity that affect sensory brain regions and lead to impaired cognitive performance. Here we examined underlying neural mechanisms of auditory plasticity deficits using combined behavioural and neurophysiological assessment, along with neuropharmacological manipulation targeted at the N-methyl-D-aspartate type glutamate receptor (NMDAR). Cortical plasticity was assessed in a cohort of 40 schizophrenia/schizoaffective patients relative to 42 healthy control subjects using a fixed reference tone auditory plasticity task. In a second cohort (n = 21 schizophrenia/schizoaffective patients, n = 13 healthy controls), event-related potential and event-related time–frequency measures of auditory dysfunction were assessed during administration of the NMDAR agonist d-serine. Mismatch negativity was used as a functional read-out of auditory-level function. Clinical trials registration numbers were NCT01474395/NCT02156908. Schizophrenia/schizoaffective patients showed significantly reduced auditory plasticity versus healthy controls (P = 0.001) that correlated with measures of cognitive, occupational and social dysfunction. In event-related potential/time-frequency analyses, patients showed highly significant reductions in sensory N1 that reflected underlying impairments in θ responses (P < 0.001), along with reduced θ and β-power modulation during retention and motor-preparation intervals. Repeated administration of d-serine led to intercorrelated improvements in (i) auditory plasticity (P < 0.001); (ii) θ-frequency response (P < 0.05); and (iii) mismatch negativity generation to trained versus untrained tones (P = 0.02). Schizophrenia/schizoaffective patients show highly significant deficits in auditory plasticity that contribute to cognitive, occupational and social dysfunction. d-serine studies suggest first that NMDAR dysfunction may contribute to underlying cortical plasticity deficits and, second, that repeated NMDAR agonist administration may enhance cortical plasticity in schizophrenia. PMID:27913408

Gaddum and LSD: the birth and growth of experimental and clinical neuropharmacology research on 5-HT in the UK.

PubMed

Green, A R

2008-08-01

The vasoconstrictor substance named serotonin was identified as 5-hydroxytryptamine (5-HT) by Maurice Rapport in 1949. In 1951, Rapport gave Gaddum samples of 5-HT substance allowing him to develop a bioassay to both detect and measure the amine. Gaddum and colleagues rapidly identified 5-HT in brain and showed that lysergic acid diethylamide (LSD) antagonized its action in peripheral tissues. Gaddum accordingly postulated that 5-HT might have a role in mood regulation. This review examines the role of UK scientists in the first 20 years following these major discoveries, discussing their role in developing assays for 5-HT in the CNS, identifying the enzymes involved in the synthesis and metabolism of 5-HT and investigating the effect of drugs on brain 5-HT. It reviews studies on the effects of LSD in humans, including Gaddum's self-administration experiments. It outlines investigations on the role of 5-HT in psychiatric disorders, including studies on the effect of antidepressant drugs on the 5-HT concentration in rodent and human brain, and the attempts to examine 5-HT biochemistry in the brains of patients with depressive illness. It is clear that a rather small group of both preclinical scientists and psychiatrists in the UK made major advances in our understanding of the role of 5-HT in the brain, paving the way for much of the knowledge now taken for granted when discussing ways that 5-HT might be involved in the control of mood and the idea that therapeutic drugs used to alleviate psychiatric illness might alter the function of cerebral 5-HT.

Discriminative-Stimulus, Subject-rated and Physiological Effects of Methamphetamine in Humans Pretreated with Aripiprazole

PubMed Central

Sevak, Rajkumar J.; Vansickel, Andrea R.; Stoops, William W.; Glaser, Paul E. A.; Hays, Lon R.; Rush, Craig R.

2013-01-01

Methamphetamine is thought to produce its behavioral effects by releasing dopamine (DA), serotonin (5-HT) and norepinephrine. Results from animal studies support this notion, while results from human laboratory studies have not consistently demonstrated the importance of monoamine systems in the behavioral effects of methamphetamine. Human laboratory procedures of drug-discrimination are well suited to assess neuropharmacological mechanisms of the training drug by studying pharmacological manipulation. In this human laboratory study, six participants with a history of recreational stimulant use learned to discriminate 10 mg oral methamphetamine. After acquiring the discrimination (i.e., ≥80% correct responding on 4 consecutive sessions), the effects of a range of doses of methamphetamine (0, 2.5, 5, 10 and 15 mg), alone and in combination with 0 and 20 mg aripiprazole (a partial agonist at D2 and 5-HT1A receptors), were assessed. Methamphetamine alone functioned as a discriminative stimulus, produced prototypical stimulant-like subject-rated drug effects (e.g., increased ratings of Good Effects, Talkative-Friendly, and Willing to Pay For) and elevated cardiovascular indices. These effects were generally a function of dose. Aripiprazole alone did not occasion methamphetamine-appropriate responding or produce subject-rated effects, but modestly impaired performance. Administration of aripiprazole significantly attenuated the discriminative-stimulus and cardiovascular effects of methamphetamine, as well as some of the subject-rated drug effects. These results indicate that monoamine systems likely play a role in the behavioral effects of methamphetamine in humans. Moreover, given the concordance between past results with d-amphetamine and the present findings, d-amphetamine can likely serve as a model for the pharmacological effects of methamphetamine. PMID:21694622

Pesticide Exposure and Neurodevelopmental Outcomes: Review of the Epidemiologic and Animal Studies

PubMed Central

Burns, Carol J.; McIntosh, Laura J.; Mink, Pamela J.; Jurek, Anne M.; Li, Abby A.

2013-01-01

Assessment of whether pesticide exposure is associated with neurodevelopmental outcomes in children can best be addressed with a systematic review of both the human and animal peer-reviewed literature. This review analyzed epidemiologic studies testing the hypothesis that exposure to pesticides during pregnancy and/or early childhood is associated with neurodevelopmental outcomes in children. Studies that directly queried pesticide exposure (e.g., via questionnaire or interview) or measured pesticide or metabolite levels in biological specimens from study participants (e.g., blood, urine, etc.) or their immediate environment (e.g., personal air monitoring, home dust samples, etc.) were eligible for inclusion. Consistency, strength of association, and dose response were key elements of the framework utilized for evaluating epidemiologic studies. As a whole, the epidemiologic studies did not strongly implicate any particular pesticide as being causally related to adverse neurodevelopmental outcomes in infants and children. A few associations were unique for a health outcome and specific pesticide, and alternative hypotheses could not be ruled out. Our survey of the in vivo peer-reviewed published mammalian literature focused on effects of the specific active ingredient of pesticides on functional neurodevelopmental endpoints (i.e., behavior, neuropharmacology and neuropathology). In most cases, effects were noted at dose levels within the same order of magnitude or higher compared to the point of departure used for chronic risk assessments in the United States. Thus, although the published animal studies may have characterized potential neurodevelopmental outcomes using endpoints not required by guideline studies, the effects were generally observed at or above effect levels measured in repeated-dose toxicology studies submitted to the U.S. Environmental Protection Agency (EPA). Suggestions for improved exposure assessment in epidemiology studies and more effective and tiered approaches in animal testing are discussed. PMID:23777200

Transport of decursin and decursinol angelate across Caco-2 and MDR-MDCK cell monolayers: in vitro models for intestinal and blood-brain barrier permeability.

PubMed

Madgula, Vamsi L; Avula, Bharathi; Reddy V L, Niranjan; Khan, Ikhlas A; Khan, Shabana I

2007-04-01

Decursin (DE) and decursinol angelate (DA) were isolated from the roots of Angelica gigas (Apiaceae) and purified by HPLC. DE and DA have been reported to exhibit significant neuropharmacological activities, but their intestinal transport and permeability in terms of CNS penetration across the blood-brain barrier (BBB) are unknown. This study was undertaken to evaluate the IN VITRO intestinal and BBB transport of DE and DA using Caco-2 and MDR-MDCK cell monolayer models, respectively. The bidirectional transport of DE and DA across Caco-2 and MDR-MDCK monolayers was examined for 2 hours. Integrity of the monolayer was determined by TEER value and by monitoring the transport of Lucifer yellow (Ly) across the monolayers. Quantitation of DE and DA was performed by HPLC. DE and DA exhibited bidirectional transport with a Papp value in the range of 9.0-12.0x10(-6) cm/sec and 7.2-11.7x10(-6) cm/sec in Caco-2 and MDR-MDCK monolayers, respectively. The TEER values were in the range of 410-440 and 1170-1230 ohm cm2 for Caco-2 and MDR-MDCK monolayers, respectively. Ly measurement, the fluorescent marker of passive paracellular diffusion, resulted in Papp values of 2.5-5.0x10(-6) in Caco-2 and 6.0-8.0x10(-6) cm/sec in MDR-MDCK monolayers, confirming that the monolayer integrity was intact at the end of the experiment. Caco-2:human colonic adenocarcinoma DA:decursinol angelate DE:decursin Ly:Lucifer yellow MDCK:Madin-Darby canine kidney MDR:multidrug resistant Papp:apparent permeability TEER:transepithelial electrical resistance.

Bacopa monniera ameliorates cognitive impairment and neurodegeneration induced by intracerebroventricular-streptozotocin in rat: behavioral, biochemical, immunohistochemical and histopathological evidences.

PubMed

Khan, M Badruzzaman; Ahmad, Muzamil; Ahmad, Saif; Ishrat, Tauheed; Vaibhav, Kumar; Khuwaja, Gulrana; Islam, Fakhrul

2015-02-01

The standardized extract of Bacopa monniera (BM) is a complex mixture of ingredients with a uniquely wide spectrum of neuropharmacological influences upon the central nervous system including enhanced learning and memory with known antioxidant potential and protection of the brain from oxidative damage. The present study demonstrates the therapeutic efficacy of BM on cognitive impairment and oxidative damage, induced by intracerebroventricular injection of streptozotocin (ICV-STZ) in rat models. Male Wistar rats were pre-treated with BM at a selected dose (30 mg/Kg) given orally for 2 weeks and then were injected bilaterally with ICV-STZ (3 mg/Kg), while sham operated rats were received the same volume of vehicle. Behavioral parameters were subsequently monitored 2 weeks after the surgery using the Morris water maze (MWM) navigation task then were sacrificed for biochemical, immunohistochemical (Cu/Zn-SOD) and histopathological assays. ICV-STZ-infused rats showed significant loss in learning and memory ability, which were significantly improved by BM supplementation. A significant increase in thiobarbituric acid reactive species and a significant decrease in reduced glutathione, antioxidant enzymes in the hippocampus were observed in ICV-STZ rats. Moreover, decrease in Cu/Zn-SOD expression positive cells were observed in the hippocampus of ICV-STZ rats. BM supplementation significantly ameliorated all alterations induced by ICV-STZ in rats. The data suggest that ICV-STZ might cause its neurotoxic effects via the production of free radicals. Our study demonstrates that BM is a powerful antioxidant which prevents cognitive impairment, oxidative damage, and morphological changes in the ICV-STZ-infused rats. Thus, BM may have therapeutic value for the treatment of cognitive impairment.

Standardized Bacopa monnieri extract ameliorates acute paraquat-induced oxidative stress, and neurotoxicity in prepubertal mice brain.

PubMed

Hosamani, Ravikumar; Krishna, Gokul; Muralidhara

2016-12-01

Bacopa monnieri (BM), an ayurvedic medicinal plant, has attracted considerable interest owing to its diverse neuropharmacological properties. Epidemiological studies have shown significant correlation between paraquat (PQ) exposure and increased risk for Parkinson's disease in humans. In this study, we examined the propensity of standardized extract of BM to attenuate acute PQ-induced oxidative stress, mitochondrial dysfunctions, and neurotoxicity in the different brain regions of prepubertal mice. To test this hypothesis, prepubertal mice provided orally with standardized BM extract (200 mg/kg body weight/day for 4 weeks) were challenged with an acute dose (15 mg/kg body weight, intraperitoneally) of PQ after 3 hours of last dose of extract. Mice were sacrificed after 48 hours of PQ injection, and different brain regions were isolated and subjected to biochemical determinations/quantification of central monoamine (dopamine, DA) levels (by high-performance liquid chromatography). Oral supplementation of BM for 4 weeks resulted in significant reduction in the basal levels of oxidative markers such as reactive oxygen species (ROS), malondialdehyde (MDA), and hydroperoxides (HP) in various brain regions. PQ at the administered dose elicited marked oxidative stress within 48 hours in various brain regions of mice. However, BM prophylaxis significantly improved oxidative homeostasis by restoring PQ-induced ROS, MDA, and HP levels and also by attenuating mitochondrial dysfunction. Interestingly, BM supplementation restored the activities of cholinergic enzymes along with the restoration of striatal DA levels among the PQ-treated mice. Based on these findings, we infer that BM prophylaxis renders the brain resistant to PQ-mediated oxidative perturbations and thus may be better exploited as a preventive approach to protect against oxidative-mediated neuronal dysfunctions.

A programmable smoke delivery device for PET imaging with cigarettes containing 11C-nicotine.

PubMed

Zuo, Yantao; Garg, Pradeep K; Nazih, Rachid; Garg, Sudha; Rose, Jed E; Murugesan, Thangaraju; Mukhin, Alexey G

2017-05-01

PET imaging with 11 C-nicotine-loaded cigarettes is a valuable tool to directly assess fast nicotine kinetics and its neuropharmacological role in tobacco dependence. To eliminate variations among puffs inhaled by subjects, this work aimed to develop a programmable smoke delivery device (SDD) to produce highly reproducible and adjustable puffs of cigarette smoke for PET experiments. The SDD was built around a programmable syringe pump as a smoking machine to draw a puff of smoke from a 11 C-nicotine-loaded cigarette and make it available for a subject to take the smoke into the mouth and then inhale it during PET data acquisition. Brain nicotine time activity curves and total body absorbed 11 C-nicotine doses (TAD) were measured in smokers who inhaled a single puff of smoke via the SDD from a 11 C-nicotine-loaded cigarette. Nearly identical brain nicotine kinetics were observed between participants who inhaled a puff of smoke through the SDD and those who inhaled directly from a cigarette. This new device minimizes puff variations that exist with earlier smoke delivery apparatuses which could introduce confounding factors. The SDD is effective in delivering 11 C-nicotine from the study cigarettes. Despite a 2-s increase in aging of smoke delivered through the SDD versus smoke taken directly from a cigarette, the difference in brain nicotine kinetics after 11 C-nicotine delivery with and without use of the SDD is negligible. This refined device may be useful for future research on the deposition and pharmacokinetics of nicotine inhaled with tobacco smoke. Copyright © 2017 Elsevier B.V. All rights reserved.

Exercise addiction- diagnosis, bio-psychological mechanisms and treatment issues.

PubMed

Weinstein, Aviv; Weinstein, Yitzhak

2014-01-01

Exercise and sports activity are beneficial both physically and psychologically but excessive exercise may have adverse physiological and psychological effects. There are methodological issues in the definition, diagnosis and etiology of exercise addiction. Several questionnaires and diagnostic tools have been developed and validated and they show high validity and reliability. Exercise addiction has been suggested as having an obsessive-compulsive dimension as well as rewarding aspects that may include it among the behavioral addictions. Biological studies show that in rodents, exercise such as wheel running activates the dopamine reward system and thus contributing to stress reduction. Further evidence suggests that running is associated with endorphins and cannabinoids thus explaining the "runners high" or euphoric feelings that may lead to exercise addiction. Genetic studies suggest that genes which control preference for drugs also control the preference for naturally rewarding behaviors such as exercise. Psychological studies also explain exercise addiction in terms of reward, habituation, social support, stress-relief, avoidance of withdrawal and reduction of anxiety. It has been suggested that exercise addiction is a part of a continuum of sportive activity that develops in stages from the recreational exercise to at-risk exercise, problematic exercise and finally into exercise addiction. Assessment and treatment should take into account the various stages of exercise addiction development, its comorbidity with other psychiatric disorders such as eating disorders or substance use and alcohol disorders. Treatment approaches for exercise addiction are based on the cognitive-behavioral approach but little is known about their effectiveness. A single-case study shows promise of pharmacological treatment for exercise addiction and further studies are required. This review summarizes diagnostic and phenomenology of exercise addiction with emphasis on physiological and neuro-pharmacological mechanisms responsible for its rewarding and addictive properties.

Hypothesizing That Neuropharmacological and Neuroimaging Studies of Glutaminergic-Dopaminergic Optimization Complex (KB220Z) Are Associated With "Dopamine Homeostasis" in Reward Deficiency Syndrome (RDS).

PubMed

Blum, Kenneth; Febo, Marcelo; Fried, Lyle; Li, Mona; Dushaj, Kristina; Braverman, Eric R; McLaughlin, Thomas; Steinberg, Bruce; Badgaiyan, Rajendra D

2017-03-21

There is need for better treatments of addictive behaviors, both substance and non-substance related, termed Reward Deficiency Syndrome (RDS). While the FDA has approved pharmaceuticals under the umbrella term Medication Assisted Treatment (MAT), these drugs are not optimal. It is our contention that these drugs work well in the short-term by blocking dopamine function leading to psychological extinction. However, use of buprenorphine/Naloxone over a long period of time results in unwanted addiction liability, reduced emotional affect, and mood changes including suicidal ideation. We are thus proposing a paradigm shift in addiction treatment, with the long-term goal of achieving "Dopamine Homeostasis." While this may be a laudable goal, it is very difficult to achieve. Nevertheless, this commentary briefly reviews past history of developing and subsequently, utilizing a glutaminergic-dopaminergic optimization complex [Kb220Z] shown to be beneficial in at least 20 human clinical trials and in a number of published and unpublished studies. It is our opinion that, while additional required studies could confirm these findings to date, the cited studies are indicative of achieving enhanced resting state functional connectivity, connectivity volume, and possibly, neuroplasticity. Conclusions/Importance: We are proposing a Reward Deficiency Solution System (RDSS) that includes: Genetic Addiction Risk Score (GARS); Comprehensive Analysis of Reported Drugs (CARD); and a glutaminergic-dopaminergic optimization complex (Kb220Z). Continued investigation of this novel strategy may lead to a better-targeted approach in the long-term, causing dopamine regulation by balancing the glutaminergic-dopaminergic pathways. This may potentially change the landscape of treating all addictions leading us to the promised land.

Cistanches Herba: An overview of its chemistry, pharmacology, and pharmacokinetics property.

PubMed

Fu, Zhifei; Fan, Xiang; Wang, Xiaoying; Gao, Xiumei

2018-06-12

Cistanches Herba is an Orobanchaceae parasitic plant. As a commonly used Traditional Chinese Medicine (TCM), its traditional functions include treating kidney deficiency, impotence, female infertility and senile constipation. Chemical analysis of Cistanches Herba revealed that phenylethanoid glycosides, iridoids, lignans, oligosaccharides, and polysaccharides were the main constituents. Pharmacological studies demonstrated that Cistanches Herba exhibited neuroprotective, immunomodulatory, hormonal balancing, anti-fatigue, anti-inflammatory, hepatoprotection, anti-oxidative, anti-bacterial, anti-viral, and anti-tumor effects, etc. The aim of this review is to provide updated, comprehensive and categorized information on the phytochemistry, pharmacological research and pharmacokinetics studies of the major constituents of Cistanches Herba. The literature search was conducted by systematic searching multiple electronic databases including SciFinder, ISI Web of Science, PubMed, Google Scholar and CNKI. Information was also collected from journals, local magazines, books, monographs. To date, more than 100 compounds have been isolated from this genus, include phenylethanoid glycosides, carbohydrates, lignans, iridoids, etc. The crude extracts and isolated compounds have exhibited a wide range of in vitro and in vivo pharmacologic effects, such as neuroprotective, immunomodulatory, anti-inflammatory, hepatoprotection, anti-oxidative, anti-bacterial, and anti-tumor effects. The phenylethanoid glycosides, echinacoside and acteoside have attracted the most attention for their significantly neuropharmacology effects. Pharmacokinetic studies of echinacoside and acteoside also have also been summarized. Phenylethanoid glycosides have demonstrated wide pharmacological actions and have great clinical value if challenges such as poor bioavailability, fast and extensive metabolism are addressed. Apart from phenylethanoid glycosides, other constituents of Cistanches Herba, their pharmacological activities and underlying mechanisms are also need to be studied further. Copyright © 2017. Published by Elsevier B.V.

Permeabilization of the blood-brain barrier via mucosal engrafting: implications for drug delivery to the brain.

PubMed

Bleier, Benjamin S; Kohman, Richie E; Feldman, Rachel E; Ramanlal, Shreshtha; Han, Xue

2013-01-01

Utilization of neuropharmaceuticals for central nervous system(CNS) disease is highly limited due to the blood-brain barrier(BBB) which restricts molecules larger than 500Da from reaching the CNS. The development of a reliable method to bypass the BBB would represent an enormous advance in neuropharmacology enabling the use of many potential disease modifying therapies. Previous attempts such as transcranial catheter implantation have proven to be temporary and associated with multiple complications. Here we describe a novel method of creating a semipermeable window in the BBB using purely autologous tissues to allow for high molecular weight(HMW) drug delivery to the CNS. This approach is inspired by recent advances in human endoscopic transnasal skull base surgical techniques and involves engrafting semipermeable nasal mucosa within a surgical defect in the BBB. The mucosal graft thereby creates a permanent transmucosal conduit for drugs to access the CNS. The main objective of this study was to develop a murine model of this technique and use it to evaluate transmucosal permeability for the purpose of direct drug delivery to the brain. Using this model we demonstrate that mucosal grafts allow for the transport of molecules up to 500 kDa directly to the brain in both a time and molecular weight dependent fashion. Markers up to 40 kDa were found within the striatum suggesting a potential role for this technique in the treatment of Parkinson's disease. This proof of principle study demonstrates that mucosal engrafting represents the first permanent and stable method of bypassing the BBB thereby providing a pathway for HMW therapeutics directly into the CNS.

Cipadesin A, a bioactive ingredient of Xylocarpus granatum, produces antidepressant-like effects in adult mice.

PubMed

Gao, Qiang; Gao, Yuan; Song, Han; Li, Jianli; Wu, Yibing; Shi, Xiaowei; Shi, Haishui; Ma, Yuxia

2016-10-28

Xylocarpus granatum Koenig, widely used in folk medicine in southeast countries, has been reported to exert neuropharmacological activities as well as mood regulation. The neuroprotective activities of limonoids, riches in X. granatum, are poorly understood. To investigate the potential antidepressant-like effects and the underlying mechanisms of cipadesin A, one limonoid component, extracted from X. granatum, in acute stress-induced depression mouse models. Antidepressant-like effects of cipadesin A were investigated through behavioral tests, and potential mechanism was assessed by neuroendocrine system. Antidepressant-like effects of cipadesin A (5, 15, 50mg/kg/day for 7days, intragastrically) were estimated through forced-swimming test (FST), tail suspension test (TST) and open field test (OFT). Effects of cipadesin A on hypothalamus-pituitary- adrenal (HPA) axis were evaluated by analysis of serum corticosterone (CORT) and adrenocorticotropic hormone (ACTH) using enzyme-linked immunosorbent assay (ELISA). Cipadesin A administration significantly reduced the floating time in the FST and immobility time in the TST (15-50mg/kg). Cipadesin A dose-dependently increased the time in the central zone in the OFT (5-50mg/kg), without altering the locomotor activity. Moreover, repeated cipadesin A treatment significantly inhibited the increase levels of serum CORT (5-50mg/kg), ACTH (15-50mg/kg) following the forced swimming, but not in the absence of stress. Cipadesin A has antidepressant-like activities in acute stressed mice model of depression, which likely occurs by inhibiting the HPA axis activity response to stress. These data support further exploration for developing cipadesin A as a potential agent to treat depression and anxiety disorders. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The quetiapine active metabolite N-desalkylquetiapine and the neurotensin NTS₁ receptor agonist PD149163 exhibit antidepressant-like effects on operant responding in male rats.

PubMed

Hillhouse, Todd M; Shankland, Zachary; Matazel, Katelin S; Keiser, Ashley A; Prus, Adam J

2014-12-01

Major depressive disorder is the most common mood disorder in the United States and European Union; however, the limitations of clinically available antidepressant drugs have led researchers to pursue novel pharmacological treatments. Clinical studies have reported that monotherapy with the atypical antipsychotic drug quetiapine produces a rapid reduction in depressive symptoms that is apparent after 1 week of treatment, and it is possible that the active metabolite N-desalkylquetiapine, which structurally resembles an antidepressant drug, produces antidepressant effects. Neuropharmacological evaluations of the neurotensin NTS1 receptor agonist PD149163 suggest antidepressant efficacy, but the effects of a NTS₁ receptor agonist in an antidepressant animal model have yet to be reported. The present study examined the antidepressant-like effects of N-desalkylquetiapine, PD14916, quetiapine, the tricyclic antidepressant drug imipramine, the atypical antipsychotic drug risperidone, and the typical antipsychotic drug raclopride on responding in male Sprague-Dawley rats trained on a differential-reinforcement-of-low-rate 72-s operant schedule, a procedure used for screening antidepressant drugs. Quetiapine, PD149163, risperidone, and imipramine exhibited antidepressant-like effects by increasing the number of reinforcers earned, decreasing the number of responses emitted, and shifting the interresponse time (IRT) distributions to the right. N-Desalkylquetiapine produced a partial antidepressant-like effect by decreasing the number of responses emitted and producing a rightward shift in the IRT distributions, but it did not significantly alter the number of reinforcers earned. Raclopride decreased reinforcers and responses. These data suggest that N-desalkylquetiapine likely contributes to quetiapine's antidepressant efficacy and identify NTS₁ receptor activation as a potential novel pharmacologic strategy for antidepressant drugs. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Issues related to sex differences in antipsychotic treatment.

PubMed

Crawford, Mitchell B; DeLisi, Lynn E

2016-05-01

The effectiveness, side-effect profiles, and numerous other characteristics of antipsychotic medications have been extensively studied. However, the majority of publications do not address the many potential sex differences in efficacy and doses of medications, as well as other sex-specific considerations. Of studies that exist, some suggest that female patients respond to lower doses of antipsychotic medications than males and that side-effect profiles vary between the sexes. However, the majority of preclinical trials use only male laboratory animals, and human clinical trials consist of too few women to analyze their response as a separate group. Although changes in hormone production occurring at multiple stages throughout a women's life (such as during pregnancy, breast feeding, menopause, and postmenopausal) are presented as too complex to deal with in clinical trials, they could instead be embraced as clinical dilemmas that require additional study and consideration. We suggest that a focus should be made to reanalyze data from existing major treatment trials of antipsychotics to determine what medications specifically provide the most efficacy for female patients and at what dose range. In addition, new prospective studies are needed to specifically address appropriate adjustments in psychopharmacologic treatment for female patients during pregnancy, and when postmenopausal. More studies of the effects of antipsychotics on male and female fetuses in utero and during breast feeding are also needed to better manage women with schizophrenia and their offspring on a long-term basis in the community. There is currently too little known about sex differences in neuropharmacology. With the new USA National Institutes of Health policy to include sex in all new proposals, the time has come to close this gap in knowledge.

The pH-dependent local anesthetic activity of diethylaminoethanol, a procaine metabolite.

PubMed

Butterworth, J F; Lief, P A; Strichartz, G R

1988-04-01

To test whether the products of procaine hydrolysis have local anesthetic actions resembling those of procaine, the authors compared the ability of procaine and its metabolites diethylaminoethanol (DEAE) and para-aminobenzoic acid (PABA) to block compound action potentials in excised, desheathed frog and rat sciatic nerves. Studies were performed in solutions of impermeant buffers at pH 7.4 (corresponding to mammalian physiologic pH) and at pH 9.2 (close to the pKa of procaine and DEAE) to test for extracellular pH-dependent increases in drug permeation and potency. Both procaine and DEAE inhibited compound action potentials at pH 7.4 and 9.2 in a reversible and dose-dependent manner, and both were approximately ten-fold more potent at pH 9.2 than at pH 7.4, procaine inhibiting the action potential height by 50% at 0.15 mM (pH 9.2) and 1.1 mM (pH 7.4), DEAE at 4 mM (pH 9.2) and 70 mM (pH 7.4). In contrast, PABA at concentrations up to 25 mM and at either pH failed to inhibit compound action potentials, and did not modify the effects of DEAE when both drugs were given together. Procaine produced greater use-dependent block at the higher pH and at higher stimulation rates (100 Hz vs. 40 Hz); DEAE produced almost no use-dependent block. These observations suggest: 1) that DEAE might account for some of the neuropharmacologic activity of procaine in techniques that favor the accumulation of metabolites (such as those requiring large doses or prolonged infusions); and 2) that alkalinization of procaine and DEAE solutions appears to increase their potency for both resting and use-dependent block of action potentials.

Psychoactive Substances Bill and Act of New Zealand: A Chance to Engage Undergraduate Scientists with Society using a Transfer Learning Paradigm

PubMed Central

Gliddon, Catherine M.; Cridge, Belinda

2015-01-01

Our aim was to develop a teaching paradigm that connected undergraduate’s neuropharmacological/toxicological knowledge to that of government policy. One goal of undergraduate education should be to help develop scientists that can use their scientific knowledge to critique government policy. There is little research, however, on whether democratization of science occurs: nor how to achieve this. Our work focused on a semi-structured workshop designed around the Psychoactive Substances Bill (PSB). Third year science students were given a questionnaire that was designed to address whether participating in the workshop enhanced their understanding of the PSB and its relationship to their established knowledge (i.e., transfer learning). Furthermore, whether they felt that they had enough expertise to consider making a submission (i.e., societal engagement). Results showed that the students appreciated the opportunity to explore potential application of their knowledge and delve into a socio-scientific issue. However, our findings suggested they felt uncomfortable discussing their ideas outside the classroom: nor, did they identify themselves as having sufficient knowledge to contribute to a submission. In conclusion, this study highlights two points. First, that discussion based transfer learning can be used in the tertiary sector and students value the opportunity to apply their knowledge to socio-scientific issue. Second, if social participation and democratization of science is a goal, then more emphasis should be placed on how students can realistically and confidently apply their learning to change social policy. In order to achieve this, education programs need to focus on legitimate real-life processes such as the PSB for engagement. PMID:26557790

Genetic dissection of behavioral flexibility: reversal learning in mice.

PubMed

Laughlin, Rick E; Grant, Tara L; Williams, Robert W; Jentsch, J David

2011-06-01

Behavioral inflexibility is a feature of schizophrenia, attention-deficit/hyperactivity disorder, and behavior addictions that likely results from heritable deficits in the inhibitory control over behavior. Here, we investigate the genetic basis of individual differences in flexibility, measured using an operant reversal learning task. We quantified discrimination acquisition and subsequent reversal learning in a cohort of 51 BXD strains of mice (2-5 mice/strain, n = 176) for which we have matched data on sequence, gene expression in key central nervous system regions, and neuroreceptor levels. Strain variation in trials to criterion on acquisition and reversal was high, with moderate heritability (∼.3). Acquisition and reversal learning phenotypes did not covary at the strain level, suggesting that these traits are effectively under independent genetic control. Reversal performance did covary with dopamine D2 receptor levels in the ventral midbrain, consistent with a similar observed relationship between impulsivity and D2 receptors in humans. Reversal, but not acquisition, is linked to a locus on mouse chromosome 10 with a peak likelihood ratio statistic at 86.2 megabase (p < .05 genome-wide). Variance in messenger RNA levels of select transcripts expressed in neocortex, hippocampus, and striatum correlated with the reversal learning phenotype, including Syn3, Nt5dc3, and Hcfc2. This work demonstrates the clear trait independence between, and genetic control of, discrimination acquisition and reversal and illustrates how globally coherent data sets for a single panel of highly related strains can be interrogated and integrated to uncover genetic sources and molecular and neuropharmacological candidates of complex behavioral traits relevant to human psychopathology. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Antidepressant-like effect of aqueous extract of Channa striatus fillet in mice models of depression.

PubMed

Saleem, A M; Taufik Hidayat, M; Mat Jais, A M; Fakurazi, S; Moklas, Mohamad; Sulaiman, M R; Amom, Z

2011-07-01

Channa (C.) striatus (Malay-Haruan), is a fresh water snakehead fish, consumed as a rejuvenating diet in post-parturition period in local Malay population. The aqueous extract of C. striatus fillet (AECSF) was reported to act through serotonergic receptor system in a previous study. There is no scientific report on neuropharmacological effects of C. striatus. Based on these data, the antidepressant-like effect of C. striatus was evaluated in mice models of depression. AECSF was prepared by steaming the fillets as described previously. Antidepressant activity was studied in male ICR mice using forced swimming test (FST) and tail suspension test (TST). Open-field test was used to evaluate any psychomotor stimulant activity. AECSF was administered intraperitoneally at the concentrations of 30%, 40% and 50% w/v at the dosage of 10 ml/kg. Amitriptyline (10 mg/kg) was used as positive control. All the three concentrations of AECSF (30%, 40% and 50% w/v) significantly reduced the immobility time (p < 0.001) in FST and TST. All the three concentrations of AECSF (30%, 40% and 50% w/v) significantly (p < 0.001) reduced locomotor activity in a dose-dependent manner in open-field test. AECSF produced significant reduction of immobility time in both FST and TST. Amitriptyline produced a significant reduction of immobility time in both FST and TST similar to previous findings. The AECSF produced a dose-dependent decrease in locomotor activity in the open-field test. This hypolocomotion effect indicated the absence of any psychomotor stimulant activity thereby supporting the antidepressant-like effect of the AECSF. The pharmacological mechanisms of the observed antidepressant-like effect and hypolocomotion effect are not understood from our study. Hence, further studies are required.

Permeabilization of the Blood-Brain Barrier via Mucosal Engrafting: Implications for Drug Delivery to the Brain

PubMed Central

Bleier, Benjamin S.; Kohman, Richie E.; Feldman, Rachel E.; Ramanlal, Shreshtha; Han, Xue

2013-01-01

Utilization of neuropharmaceuticals for central nervous system(CNS) disease is highly limited due to the blood-brain barrier(BBB) which restricts molecules larger than 500Da from reaching the CNS. The development of a reliable method to bypass the BBB would represent an enormous advance in neuropharmacology enabling the use of many potential disease modifying therapies. Previous attempts such as transcranial catheter implantation have proven to be temporary and associated with multiple complications. Here we describe a novel method of creating a semipermeable window in the BBB using purely autologous tissues to allow for high molecular weight(HMW) drug delivery to the CNS. This approach is inspired by recent advances in human endoscopic transnasal skull base surgical techniques and involves engrafting semipermeable nasal mucosa within a surgical defect in the BBB. The mucosal graft thereby creates a permanent transmucosal conduit for drugs to access the CNS. The main objective of this study was to develop a murine model of this technique and use it to evaluate transmucosal permeability for the purpose of direct drug delivery to the brain. Using this model we demonstrate that mucosal grafts allow for the transport of molecules up to 500 kDa directly to the brain in both a time and molecular weight dependent fashion. Markers up to 40 kDa were found within the striatum suggesting a potential role for this technique in the treatment of Parkinson’s disease. This proof of principle study demonstrates that mucosal engrafting represents the first permanent and stable method of bypassing the BBB thereby providing a pathway for HMW therapeutics directly into the CNS. PMID:23637885

Resolving the contributions of the membrane-bound and periplasmic nitrate reductase systems to nitric oxide and nitrous oxide production in Salmonella enterica serovar Typhimurium.

PubMed

Rowley, Gary; Hensen, Daniela; Felgate, Heather; Arkenberg, Anke; Appia-Ayme, Corinne; Prior, Karen; Harrington, Carl; Field, Sarah J; Butt, Julea N; Baggs, Elizabeth; Richardson, David J

2012-01-15

The production of cytotoxic nitric oxide (NO) and conversion into the neuropharmacological agent and potent greenhouse gas nitrous oxide (N₂O) is linked with anoxic nitrate catabolism by Salmonella enterica serovar Typhimurium. Salmonella can synthesize two types of nitrate reductase: a membrane-bound form (Nar) and a periplasmic form (Nap). Nitrate catabolism was studied under nitrate-rich and nitrate-limited conditions in chemostat cultures following transition from oxic to anoxic conditions. Intracellular NO production was reported qualitatively by assessing transcription of the NO-regulated genes encoding flavohaemoglobin (Hmp), flavorubredoxin (NorV) and hybrid cluster protein (Hcp). A more quantitative analysis of the extent of NO formation was gained by measuring production of N₂O, the end-product of anoxic NO-detoxification. Under nitrate-rich conditions, the nar, nap, hmp, norV and hcp genes were all induced following transition from the oxic to anoxic state, and 20% of nitrate consumed in steady-state was released as N₂O when nitrite had accumulated to millimolar levels. The kinetics of nitrate consumption, nitrite accumulation and N₂O production were similar to those of wild-type in nitrate-sufficient cultures of a nap mutant. In contrast, in a narG mutant, the steady-state rate of N₂O production was ~30-fold lower than that of the wild-type. Under nitrate-limited conditions, nap, but not nar, was up-regulated following transition from oxic to anoxic metabolism and very little N₂O production was observed. Thus a combination of nitrate-sufficiency, nitrite accumulation and an active Nar-type nitrate reductase leads to NO and thence N₂O production, and this can account for up to 20% of the nitrate catabolized.

Effects of Environmental Manipulations and Treatment with Bupropion and Risperidone on Choice between Methamphetamine and Food in Rhesus Monkeys.

PubMed

Banks, Matthew L; Blough, Bruce E

2015-08-01

Preclinical and human laboratory choice procedures have been invaluable in improving our knowledge of the neurobiological mechanisms of drug reinforcement and in the drug development process for candidate medications to treat drug addiction. However, little is known about the neuropharmacological mechanisms of methamphetamine vs food choice. The aims of this study were to develop a methamphetamine vs food choice procedure and determine treatment effects with two clinically relevant compounds: the monoamine uptake inhibitor bupropion and the dopamine antagonist risperidone. Rhesus monkeys (n=6) responded under a concurrent schedule of food delivery (1-g pellets, fixed-ratio (FR) 100 schedule) and intravenous methamphetamine injections (0-0.32 mg/kg/injection, FR10 schedule) during 7-day bupropion (0.32-1.8 mg/kg/h) and risperidone (0.001-0.0056 mg/kg/h) treatment periods. For comparison, effects of removing food pellets or methamphetamine injections and FR response requirement manipulations were also examined. Under saline treatment conditions, food was preferred over no methamphetamine or small unit methamphetamine doses (0.01-0.032 mg/kg/injection). Larger methamphetamine doses resulted in greater methamphetamine preference and 0.32 mg/kg/injection methamphetamine maintained near exclusive preference. Removing food availability increased methamphetamine choice, whereas removing methamphetamine availability decreased methamphetamine choice. Methamphetamine choice was not significantly altered when the FR response requirements for food and drug were the same (FR100:FR100 or FR10:FR10). Risperidone treatment increased methamphetamine choice, whereas bupropion treatment did not alter methamphetamine choice up to doses that decreased rates of operant behavior. Overall, these negative results with bupropion and risperidone are concordant with previous human laboratory and clinical trials and support the potential validity of this preclinical methamphetamine vs food choice model.

Characterization of endogenous calcium responses in neuronal cell lines.

PubMed

Vetter, Irina; Lewis, Richard J

2010-03-15

An increasing number of putative therapeutic targets have been identified in recent years for the treatment of neuronal pathophysiologies including pain, epilepsy, stroke and schizophrenia. Many of these targets signal through calcium (Ca(2+)), either by directly facilitating Ca(2+) influx through an ion channel, or through activation of G proteins that couple to intracellular Ca(2+) stores or voltage-gated Ca(2+) channels. Immortalized neuronal cell lines are widely used models to study neuropharmacology. However, systematic pharmacological characterization of the receptors and ion channels expressed in these cell lines is lacking. In this study, we systematically assessed endogenous Ca(2+) signaling in response to addition of agonists at potential therapeutic targets in a range of cell lines of neuronal origin (ND7/23, SH-SY5Y, 50B11, F11 and Neuro2A cells) as well as HEK293 cells, a cell line commonly used for over-expression of receptors and ion channels. This study revealed a remarkable diversity of endogenous Ca(2+) responses in these cell lines, with one or more cell lines responding to addition of trypsin, bradykinin, ATP, nicotine, acetylcholine, histamine and neurotensin. Subtype specificity of these responses was inferred from agonist potency and the effect of receptor subtype specific antagonist. Surprisingly, HEK293 and SH-SY5Y cells responded to the largest number of agonists with potential roles in neuronal signaling. These findings have implications for the heterologous expression of neuronal receptors and ion channels in these cell lines, and highlight the potential of neuron-derived cell lines for the study of a range of endogenously expressed receptors and ion channels that signal through Ca(2+). Crown Copyright 2009. Published by Elsevier Inc. All rights reserved.

Separating Analgesia from Reward within the Ventral Tegmental Area

PubMed Central

Schifirneţ, Elena; Bowen, Scott E.; Borszcz, George S.

2014-01-01

Activation of the dopaminergic mesolimbic reward circuit that originates in the ventral tegmental area (VTA) is postulated to preferentially suppress emotional responses to noxious stimuli, and presumably contributes to the addictive liability of strong analgesics. VTA dopamine neurons are activated via cholinergic afferents and microinjection of carbachol (cholinergic agonist) into VTA is rewarding. Here, we evaluated regional differences within VTA in the capacity of carbachol to suppress rats' affective response to pain (vocalization afterdischarges, VADs) and to support conditioned place preference (CPP) learning. As carbachol is a non-specific agonist, muscarinic and nicotinic receptor involvement was assessed by administering atropine (muscarinic antagonist) and mecamylamine (nicotinic antagonist) into VTA prior to carbachol treatment. Unilateral injections of carbachol (4 μg) into anterior VTA (aVTA) and posterior VTA (pVTA) suppressed VADs and supported CPP; whereas, injections into midVTA failed to effect either VADs or CPP. These findings corroborate the hypothesis that the neural substrates underlying affective analgesia and reward overlap. However, the extent of the overlap was only partial. Whereas both nicotinic and muscarinic receptors contributed to carbachol-induced affective analgesia in aVTA, only muscarinic receptors mediated the analgesic action of carbachol in pVTA. The rewarding effects of carbachol are mediated by the activation of both nicotinic and muscarinic receptors in both aVTA and pVTA. The results indicate that analgesia and reward are mediated by separate cholinergic mechanisms within pVTA. Nicotinic receptor antagonism within pVTA failed to attenuate carbachol-induced analgesia, but prevented carbachol-induced reward. As addictive liability of analgesics stem from their rewarding properties, the present findings suggest that these processes can be neuropharmacologically separated within pVTA. PMID:24434773

Effect of Ambient Temperature on the Thermoregulatory and Locomotor Stimulant Effects of 4-Methylmethcathinone in Wistar and Sprague-Dawley Rats

PubMed Central

Wright, M. Jerry; Angrish, Deepshikha; Aarde, Shawn M.; Barlow, Deborah J.; Buczynski, Matthew W.; Creehan, Kevin M.; Vandewater, Sophia A.; Parsons, Loren H.; Houseknecht, Karen L.; Dickerson, Tobin J.; Taffe, Michael A.

2012-01-01

The drug 4-methylmethcathinone (4-MMC; aka, mephedrone, MMCAT, “plant food”, “bath salts”) is a recent addition to the list of popular recreational psychomotor-stimulant compounds. Relatively little information about this drug is available in the scientific literature, but popular media reports have driven recent drug control actions in the UK and several US States. Online user reports of subjective similarity to 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) prompted the current investigation of the thermoregulatory and locomotor effects of 4-MMC. Male Wistar and Sprague-Dawley rats were monitored after subcutaneous administration of 4-MMC (1–10 mg/kg ) using an implantable radiotelemetry system under conditions of low (23°C) and high (27°C) ambient temperature. A reliable reduction of body temperature was produced by 4-MMC in Wistar rats at 23°C or 27°C with only minimal effect in Sprague-Dawley rats. Increased locomotor activity was observed after 4-MMC administration in both strains with significantly more activity produced in the Sprague-Dawley strain. The 10 mg/kg s.c. dose evoked greater increase in extracellular serotonin, compared with dopamine, in the nucleus accumbens. Follow-up studies confirmed that the degree of locomotor stimulation produced by 10 mg/kg 4-MMC was nearly identical to that produced by 1 mg/kg d-methamphetamine in each strain. Furthermore, hypothermia produced by the serotonin 1A/7 receptor agonist 8-hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT) was similar in each strain. These results show that the cathinone analog 4-MMC exhibits thermoregulatory and locomotor properties that are distinct from those established for methamphetamine or MDMA in prior work, despite recent evidence of neuropharmacological similarity with MDMA. PMID:22952999

Effects of acute MDMA intoxication on mood and impulsivity: role of the 5-HT2 and 5-HT1 receptors.

PubMed

van Wel, Janelle H P; Kuypers, Kim P C; Theunissen, Eef L; Bosker, Wendy M; Bakker, Katja; Ramaekers, Johannes G

2012-01-01

MDMA induces positive mood and increases impulse control during intoxication, but only a few studies on the neuropharmacological mechanisms underlying these processes have been conducted. It was hypothesized that pretreatment with 5-HT(1) and 5-HT(2) receptor blockers would prevent MDMA effects on mood and impulsivity. Subjects (N = 17) participated in a double-blind, placebo controlled, within-subject design involving 6 experimental conditions consisting of pretreatment (T1) and treatment (T2). T1 preceded T2 by 30 minutes. T1-T2 combinations were: placebo-placebo, 20 mg pindolol-placebo, 50 mg ketanserin-placebo, placebo-75 mg MDMA, 20 mg pindolol-75 mg MDMA and 50 mg ketanserin-75 g MDMA. Subjects completed a Profile of Mood States (POMS) questionnaire and several impulsivity tasks (Stop signal task, Matching familiar figures task, Cue dependent reversal learning task) at 1.5 hrs post-treatment. MDMA alone increased both positive (vigor, arousal, friendliness, elation, positive mood) and negative affect (anxiety, confusion) as assessed by the POMS questionnaire. MDMA also increased stop reaction time in the Stop signal task and reaction time in the Matching familiar figures task. Pretreatment with ketanserin blocked MDMA effects on positive affect, but not negative affect. Ketanserin did not influence the effects of MDMA on impulsivity. Pindolol did not interact with MDMA on any of the measures. In conclusion, 5-HT(2) receptors mediate positive moods induced by MDMA but not negative moods or impulsivity. 5-HT(1) receptors do not appear to be involved in MDMA effects on mood and impulse control. Nederlands Trial Register NTR2352.

Effects of Acute MDMA Intoxication on Mood and Impulsivity: Role of the 5-HT2 and 5-HT1 Receptors

PubMed Central

van Wel, Janelle H. P.; Kuypers, Kim P. C.; Theunissen, Eef L.; Bosker, Wendy M.; Bakker, Katja; Ramaekers, Johannes G.

2012-01-01

MDMA induces positive mood and increases impulse control during intoxication, but only a few studies on the neuropharmacological mechanisms underlying these processes have been conducted. It was hypothesized that pretreatment with 5-HT1 and 5-HT2 receptor blockers would prevent MDMA effects on mood and impulsivity. Subjects (N = 17) participated in a double-blind, placebo controlled, within-subject design involving 6 experimental conditions consisting of pretreatment (T1) and treatment (T2). T1 preceded T2 by 30 minutes. T1–T2 combinations were: placebo-placebo, 20 mg pindolol-placebo, 50 mg ketanserin-placebo, placebo-75 mg MDMA, 20 mg pindolol-75 mg MDMA and 50 mg ketanserin-75 g MDMA. Subjects completed a Profile of Mood States (POMS) questionnaire and several impulsivity tasks (Stop signal task, Matching familiar figures task, Cue dependent reversal learning task) at 1.5 hrs post-treatment. MDMA alone increased both positive (vigor, arousal, friendliness, elation, positive mood) and negative affect (anxiety, confusion) as assessed by the POMS questionnaire. MDMA also increased stop reaction time in the Stop signal task and reaction time in the Matching familiar figures task. Pretreatment with ketanserin blocked MDMA effects on positive affect, but not negative affect. Ketanserin did not influence the effects of MDMA on impulsivity. Pindolol did not interact with MDMA on any of the measures. In conclusion, 5-HT2 receptors mediate positive moods induced by MDMA but not negative moods or impulsivity. 5-HT1 receptors do not appear to be involved in MDMA effects on mood and impulse control. Trial Registration Nederlands Trial Register NTR2352 PMID:22808116

Hypothesizing That Neuropharmacological and Neuroimaging Studies of Glutaminergic-Dopaminergic Optimization Complex (KB220Z) Are Associated With “Dopamine Homeostasis” in Reward Deficiency Syndrome (RDS)

PubMed Central

Blum, Kenneth; Febo, Marcelo; Fried, Lyle; Li, Mona; Dushaj, Kristina; Braverman, Eric R.; McLaughlin, Thomas; Steinberg, Bruce; Badgaiyan, Rajendra D.

2017-01-01

Background There is need for better treatments of addictive behaviors, both substance and non-substance related, termed “Reward Deficiency Syndrome” (RDS). While the FDA has approved pharmaceuticals under the umbrella term Medication Assisted Treatment (MAT), these drugs are not optimal. Objectives It is our contention that these drugs work well in the short-term by blocking dopamine function leading to psychological extinction. However, use of buprenorphine/Naloxone over a long period of time results in unwanted addiction liability, reduced emotional affect, and mood changes including suicidal ideation. Methods We are thus proposing a paradigm shift in addiction treatment, with the long-term goal of achieving “Dopamine Homeostasis.” While this may be a laudable goal, it is very difficult to achieve. Nevertheless, this commentary briefly reviews past history of developing and subsequently, utilizing a glutaminergic-dopaminergic optimization complex [Kb220Z] shown to be beneficial in at least 20 human clinical trials and in a number of published and unpublished studies. Results It is our opinion that, while additional required studies could confirm these findings to date, the cited studies are indicative of achieving enhanced resting state functional connectivity, connectivity volume, and possibly, neuroplasticity. Conclusions/Importance We are proposing a Reward Deficiency Solution System (RDSS) that includes: Genetic Addiction Risk Score (GARS); Comprehensive Analysis of Reported Drugs (CARD); and a glutaminergic-dopaminergic optimization complex (Kb220Z). Continued investigation of this novel strategy may lead to a better-targeted approach in the long-term, causing dopamine regulation by balancing the glutaminergic-dopaminergic pathways. This may potentially change the landscape of treating all addictions leading us to the promised land. PMID:28033474

On Lateral Septum-Like Characteristics of Outputs From the Accumbal Hedonic “Hotspot” of Peciña and Berridge With Commentary on the Transitional Nature of Basal Forebrain “Boundaries”

PubMed Central

Zahm, Daniel S.; Parsley, Kenneth P.; Schwartz, Zachary M.; Cheng, Anita Y.

2014-01-01

Peciña and Berridge (2005; J Neurosci 25:11777–11786) observed that an injection of the μ-opioid receptor agonist DAMGO (D-ala2-N-Me-Phe4-Glycol5-enkephalin) into the rostrodorsal part of the accumbens shell (rdAcbSh) enhances expression of hedonic “liking” responses to the taste of an appetitive sucrose solution. Insofar as the connections of this hedonic “hotspot” were not singled out for special attention in the earlier neuroanatomical literature, we undertook to examine them. We observed that the patterns of inputs and outputs of the rdAcbSh are not qualitatively different from those of the rest of the Acb, except that outputs from the rdAcbSh to the lateral preoptic area and anterior and lateral hypothalamic areas are anomalously robust and overlap extensively with those of the lateral septum. We also detected reciprocal interconnections between the rdAcbSh and lateral septum. Whether and how these connections subserve hedonic impact remains to be learned, but these observations lead us to hypothesize that the rdAcbSh represents a basal forebrain transition area, in the sense that it is invaded by neurons of the lateral septum, or possibly transitional neuronal forms sharing properties of both structures. We note that the proposed transition zone between lateral septum and rdAcbSh would be but one of many in the basal forebrain and conclude by reiterating the longstanding argument that the transitional nature of such boundary areas has functional importance, of which the precise nature will remain elusive until the neurophysiological and neuropharmacological implications of such zones of transition are more generally acknowledged and better addressed. PMID:22628122

Analysis of lipid raft molecules in the living brain slices.

PubMed

Kotani, Norihiro; Nakano, Takanari; Ida, Yui; Ito, Rina; Hashizume, Miki; Yamaguchi, Arisa; Seo, Makoto; Araki, Tomoyuki; Hojo, Yasushi; Honke, Koichi; Murakoshi, Takayuki

2017-08-24

Neuronal plasma membrane has been thought to retain a lot of lipid raft components which play important roles in the neural function. Although the biochemical analyses of lipid raft using brain tissues have been extensively carried out in the past 20 years, many of their experimental conditions do not coincide with those of standard neuroscience researches such as neurophysiology and neuropharmacology. Hence, the physiological methods for lipid raft analysis that can be compatible with general neuroscience have been required. Herein, we developed a system to physiologically analyze ganglioside GM1-enriched lipid rafts in brain tissues using the "Enzyme-Mediated Activation of Radical Sources (EMARS)" method that we reported (Kotani N. et al. Proc. Natl. Acad. Sci. U S A 105, 7405-7409 (2008)). The EMARS method was applied to acute brain slices prepared from mouse brains in aCSF solution using the EMARS probe, HRP-conjugated cholera toxin subunit B, which recognizes ganglioside GM1. The membrane molecules present in the GM1-enriched lipid rafts were then labeled with fluorescein under the physiological condition. The fluorescein-tagged lipid raft molecules called "EMARS products" distributed differentially among various parts of the brain. On the other hand, appreciable differences were not detected among segments along the longitudinal axis of the hippocampus. We further developed a device to label the lipid raft molecules in acute hippocampal slices under two different physiological conditions to detect dynamics of the lipid raft molecules during neural excitation. Using this device, several cell membrane molecules including Thy1, known as a lipid raft resident molecule in neurons, were confirmed by the EMARS method in living hippocampal slices. Copyright © 2017 Elsevier Ltd. All rights reserved.

Quetiapine and its metabolite norquetiapine: translation from in vitro pharmacology to in vivo efficacy in rodent models

PubMed Central

Widzowski, D; Maciag, C; Zacco, A; Hudzik, T; Liu, J; Nyberg, S; Wood, M W

2015-01-01

Background and Purpose Quetiapine has a range of clinical activity distinct from other atypical antipsychotic drugs, demonstrating efficacy as monotherapy in bipolar depression, major depressive disorder and generalized anxiety disorder. The neuropharmacological mechanisms underlying this clinical profile are not completely understood; however, the major active metabolite, norquetiapine, has been shown to have a distinct in vitro pharmacological profile consistent with a broad therapeutic range and may contribute to the clinical profile of quetiapine. Experimental Approach We evaluated quetiapine and norquetiapine, using in vitro binding and functional assays of targets known to be associated with antidepressant and anxiolytic drug actions and compared these activities with a representative range of established antipsychotics and antidepressants. To determine how the in vitro pharmacological properties translate into in vivo activity, we used preclinical animal models with translational relevance to established antidepressant‐like and anxiolytic‐like drug action. Key Results Norquetiapine had equivalent activity to established antidepressants at the noradrenaline transporter (NET), while quetiapine was inactive. Norquetiapine was active in the mouse forced swimming and rat learned helplessness tests. In in vivo receptor occupancy studies, norquetiapine had significant occupancy at NET at behaviourally relevant doses. Both quetiapine and norquetiapine were agonists at 5‐HT1A receptors, and the anxiolytic‐like activity of norquetiapine in rat punished responding was blocked by the 5‐HT1A antagonist, WAY100635. Conclusions and Implications Quetiapine and norquetiapine have multiple in vitro pharmacological actions, and results from preclinical studies suggest that activity at NET and 5‐HT1A receptors contributes to the antidepressant and anxiolytic effects in patients treated with quetiapine. PMID:26436896

Egocentric-updating during navigation facilitates episodic memory retrieval.

PubMed

Gomez, Alice; Rousset, Stéphane; Baciu, Monica

2009-11-01

Influential models suggest that spatial processing is essential for episodic memory [O'Keefe, J., & Nadel, L. (1978). The hippocampus as a cognitive map. London: Oxford University Press]. However, although several types of spatial relations exist, such as allocentric (i.e. object-to-object relations), egocentric (i.e. static object-to-self relations) or egocentric updated on navigation information (i.e. self-to-environment relations in a dynamic way), usually only allocentric representations are described as potentially subserving episodic memory [Nadel, L., & Moscovitch, M. (1998). Hippocampal contributions to cortical plasticity. Neuropharmacology, 37(4-5), 431-439]. This study proposes to confront the allocentric representation hypothesis with an egocentric updated with self-motion representation hypothesis. In the present study, we explored retrieval performance in relation to these two types of spatial processing levels during learning. Episodic remembering has been assessed through Remember responses in a recall and in a recognition task, combined with a "Remember-Know-Guess" paradigm [Gardiner, J. M. (2001). Episodic memory and autonoetic consciousness: A first-person approach. Philosophical Transactions of the Royal Society B: Biological Sciences, 356(1413), 1351-1361] to assess the autonoetic level of responses. Our results show that retrieval performance was significantly higher when encoding was performed in the egocentric-updated condition. Although egocentric updated with self-motion and allocentric representations are not mutually exclusive, these results suggest that egocentric updating processing facilitates remember responses more than allocentric processing. The results are discussed according to Burgess and colleagues' model of episodic memory [Burgess, N., Becker, S., King, J. A., & O'Keefe, J. (2001). Memory for events and their spatial context: models and experiments. Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences, 356(1413), 1493-1503].

The effect of ondansetron, a 5-HT3 receptor antagonist, in chronic fatigue syndrome: a randomized controlled trial.

PubMed

The, Gerard K H; Bleijenberg, Gijs; Buitelaar, Jan K; van der Meer, Jos W M

2010-05-01

Accumulating data support the involvement of the serotonin (5-hydroxytryptamine [5-HT]) system in the pathophysiology of chronic fatigue syndrome. Neuropharmacologic studies point to a hyperactive 5-HT system, and open-label treatment studies with 5-HT(3) receptor antagonists have shown promising results. In this randomized controlled clinical trial, the effect of ondansetron, a 5-HT(3) receptor antagonist, was assessed on fatigue severity and functional impairment in adult patients with chronic fatigue syndrome. A randomized, placebo-controlled, double-blind clinical trial was conducted at Radboud University Nijmegen Medical Centre, The Netherlands. Sixty-seven adult patients who fulfilled the US Centers for Disease Control and Prevention (CDC) criteria for chronic fatigue syndrome and who were free from current psychiatric comorbidity participated in the clinical trial. Participants received either ondansetron 16 mg per day or placebo for 10 weeks. The primary outcome variables were fatigue severity (Checklist Individual Strength fatigue severity subscale [CIS-fatigue]) and functional impairment (Sickness Impact Profile-8 [SIP-8]). The effect of ondansetron was assessed by analysis of covariance. Data were analyzed on an intention-to-treat basis. All patients were recruited between June 2003 and March 2006. Thirty-three patients were allocated to the ondansetron condition, 34 to the placebo condition. The 2 groups were well matched in terms of age, sex, fatigue severity, functional impairment, and CDC symptoms. Analysis of covariance showed no significant differences between the ondansetron- and placebo-treated groups during the 10-week treatment period in fatigue severity and functional impairment. This clinical trial demonstrates no benefit of ondansetron compared to placebo in the treatment of chronic fatigue syndrome. www.trialregister.nl: ISRCTN02536681. ©Copyright 2010 Physicians Postgraduate Press, Inc.

Evaluation of Epidemiology and Animal Data for Risk Assessment: Chlorpyrifos Developmental Neurobehavioral Outcomes

PubMed Central

Li, Abby A.; Lowe, Kimberly A.; McIntosh, Laura J.; Mink, Pamela J.

2012-01-01

Developmental neurobehavioral outcomes attributed to exposure to chlorpyrifos (CPF) obtained from epidemiologic and animal studies published before June 2010 were reviewed for risk assessment purposes. For epidemiological studies, this review considered (1) overall strength of study design, (2) specificity of CPF exposure biomarkers, (3) potential for bias, and (4) Hill guidelines for causal inference. In the case of animal studies, this review focused on evaluating the consistency of outcomes for developmental neurobehavioral endpoints from in vivo mammalian studies that exposed dams and/or offspring to CPF prior to weaning. Developmental neuropharmacologic and neuropathologic outcomes were also evaluated. Experimental design and methods were examined as part of the weight of evidence. There was insufficient evidence that human developmental exposures to CPF produce adverse neurobehavioral effects in infants and children across different cohort studies that may be relevant to CPF exposure. In animals, few behavioral parameters were affected following gestational exposures to 1 mg/kg-d but were not consistently reported by different laboratories. For postnatal exposures, behavioral effects found in more than one study at 1 mg/kg-d were decreased errors on a radial arm maze in female rats and increased errors in males dosed subcutaneously from postnatal day (PND) 1 to 4. A similar finding was seen in rats exposed orally from PND 1 to 21 with incremental dose levels of 1, 2, and 4 mg/kg-d, but not in rats dosed with constant dose level of 1 mg/kg-d. Neurodevelopmental behavioral, pharmacological, and morphologic effects occurred at doses that produced significant brain or red blood cell acetylcholinesterase inhibition in dams or offspring. PMID:22401178

Effects of aberrant gamma frequency oscillations on prepulse inhibition.

PubMed

Jones, Nigel C; Anderson, Paul; Rind, Gil; Sullivan, Caley; van den Buuse, Maarten; O'Brien, Terence J

2014-10-01

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.

Thymoquinone-rich fraction nanoemulsion (TQRFNE) decreases Aβ40 and Aβ42 levels by modulating APP processing, up-regulating IDE and LRP1, and down-regulating BACE1 and RAGE in response to high fat/cholesterol diet-induced rats.

PubMed

Ismail, Norsharina; Ismail, Maznah; Azmi, Nur Hanisah; Bakar, Muhammad Firdaus Abu; Yida, Zhang; Abdullah, Maizaton Atmadini; Basri, Hamidon

2017-11-01

Though the causes of Alzheimer's disease (AD) are yet to be understood, much evidence has suggested that excessive amyloid-β (Aβ) accumulation due to abnormal amyloid-β precursor protein (APP) processing and Aβ metabolism are crucial processes towards AD pathogenesis. Hence, approaches aiming at APP processing and Aβ metabolism are currently being actively pursued for the management of AD. Studies suggest that high cholesterol and a high fat diet have harmful effects on cognitive function and may instigate the commencement of AD pathogenesis. Despite the neuropharmacological attributes of black cumin seed (Nigella sativa) extracts and its main active compound, thymoquinone (TQ), limited records are available in relation to AD research. Nanoemulsion (NE) is exploited as drug delivery systems due to their capacity of solubilising non-polar active compounds and is widely examined for brain targeting. Herewith, the effects of thymoquinone-rich fraction nanoemulsion (TQRFNE), thymoquinone nanoemulsion (TQNE) and their counterparts' conventional emulsion in response to high fat/cholesterol diet (HFCD)-induced rats were investigated. Particularly, the Aβ generation; APP processing, β-secretase 1 (BACE1), γ-secretases of presenilin 1 (PSEN1) and presenilin 2 (PSEN2), Aβ degradation; insulin degrading enzyme (IDE), Aβ transportation; low density lipoprotein receptor-related protein 1 (LRP1) and receptor for advanced glycation end products (RAGE) were measured in brain tissues. TQRFNE reduced the brain Aβ fragment length 1-40 and 1-42 (Aβ40 and Aβ42) levels, which would attenuate the AD pathogenesis. This reduction could be due to the modulation of β- and γ-secretase enzyme activity, and the Aβ degradation and transportation in/out of the brain. The findings show the mechanistic actions of TQRFNE in response to high fat and high cholesterol diet associated to Aβ generation, degradation and transportation in the rat's brain tissue. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Current Evaluation of the Millennium Phytomedicine— Ginseng (II): Collected Chemical Entities, Modern Pharmacology, and Clinical Applications Emanated from Traditional Chinese Medicine

PubMed Central

Jia, Lee; Zhao, Yuqing; Liang, Xing-Jie

2009-01-01

This review, a sequel to part 1 in the series, collects about 107 chemical entities separated from the roots, leaves and flower buds of Panax ginseng, quinquefolius and notoginseng, and categorizes these entities into about 18 groups based on their structural similarity. The bioactivities of these chemical entities are described. The ‘Yin and Yang’ theory and the fundamentals of the ‘five elements’ applied to the traditional Chinese medicine (TCM) are concisely introduced to help readers understand how ginseng balances the dynamic equilibrium of human physiological processes from the TCM perspectives. This paper concerns the observation and experimental investigation of biological activities of ginseng used in the TCM of past and present cultures. The current biological findings of ginseng and its medical applications are narrated and critically discussed, including 1) its antihyperglycemic effect that may benefit type II diabetics; in vitro and in vivo studies demonstrated protection of ginseng on beta-cells and obese diabetic mouse models. The related clinical trial results are stated. 2) its aphrodisiac effect and cardiovascular effect that partially attribute to ginseng’s bioactivity on nitric oxide (NO); 3) its cognitive effect and neuropharmacological effect that are intensively tested in various rat models using purified ginsenosides and show a hope to treat Parkinson’s disease (PD); 4) its uses as an adjuvant or immunotherapeutic agent to enhance immune activity, appetite and life quality of cancer patients during their chemotherapy and radiation. Although the apoptotic effect of ginsenosides, especially Rh2, Rg3 and Compound K, on various tumor cells has been shown via different pathways, their clinical effectiveness remains to be tested. This paper also updates the antioxidant, anti-inflammatory, anti-apoptotic and immune-stimulatory activities of ginseng, its ingredients and commercial products, as well as common side effects of ginseng mainly due to its overdose, and its pharmacokinetics. PMID:19689273

Serotonin Reuptake Transporter Deficiency Modulates the Acute Thermoregulatory and Locomotor Activity Response to 3,4-(±)-Methylenedioxymethamphetamine, and Attenuates Depletions in Serotonin Levels in SERT-KO Rats

PubMed Central

Lizarraga, Lucina E.; Phan, Andy V.; Cholanians, Aram B.; Herndon, Joseph M.; Lau, Serrine S.; Monks, Terrence J.

2014-01-01

3,4-(±)-Methylenedioxymethamphetamine (MDMA) is a ring-substituted amphetamine derivative with potent psychostimulant properties. The neuropharmacological effects of MDMA are biphasic in nature, initially causing synaptic monoamine release, primarily of serotonin (5-HT), inducing thermogenesis and hyperactivity (5-HT syndrome). The long-term effects of MDMA manifest as a prolonged depletion in 5-HT, and structural damage to 5-HT nerve terminals. MDMA toxicity is in part mediated by an ability to inhibit the presynaptic 5-HT reuptake transporter (SERT). Using a SERT-knockout (SERT-KO) rat model, we determined the impact of SERT deficiency on thermoregulation, locomotor activity, and neurotoxicity in SERT-KO or Wistar-based wild-type (WT) rats exposed to MDMA. WT and SERT-KO animals exhibited the highest thermogenic responses to MDMA (four times 10 mg/kg, sc at 12 h intervals) during the diurnal (first and third) doses according to peak body temperature and area under the curve (∑°C × h) analysis. Although no differences in peak body temperature were observed between MDMA-treated WT and SERT-KO animals, ∑°C × h following the first MDMA dose was reduced in SERT-KO rats. Exposure to a single dose of MDMA stimulated horizontal velocity in both WT and SERT-KO rats, however, this effect was delayed and attenuated in the KO animals. Finally, SERT-KO rats were insensitive to MDMA-induced long-term (7 days) depletions in 5-HT and its metabolite, 5-hydroxyindole acetic acid, in both cortex and striatum. In conclusion, SERT deficiency modulated MDMA-mediated thermogenesis, hyperactivity and neurotoxicity in KO rats. The data confirm that the SERT is essential for the manifestation of the acute and long-term toxicities of MDMA. PMID:24595820

The Neuropharmacology of Cluster Headache and other Trigeminal Autonomic Cephalalgias

PubMed Central

Costa, Alfredo; Antonaci, Fabio; Ramusino, Matteo Cotta; Nappi, Giuseppe

2015-01-01

Trigeminal autonomic cephalalgias (TACs) are a group of primary headaches including cluster headache (CH), paroxysmal hemicrania (PH) and short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT). Another form, hemicrania continua (HC), is also included this group due to its clinical and pathophysiological similarities. CH is the most common of these syndromes, the others being infrequent in the general population. The pathophysiology of the TACs has been partly elucidated by a number of recent neuroimaging studies, which implicate brain regions associated with nociception (pain matrix). In addition, the hypothalamic activation observed in the course of TAC attacks and the observed efficacy of hypothalamic neurostimulation in CH patients suggest that the hypothalamus is another key structure. Hypothalamic activation may indeed be involved in attack initiation, but it may also lead to a condition of central facilitation underlying the recurrence of pain episodes. The TACs share many pathophysiological features, but are characterised by differences in attack duration and frequency, and to some extent treatment response. Although alternative strategies for the TACs, especially CH, are now emerging (such as neurostimulation techniques), this review focuses on the available pharmacological treatments complying with the most recent guidelines. We discuss the clinical efficacy and tolerability of the currently used drugs. Due to the low frequency of most TACs, few randomised controlled trials have been conducted. The therapies of choice in CH continue to be the triptans and oxygen for acute treatment, and verapamil and lithium for prevention, but promising results have recently been obtained with novel modes of administration of the triptans and other agents, and several other treatments are currently under study. Indomethacin is extremely effective in PH and HC, while antiepileptic drugs (especially lamotrigine) appear to be increasingly useful in SUNCT. We highlight the need for appropriate studies investigating treatments for these rare, but lifelong and disabling conditions. PMID:26411963

Dose-response characteristics of intravenous ketamine on dissociative stereotypy, locomotion, sensorimotor gating, and nociception in male Sprague-Dawley rats.

PubMed

Radford, Kennett D; Park, Thomas Y; Lee, Bong Hyo; Moran, Sean; Osborne, Lisa A; Choi, Kwang H

2017-02-01

Clinicians administer subanesthetic intravenous (IV) ketamine infusions for treatment of refractory depression, chronic pain, and post-traumatic stress disorder in humans. However, ketamine is administered via the subcutaneous (SC) or intraperitoneal (IP) routes to rodents in most pre-clinical research, which may limit translational application. The present study characterized the dose-response of a subanesthetic IV ketamine bolus (2 and 5mg/kg) and 1-h infusion (5, 10, and 20mg/kg/h) on dissociative stereotypy, locomotion, sensorimotor gating, and thermal nociception in male Sprague-Dawley rats. The secondary aim was to measure ketamine and norketamine plasma concentrations following IV ketamine bolus at 1, 20, and 50min and at the conclusion of the 1-h infusion using liquid chromatography/mass spectrometry. The results showed that ketamine bolus and infusions produced dose-dependent dissociative stereotypy. Bolus (2 and 5mg/kg) and 20mg/kg/h infusion increased locomotor activity while 5mg/kg/h infusion decreased locomotor activity. Both 10 and 20mg/kg/h infusions reduced the acoustic startle reflex, while 5mg/kg bolus and 20mg/kg/h infusion impaired pre-pulse inhibition. Ketamine 5mg/kg bolus and the 10 and 20mg/kg/h infusions induced significant and prolonged antinociception to the hotplate test. Plasma concentrations of ketamine decreased quickly after bolus while norketamine levels increased from 1 to 20min and plateaued from 20 to 50min. The peak ketamine plasma concentrations [ng/ml] were similar between 5mg/kg bolus [4100] vs. 20mg/kg/h infusion [3900], and 2mg/kg bolus [1700] vs. 10mg/kg/h infusion [1500]. These results support the findings from previous ketamine injection studies and further validate the feasibility of administering subanesthetic doses of IV ketamine infusion to rats for neuropharmacological studies. Published by Elsevier Inc.

Effects of Environmental Manipulations and Treatment with Bupropion and Risperidone on Choice between Methamphetamine and Food in Rhesus Monkeys

PubMed Central

Banks, Matthew L; Blough, Bruce E

2015-01-01

Preclinical and human laboratory choice procedures have been invaluable in improving our knowledge of the neurobiological mechanisms of drug reinforcement and in the drug development process for candidate medications to treat drug addiction. However, little is known about the neuropharmacological mechanisms of methamphetamine vs food choice. The aims of this study were to develop a methamphetamine vs food choice procedure and determine treatment effects with two clinically relevant compounds: the monoamine uptake inhibitor bupropion and the dopamine antagonist risperidone. Rhesus monkeys (n=6) responded under a concurrent schedule of food delivery (1-g pellets, fixed-ratio (FR) 100 schedule) and intravenous methamphetamine injections (0–0.32 mg/kg/injection, FR10 schedule) during 7-day bupropion (0.32–1.8 mg/kg/h) and risperidone (0.001–0.0056 mg/kg/h) treatment periods. For comparison, effects of removing food pellets or methamphetamine injections and FR response requirement manipulations were also examined. Under saline treatment conditions, food was preferred over no methamphetamine or small unit methamphetamine doses (0.01–0.032 mg/kg/injection). Larger methamphetamine doses resulted in greater methamphetamine preference and 0.32 mg/kg/injection methamphetamine maintained near exclusive preference. Removing food availability increased methamphetamine choice, whereas removing methamphetamine availability decreased methamphetamine choice. Methamphetamine choice was not significantly altered when the FR response requirements for food and drug were the same (FR100:FR100 or FR10:FR10). Risperidone treatment increased methamphetamine choice, whereas bupropion treatment did not alter methamphetamine choice up to doses that decreased rates of operant behavior. Overall, these negative results with bupropion and risperidone are concordant with previous human laboratory and clinical trials and support the potential validity of this preclinical methamphetamine vs food choice model. PMID:25742872

The Influence of Neuronal Density and Maturation on Network Activity of Hippocampal Cell Cultures: A Methodological Study

PubMed Central

Menegon, Andrea; Ferrigno, Giancarlo; Pedrocchi, Alessandra

2013-01-01

It is known that cell density influences the maturation process of in vitro neuronal networks. Neuronal cultures plated with different cell densities differ in number of synapses per neuron and thus in single neuron synaptic transmission, which results in a density-dependent neuronal network activity. Although many authors provided detailed information about the effects of cell density on neuronal culture activity, a dedicated report of density and age influence on neuronal hippocampal culture activity has not yet been reported. Therefore, this work aims at providing reference data to researchers that set up an experimental study on hippocampal neuronal cultures, helping in planning and decoding the experiments. In this work, we analysed the effects of both neuronal density and culture age on functional attributes of maturing hippocampal cultures. We characterized the electrophysiological activity of neuronal cultures seeded at three different cell densities, recording their spontaneous electrical activity over maturation by means of MicroElectrode Arrays (MEAs). We had gather data from 86 independent hippocampal cultures to achieve solid statistic results, considering the high culture-to-culture variability. Network activity was evaluated in terms of simple spiking, burst and network burst features. We observed that electrical descriptors were characterized by a functional peak during maturation, followed by a stable phase (for sparse and medium density cultures) or by a decrease phase (for high dense neuronal cultures). Moreover, 900 cells/mm2 cultures showed characteristics suitable for long lasting experiments (e.g. chronic effect of drug treatments) while 1800 cells/mm2 cultures should be preferred for experiments that require intense electrical activity (e.g. to evaluate the effect of inhibitory molecules). Finally, cell cultures at 3600 cells/mm2 are more appropriate for experiments in which time saving is relevant (e.g. drug screenings). These results are intended to be a reference for the planning of in vitro neurophysiological and neuropharmacological experiments with MEAs. PMID:24386305

The influence of neuronal density and maturation on network activity of hippocampal cell cultures: a methodological study.

PubMed

Biffi, Emilia; Regalia, Giulia; Menegon, Andrea; Ferrigno, Giancarlo; Pedrocchi, Alessandra

2013-01-01

It is known that cell density influences the maturation process of in vitro neuronal networks. Neuronal cultures plated with different cell densities differ in number of synapses per neuron and thus in single neuron synaptic transmission, which results in a density-dependent neuronal network activity. Although many authors provided detailed information about the effects of cell density on neuronal culture activity, a dedicated report of density and age influence on neuronal hippocampal culture activity has not yet been reported. Therefore, this work aims at providing reference data to researchers that set up an experimental study on hippocampal neuronal cultures, helping in planning and decoding the experiments. In this work, we analysed the effects of both neuronal density and culture age on functional attributes of maturing hippocampal cultures. We characterized the electrophysiological activity of neuronal cultures seeded at three different cell densities, recording their spontaneous electrical activity over maturation by means of MicroElectrode Arrays (MEAs). We had gather data from 86 independent hippocampal cultures to achieve solid statistic results, considering the high culture-to-culture variability. Network activity was evaluated in terms of simple spiking, burst and network burst features. We observed that electrical descriptors were characterized by a functional peak during maturation, followed by a stable phase (for sparse and medium density cultures) or by a decrease phase (for high dense neuronal cultures). Moreover, 900 cells/mm(2) cultures showed characteristics suitable for long lasting experiments (e.g. chronic effect of drug treatments) while 1800 cells/mm(2) cultures should be preferred for experiments that require intense electrical activity (e.g. to evaluate the effect of inhibitory molecules). Finally, cell cultures at 3600 cells/mm(2) are more appropriate for experiments in which time saving is relevant (e.g. drug screenings). These results are intended to be a reference for the planning of in vitro neurophysiological and neuropharmacological experiments with MEAs.

GABAA receptor positive allosteric modulators modify the abuse-related behavioral and neurochemical effects of methamphetamine in rhesus monkeys.

PubMed

Berro, Laís F; Andersen, Monica L; Tufik, Sergio; Howell, Leonard L

2017-09-01

GABA A receptor positive allosteric modulators (GABA A receptor modulators) are commonly used for the treatment of insomnia. Nevertheless, the effects of these compounds on psychostimulant-induced sleep impairment are poorly understood. Because GABA A receptor modulators have been shown to decrease the abuse-related effects of psychostimulants, the aim of the present study was to evaluate the effects of temazepam (0.3, 1.0 or 3.0 mg/kg) and eszopiclone (0.3, 1.0 or 3.0 mg/kg), two GABA A receptor modulators, on the behavioral neuropharmacology of methamphetamine in adult rhesus macaques (n = 5). Sleep-like measures and general daytime activity were evaluated with Actiwatch monitors. Methamphetamine self-administration (0.03 mg/kg/inf) was evaluated during morning sessions. Methamphetamine-induced dopamine overflow was assessed through in vivo microdialysis targeting the nucleus accumbens. Nighttime treatment with either temazepam or eszopiclone was ineffective in improving sleep-like measures disrupted by methamphetamine self-administration. Acute pretreatment with a low dose of temazepam before self-administration sessions increased methamphetamine self-administration without affecting normal daytime home-cage activity. At a high dose, acute temazepam pretreatment decreased methamphetamine self-administration and attenuated methamphetamine-induced increases in dopamine in the nucleus accumbens, without decreasing general daytime activity. Acute eszopiclone treatment exerted no effects on methamphetamine intake or drug-induced increases in dopamine. Our study suggests that treatments based on GABA A receptor modulators are not effective for the treatment of sleep disruption in the context of psychostimulant use. In addition, distinct GABA A receptor modulators differentially modulated the abuse-related effects of methamphetamine, with acute treatment with the high efficacy GABA A receptor modulator temazepam decreasing the behavioral and neurochemical effects of methamphetamine. Copyright © 2017 Elsevier Ltd. All rights reserved.

Differential discriminative-stimulus effects of cigarette smoke condensate and nicotine in nicotine-discriminating rats.

PubMed

Lee, Jun-Yeob; Choi, Mee Jung; Choe, Eun Sang; Lee, Young-Ju; Seo, Joung-Wook; Yoon, Seong Shoon

2016-06-01

Although it is widely accepted that nicotine plays a key role in tobacco dependence, nicotine alone cannot account for all of the pharmacological effects associated with cigarette smoke found in preclinical models. Thus, the present study aimed to determine the differential effects of the interoceptive cues of nicotine alone versus those of cigarette smoke condensate (CSC) in nicotine-trained rats. First, the rats were trained to discriminate nicotine (0.4mg/kg, subcutaneous [s.c.]) from saline in a two-lever drug discrimination paradigm. Then, to clarify the different neuropharmacological mechanisms underlying the discriminative-stimulus effects in the nicotine and CSC in nicotine-trained rats, either the α4β2 nicotinic acetylcholine receptor (nAChR) antagonist dihydro-β-erythroidine (DHβE; 0.3-1.0mg/kg, s.c.) or the α7 nAChR antagonist methyllycaconitine citrate (MLA; 5-10mg/kg, intraperitoneal [i.p.]) was administered prior to the injection of either nicotine or CSC. Separate set of experiments was performed to compare the duration of action of the discriminative-stimulus effects of CSC and nicotine. CSC exhibited a dose-dependent nicotine generalization, and interestingly, 1.0mg/kg of DHβE antagonized the discriminative effects of nicotine (0.4mg/kg) but not CSC (0.4mg/kg nicotine content). However, pretreatment with MLA had no effect. In the time-course study, CSC had a relatively longer half-life in terms of the discriminative-stimulus effects compared with nicotine alone. Taken together, the present findings indicate that CSC has a distinct influence on interoceptive effects relative to nicotine alone and that these differential effects might be mediated, at least in part, by the α4β2, but not the α7, nAChR. Copyright © 2016 Elsevier B.V. All rights reserved.

Buprenorphine and a CRF1 antagonist block the acquisition of opiate withdrawal-induced conditioned place aversion in rats.

PubMed

Stinus, Luis; Cador, Martine; Zorrilla, Eric P; Koob, George F

2005-01-01

Conditioned place aversion in rats has face validity as a measure of the aversive stimulus effects of opiate withdrawal that reflects an important motivational component of opiate dependence. The purpose of the present study was to validate conditioned place aversion as sensitive to medications that will alleviate the aversive stimulus effects of opiate withdrawal in humans, and to extend this model to the exploration of the neuropharmacological basis of the motivational effects of opiate withdrawal. Male Sprague-Dawley rats were implanted with two subcutaneous morphine pellets and 5 days later began place conditioning training following subcutaneous administration of a low dose of naloxone. Animals were subjected to three pairings of a low dose of naloxone (15 microg/kg, s.c.) to one arm of a three-chambered place conditioning apparatus. Buprenorphine administered prior to each pairing dose-dependently blocked the place aversion produced by precipitated opiate withdrawal. A corticotropin-releasing factor-1 (CRF1) receptor antagonist (antalarmin) also reversed the place aversion produced by precipitated opiate withdrawal. Antalarmin did not produce a place preference or place aversion by itself in morphine-dependent rats. No effect was observed with pretreatment of the dopamine partial agonist terguride or the selective serotonin reuptake inhibitor fluoxetine. Also, chronic pretreatment with acamprosate (a glutamate receptor modulator used to prevent relapse in alcohol dependence) did not alter naloxone-induced place aversion. Buprenorphine by itself in dependent rats produced a mild place preference at low doses and a mild place aversion at higher doses. These results suggest that buprenorphine blocks the aversive stimulus effects of precipitated opiate withdrawal in rats and provides some validity for the use of place conditioning as a measure that is sensitive to potential opiate-dependence medications. In addition, these results suggest that CRF1 antagonists can block the aversive stimulus effects of opiate withdrawal and may be potential therapeutic targets for opiate dependence.

COLLEGIUM INTERNATIONALE NEURO-PSYCHOPHARMACOLOGICUM (C.I.N.P.) 24th CONGRESS (Paris, France, 20-24 June 2004).

PubMed

Pivac, Nela

2004-09-01

The 24th C.I.N.P. meeting was held in Paris, France, from June 20-24, 2004. The opening ceremony and welcome reception was chaired by Professor Herbert Y Meltzer, Vanderbilt University, Nashville, TN, USA, President of C.I.N.P., and a new president was elected (Professor Brian E. Leonard, Ireland). Congress included the rich social program, combined with lectures of invited speakers, speeches and awards. There were 6650 registered participants all over the world. The meeting consisted of 4 plenary lectures (held by Professor FE Bloom, Department of Neuropharmacology, The Scripps Research Institute, La Jolla USA, Professor HY Meltzer, Vanderbilt University, Nashville, TN, USA, Professor CL Masters, The University of Melbourne, and the Mental Health Research Institute of Victoria, Melbourne, Australia, and Professor JP Changeux, CNRS URA 2182 Recepteurs and Cognition, Paris, France), 69 symposia, 5 synthesia, 25 satellite symposia, 2 electronic interactive sessions, 6 meet the expert sessions, 11 sessions that were held under the name breaking scientific news, 6 workshops, 5 joint meetings, and 2 poster sessions with 657 posters. Posters were displayed for 2 days between 12.00 to 18.00 h, and presenters were available between 16.30 and 18.00 h to answer the questions. Abstracts from the congress were published in International Journal of Neuropsychopharmacology, vol 7, Supplement 1, June 2004. The 24th Collegium Internationale Neuro-Psychopharmacologicum (C.I.N.P.) Congress introduced some new exciting data, summarized some new knowledge, and its goal was to connect the preclinical and clinical data and to introduce some news into clinical practice. The smaller part of the congress that I was able to follow was well organized, and very good attended, with diverse topics, covering all aspects of neuropsychopharmacological research. The sponsorship by the pharmaceutical industries was visible only in the selected sponsored symposia.

Looking for the Self: Phenomenology, Neurophysiology and Philosophical Significance of Drug-induced Ego Dissolution.

PubMed

Millière, Raphaël

2017-01-01

There is converging evidence that high doses of hallucinogenic drugs can produce significant alterations of self-experience, described as the dissolution of the sense of self and the loss of boundaries between self and world. This article discusses the relevance of this phenomenon, known as "drug-induced ego dissolution (DIED)", for cognitive neuroscience, psychology and philosophy of mind. Data from self-report questionnaires suggest that three neuropharmacological classes of drugs can induce ego dissolution: classical psychedelics, dissociative anesthetics and agonists of the kappa opioid receptor (KOR). While these substances act on different neurotransmitter receptors, they all produce strong subjective effects that can be compared to the symptoms of acute psychosis, including ego dissolution. It has been suggested that neuroimaging of DIED can indirectly shed light on the neural correlates of the self. While this line of inquiry is promising, its results must be interpreted with caution. First, neural correlates of ego dissolution might reveal the necessary neurophysiological conditions for the maintenance of the sense of self, but it is more doubtful that this method can reveal its minimally sufficient conditions. Second, it is necessary to define the relevant notion of self at play in the phenomenon of DIED. This article suggests that DIED consists in the disruption of subpersonal processes underlying the "minimal" or "embodied" self, i.e., the basic experience of being a self rooted in multimodal integration of self-related stimuli. This hypothesis is consistent with Bayesian models of phenomenal selfhood, according to which the subjective structure of conscious experience ultimately results from the optimization of predictions in perception and action. Finally, it is argued that DIED is also of particular interest for philosophy of mind. On the one hand, it challenges theories according to which consciousness always involves self-awareness. On the other hand, it suggests that ordinary conscious experience might involve a minimal kind of self-awareness rooted in multisensory processing, which is what appears to fade away during DIED.

[Neuroscience in Al Andalus and its influence on medieval scholastic medicine].

PubMed

Martín-Araguz, A; Bustamante-Martínez, C; Fernández-Armayor Ajo, V; Moreno-Martínez, J M

Since the application of technical medicine by the Greeks, modern neurology has been based on a body of knowledge and cultural heritage from ancient times. In this paper we review the contribution made by Al Andalus to neuroscience during the Middle Ages and its repercussions on modern neurology. Following the death of Mohammed in the vii century AD, Islam enjoyed one of the most spectacular periods of expansion in the history of mankind. Occupation of the cities of Alexandria and Gundishapur put the Arabs into contact with original Greco Latin manuscripts, which were assimilated and divulged by Islamic scientists in the middle eastern caliphates of Damascus and Bagdad as well as the western caliphates of Al Andalus (Spain) and Kairwan (Tunis). This classical hippocratico galenico medicine was refashioned into the so called arabized galenism, which markedly influenced the Scholastics and the cultured world of the lower Middle Ages and became the basis of European medicine until well into the Renaissance period. There was a first Spanish cultural Renaissance in Al Andalus during the ix xii centuries, which led to a flowering unheard of in the Middle Ages before then. Andalusian doctors made major contributions to the body of knowledge about neuroscience and developed major philosophical concepts of human understanding. Thus, Abulcasis (936 1013), the father of modern surgery, developed material and technical designs which are still used in neurosurgery. Averroes suggested the existence of Parkinson s syndrome and attributed photoreceptor properties to the retina. Avenzoar described meningitis, intracranial thrombophlebitis, mediastinal tumours and made contributions to modern neuropharmacology. Maimonides wrote about neuropsychiatric disorders and described rabies and belladonna intoxication. Aside from the political, religious and cultural differences between Al Andalus and the Christian kingdoms of the Iberian peninsula, the historical Andalusian period (711 1492) forms one of the most brilliant periods of Spanish neuroscience.

The Neuropharmacology of Cluster Headache and other Trigeminal Autonomic Cephalalgias.

PubMed

Costa, Alfredo; Antonaci, Fabio; Ramusino, Matteo Cotta; Nappi, Giuseppe

2015-01-01

Trigeminal autonomic cephalalgias (TACs) are a group of primary headaches including cluster headache (CH), paroxysmal hemicrania (PH) and short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT). Another form, hemicrania continua (HC), is also included this group due to its clinical and pathophysiological similarities. CH is the most common of these syndromes, the others being infrequent in the general population. The pathophysiology of the TACs has been partly elucidated by a number of recent neuroimaging studies, which implicate brain regions associated with nociception (pain matrix). In addition, the hypothalamic activation observed in the course of TAC attacks and the observed efficacy of hypothalamic neurostimulation in CH patients suggest that the hypothalamus is another key structure. Hypothalamic activation may indeed be involved in attack initiation, but it may also lead to a condition of central facilitation underlying the recurrence of pain episodes. The TACs share many pathophysiological features, but are characterised by differences in attack duration and frequency, and to some extent treatment response. Although alternative strategies for the TACs, especially CH, are now emerging (such as neurostimulation techniques), this review focuses on the available pharmacological treatments complying with the most recent guidelines. We discuss the clinical efficacy and tolerability of the currently used drugs. Due to the low frequency of most TACs, few randomised controlled trials have been conducted. The therapies of choice in CH continue to be the triptans and oxygen for acute treatment, and verapamil and lithium for prevention, but promising results have recently been obtained with novel modes of administration of the triptans and other agents, and several other treatments are currently under study. Indomethacin is extremely effective in PH and HC, while antiepileptic drugs (especially lamotrigine) appear to be increasingly useful in SUNCT. We highlight the need for appropriate studies investigating treatments for these rare, but lifelong and disabling conditions.

Neurophysiological mechanisms of cortical plasticity impairments in schizophrenia and modulation by the NMDA receptor agonist D-serine.

PubMed

Kantrowitz, Joshua T; Epstein, Michael L; Beggel, Odeta; Rohrig, Stephanie; Lehrfeld, Jonathan M; Revheim, Nadine; Lehrfeld, Nayla P; Reep, Jacob; Parker, Emily; Silipo, Gail; Ahissar, Merav; Javitt, Daniel C

2016-12-01

Schizophrenia is associated with deficits in cortical plasticity that affect sensory brain regions and lead to impaired cognitive performance. Here we examined underlying neural mechanisms of auditory plasticity deficits using combined behavioural and neurophysiological assessment, along with neuropharmacological manipulation targeted at the N-methyl-D-aspartate type glutamate receptor (NMDAR). Cortical plasticity was assessed in a cohort of 40 schizophrenia/schizoaffective patients relative to 42 healthy control subjects using a fixed reference tone auditory plasticity task. In a second cohort (n = 21 schizophrenia/schizoaffective patients, n = 13 healthy controls), event-related potential and event-related time-frequency measures of auditory dysfunction were assessed during administration of the NMDAR agonist d-serine. Mismatch negativity was used as a functional read-out of auditory-level function. Clinical trials registration numbers were NCT01474395/NCT02156908 Schizophrenia/schizoaffective patients showed significantly reduced auditory plasticity versus healthy controls (P = 0.001) that correlated with measures of cognitive, occupational and social dysfunction. In event-related potential/time-frequency analyses, patients showed highly significant reductions in sensory N1 that reflected underlying impairments in θ responses (P < 0.001), along with reduced θ and β-power modulation during retention and motor-preparation intervals. Repeated administration of d-serine led to intercorrelated improvements in (i) auditory plasticity (P < 0.001); (ii) θ-frequency response (P < 0.05); and (iii) mismatch negativity generation to trained versus untrained tones (P = 0.02). Schizophrenia/schizoaffective patients show highly significant deficits in auditory plasticity that contribute to cognitive, occupational and social dysfunction. d-serine studies suggest first that NMDAR dysfunction may contribute to underlying cortical plasticity deficits and, second, that repeated NMDAR agonist administration may enhance cortical plasticity in schizophrenia. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

MK-801 and memantine act differently on short-term memory tested with different time-intervals in the Morris water maze test.

PubMed

Duda, Weronika; Wesierska, Malgorzata; Ostaszewski, Pawel; Vales, Karel; Nekovarova, Tereza; Stuchlik, Ales

2016-09-15

N-methyl-d-aspartate receptors (NMDARs) play a crucial role in spatial memory formation. In neuropharmacological studies their functioning strongly depends on testing conditions and the dosage of NMDAR antagonists. The aim of this study was to assess the immediate effects of NMDAR block by (+)MK-801 or memantine on short-term allothetic memory. Memory was tested in a working memory version of the Morris water maze test. In our version of the test, rats underwent one day of training with 8 trials, and then three experimental days when rats were injected intraperitoneally with low- 5 (MeL), high - 20 (MeH) mg/kg memantine, 0.1mg/kg MK-801 or 1ml/kg saline (SAL) 30min before testing, for three consecutive days. On each experimental day there was just one acquisition and one test trial, with an inter-trial interval of 5 or 15min. During training the hidden platform was relocated after each trial and during the experiment after each day. The follow-up effect was assessed on day 9. Intact rats improved their spatial memory across the one training day. With a 5min interval MeH rats had longer latency then all rats during retrieval. With a 15min interval the MeH rats presented worse working memory measured as retrieval minus acquisition trial for path than SAL and MeL and for latency than MeL rats. MK-801 rats had longer latency than SAL during retrieval. Thus, the high dose of memantine, contrary to low dose of MK-801 disrupts short-term memory independent on the time interval between acquisition and retrieval. This shows that short-term memory tested in a working memory version of water maze is sensitive to several parameters: i.e., NMDA receptor antagonist type, dosage and the time interval between learning and testing. Copyright © 2016. Published by Elsevier B.V.

Endogenous cholinergic tone modulates spontaneous network level neuronal activity in primary cortical cultures grown on multi-electrode arrays.

PubMed

Hammond, Mark W; Xydas, Dimitris; Downes, Julia H; Bucci, Giovanna; Becerra, Victor; Warwick, Kevin; Constanti, Andrew; Nasuto, Slawomir J; Whalley, Benjamin J

2013-03-26

Cortical cultures grown long-term on multi-electrode arrays (MEAs) are frequently and extensively used as models of cortical networks in studies of neuronal firing activity, neuropharmacology, toxicology and mechanisms underlying synaptic plasticity. However, in contrast to the predominantly asynchronous neuronal firing activity exhibited by intact cortex, electrophysiological activity of mature cortical cultures is dominated by spontaneous epileptiform-like global burst events which hinders their effective use in network-level studies, particularly for neurally-controlled animat ('artificial animal') applications. Thus, the identification of culture features that can be exploited to produce neuronal activity more representative of that seen in vivo could increase the utility and relevance of studies that employ these preparations. Acetylcholine has a recognised neuromodulatory role affecting excitability, rhythmicity, plasticity and information flow in vivo although its endogenous production by cortical cultures and subsequent functional influence upon neuronal excitability remains unknown. Consequently, using MEA electrophysiological recording supported by immunohistochemical and RT-qPCR methods, we demonstrate for the first time, the presence of intrinsic cholinergic neurons and significant, endogenous cholinergic tone in cortical cultures with a characterisation of the muscarinic and nicotinic components that underlie modulation of spontaneous neuronal activity. We found that tonic muscarinic ACh receptor (mAChR) activation affects global excitability and burst event regularity in a culture age-dependent manner whilst, in contrast, tonic nicotinic ACh receptor (nAChR) activation can modulate burst duration and the proportion of spikes occurring within bursts in a spatio-temporal fashion. We suggest that the presence of significant endogenous cholinergic tone in cortical cultures and the comparability of its modulatory effects to those seen in intact brain tissues support emerging, exploitable commonalities between in vivo and in vitro preparations. We conclude that experimental manipulation of endogenous cholinergic tone could offer a novel opportunity to improve the use of cortical cultures for studies of network-level mechanisms in a manner that remains largely consistent with its functional role.

Relevance of Excitable Media Theory and Retinal Spreading Depression Experiments in Preclinical Pharmacological Research

PubMed Central

V.M, Fernandes de Lima; W, Hanke

2014-01-01

In preclinical neuropharmacological research, molecular, cell-based, and systems using animals are well established. On the tissue level the situation is less comfortable, although during the last decades some effort went into establishing such systems, i.e. using slices of the vertebrate brain together with optical and electrophysiological techniques. However, these methods are neither fast, nor can they be automated or upscaled. By contrast, the chicken retina can be used as a suitable model. It is easy accessible and can be kept alive in vitro for hours up to days. Due to its structure, in addition the retina displays remarkable intrinsic optical signals, which can be easily used in experiments. Also to electrophysiological methods the retina is well accessible. In excitable tissue, to which the brain and the retina belong, propagating excitation waves can be expected, and the spreading depression is such a phenomenon. It has been first observed in the forties of the last century. Later, Martins-Ferreira established it in the chicken retina (retinal spreading depression or RSD). The electrophysiological characteristics of it are identical with those of the cortical SD. The metabolic differences are known and can be taken into account. The experimental advantage of the RSD compared to the cortical SD is the pronounced intrinsic optical signal (IOS) associated with the travelling wave. This is due to the maximum transparency of retinal tissue in the functional state; thus any physiological event will change it markedly and therefore can be easily seen even by naked eye. The theory can explain wave spread in one (action potentials), two (RSDs) and three dimensions (one heart beat). In this review we present the experimental and the excitable media context for the data interpretation using as example the cholinergic pharmacology in relation to functional syndromes. We also discuss the intrinsic optical signal and how to use it in pre-clinical research. PMID:25426010

A Wasp Manipulates Neuronal Activity in the Sub-Esophageal Ganglion to Decrease the Drive for Walking in Its Cockroach Prey

PubMed Central

Gal, Ram; Libersat, Frederic

2010-01-01

Background The parasitoid Jewel Wasp hunts cockroaches to serve as a live food supply for its offspring. The wasp stings the cockroach in the head and delivers a cocktail of neurotoxins directly inside the prey's cerebral ganglia. Although not paralyzed, the stung cockroach becomes a living yet docile ‘zombie’, incapable of self-initiating spontaneous or evoked walking. We show here that such neuro-chemical manipulation can be attributed to decreased neuronal activity in a small region of the cockroach cerebral nervous system, the sub-esophageal ganglion (SEG). A decrease in descending permissive inputs from this ganglion to thoracic central pattern generators decreases the propensity for walking-related behaviors. Methodology and Principal Findings We have used behavioral, neuro-pharmacological and electrophysiological methods to show that: (1) Surgically removing the cockroach SEG prior to wasp stinging prolongs the duration of the sting 5-fold, suggesting that the wasp actively targets the SEG during the stinging sequence; (2) injecting a sodium channel blocker, procaine, into the SEG of non-stung cockroaches reversibly decreases spontaneous and evoked walking, suggesting that the SEG plays an important role in the up-regulation of locomotion; (3) artificial focal injection of crude milked venom into the SEG of non-stung cockroaches decreases spontaneous and evoked walking, as seen with naturally-stung cockroaches; and (4) spontaneous and evoked neuronal spiking activity in the SEG, recorded with an extracellular bipolar microelectrode, is markedly decreased in stung cockroaches versus non-stung controls. Conclusions and Significance We have identified the neuronal substrate responsible for the venom-induced manipulation of the cockroach's drive for walking. Our data strongly support previous findings suggesting a critical and permissive role for the SEG in the regulation of locomotion in insects. By injecting a venom cocktail directly into the SEG, the parasitoid Jewel Wasp selectively manipulates the cockroach's motivation to initiate walking without interfering with other non-related behaviors. PMID:20383324

Current evaluation of the millennium phytomedicine- ginseng (II): Collected chemical entities, modern pharmacology, and clinical applications emanated from traditional Chinese medicine.

PubMed

Jia, Lee; Zhao, Yuqing; Liang, Xing-Jie

2009-01-01

This review, a sequel to part 1 in the series, collects about 107 chemical entities separated from the roots, leaves and flower buds of Panax ginseng, quinquefolius and notoginseng, and categorizes these entities into about 18 groups based on their structural similarity. The bioactivities of these chemical entities are described. The 'Yin and Yang' theory and the fundamentals of the 'five elements' applied to the traditional Chinese medicine (TCM) are concisely introduced to help readers understand how ginseng balances the dynamic equilibrium of human physiological processes from the TCM perspectives. This paper concerns the observation and experimental investigation of biological activities of ginseng used in the TCM of past and present cultures. The current biological findings of ginseng and its medical applications are narrated and critically discussed, including 1) its antihyperglycemic effect that may benefit type II diabetics; in vitro and in vivo studies demonstrated protection of ginseng on beta-cells and obese diabetic mouse models. The related clinical trial results are stated. 2) its aphrodisiac effect and cardiovascular effect that partially attribute to ginseng's bioactivity on nitric oxide (NO); 3) its cognitive effect and neuropharmacological effect that are intensively tested in various rat models using purified ginsenosides and show a hope to treat Parkinson's disease (PD); 4) its uses as an adjuvant or immunotherapeutic agent to enhance immune activity, appetite and life quality of cancer patients during their chemotherapy and radiation. Although the apoptotic effect of ginsenosides, especially Rh2, Rg3 and Compound K, on various tumor cells has been shown via different pathways, their clinical effectiveness remains to be tested. This paper also updates the antioxidant, anti-inflammatory, anti-apoptotic and immune-stimulatory activities of ginseng, its ingredients and commercial products, as well as common side effects of ginseng mainly due to its overdose, and its pharmacokinetics.

Imbalanced decision hierarchy in addicts emerging from drug-hijacked dopamine spiraling circuit.

PubMed

Keramati, Mehdi; Gutkin, Boris

2013-01-01

Despite explicitly wanting to quit, long-term addicts find themselves powerless to resist drugs, despite knowing that drug-taking may be a harmful course of action. Such inconsistency between the explicit knowledge of negative consequences and the compulsive behavioral patterns represents a cognitive/behavioral conflict that is a central characteristic of addiction. Neurobiologically, differential cue-induced activity in distinct striatal subregions, as well as the dopamine connectivity spiraling from ventral striatal regions to the dorsal regions, play critical roles in compulsive drug seeking. However, the functional mechanism that integrates these neuropharmacological observations with the above-mentioned cognitive/behavioral conflict is unknown. Here we provide a formal computational explanation for the drug-induced cognitive inconsistency that is apparent in the addicts' "self-described mistake". We show that addictive drugs gradually produce a motivational bias toward drug-seeking at low-level habitual decision processes, despite the low abstract cognitive valuation of this behavior. This pathology emerges within the hierarchical reinforcement learning framework when chronic exposure to the drug pharmacologically produces pathologicaly persistent phasic dopamine signals. Thereby the drug hijacks the dopaminergic spirals that cascade the reinforcement signals down the ventro-dorsal cortico-striatal hierarchy. Neurobiologically, our theory accounts for rapid development of drug cue-elicited dopamine efflux in the ventral striatum and a delayed response in the dorsal striatum. Our theory also shows how this response pattern depends critically on the dopamine spiraling circuitry. Behaviorally, our framework explains gradual insensitivity of drug-seeking to drug-associated punishments, the blocking phenomenon for drug outcomes, and the persistent preference for drugs over natural rewards by addicts. The model suggests testable predictions and beyond that, sets the stage for a view of addiction as a pathology of hierarchical decision-making processes. This view is complementary to the traditional interpretation of addiction as interaction between habitual and goal-directed decision systems.

The prototypical ranitidine analog JWS-USC-75-IX improves information processing and cognitive function in animal models.

PubMed

Terry, Alvin V; Buccafusco, Jerry J; Herman, Elizabeth J; Callahan, Patrick M; Beck, Wayne D; Warner, Samantha; Vandenhuerk, Leah; Bouchard, Kristy; Schwarz, Gary M; Gao, Jie; Chapman, James M

2011-03-01

This study was designed to evaluate further a prototypical ranitidine analog, JWS-USC-75-IX, [(3-[[[2-[[(5-dimethylaminomethyl)-2-furanyl]methyl]thio]ethyl]amino]-4-nitropyridazine, JWS], for neuropharmacologic properties that would theoretically be useful for treating cognitive and noncognitive behavioral symptoms of neuropsychiatric disorders. JWS was previously found to inhibit acetylcholinesterase (AChE) activity, serve as a potent ligand at muscarinic M₂ acetylcholine receptors, and elicit positive effects on spatial learning, passive avoidance, and working memory in rodents. In the current study, JWS was evaluated for binding activity at more than 60 neurotransmitter receptors, transporters, and ion channels, as well as for inhibitory activity at AChE and butyrylcholinesterase (BChE). The results indicate that JWS inhibits AChE and BChE at low (micromolar) concentrations and that it is a functional antagonist at M₂ receptors (K(B) = 320 nM). JWS was subsequently evaluated orally across additional behavioral assays in rodents (dose range, 0.03-10.0 mg/kg) as well as nonhuman primates (dose range, 0.05-2.0 mg/kg). In rats, JWS improved prepulse inhibition (PPI) of the acoustic startle response in nonimpaired rats and attenuated PPI deficits in three pharmacologic impairment models. JWS also attenuated scopolamine and (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801)-related impairments in a spontaneous novel object recognition task and a five-choice serial reaction time task, respectively. In monkeys, JWS elicited dose-dependent improvements of a delayed match-to-sample task as well as an attention-related version of the task where randomly presented (task-relevant) distractors were presented. Thus, JWS (potentially via effects at several drug targets) improves information processing, attention, and memory in animal models and could potentially treat the cognitive and behavioral symptoms of some neuropsychiatric illnesses.

The Prototypical Ranitidine Analog JWS-USC-75-IX Improves Information Processing and Cognitive Function in Animal Models

PubMed Central

Buccafusco, Jerry J.; Herman, Elizabeth J.; Callahan, Patrick M.; Beck, Wayne D.; Warner, Samantha; Vandenhuerk, Leah; Bouchard, Kristy; Schwarz, Gary M.; Gao, Jie; Chapman, James M.

2011-01-01

This study was designed to evaluate further a prototypical ranitidine analog, JWS-USC-75-IX, [(3-[[[2-[[(5-dimethylaminomethyl)-2-furanyl]methyl]thio]ethyl]amino]-4-nitropyridazine, JWS], for neuropharmacologic properties that would theoretically be useful for treating cognitive and noncognitive behavioral symptoms of neuropsychiatric disorders. JWS was previously found to inhibit acetylcholinesterase (AChE) activity, serve as a potent ligand at muscarinic M2 acetylcholine receptors, and elicit positive effects on spatial learning, passive avoidance, and working memory in rodents. In the current study, JWS was evaluated for binding activity at more than 60 neurotransmitter receptors, transporters, and ion channels, as well as for inhibitory activity at AChE and butyrylcholinesterase (BChE). The results indicate that JWS inhibits AChE and BChE at low (micromolar) concentrations and that it is a functional antagonist at M2 receptors (KB = 320 nM). JWS was subsequently evaluated orally across additional behavioral assays in rodents (dose range, 0.03–10.0 mg/kg) as well as nonhuman primates (dose range, 0.05–2.0 mg/kg). In rats, JWS improved prepulse inhibition (PPI) of the acoustic startle response in nonimpaired rats and attenuated PPI deficits in three pharmacologic impairment models. JWS also attenuated scopolamine and (−)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801)-related impairments in a spontaneous novel object recognition task and a five-choice serial reaction time task, respectively. In monkeys, JWS elicited dose-dependent improvements of a delayed match-to-sample task as well as an attention-related version of the task where randomly presented (task-relevant) distractors were presented. Thus, JWS (potentially via effects at several drug targets) improves information processing, attention, and memory in animal models and could potentially treat the cognitive and behavioral symptoms of some neuropsychiatric illnesses. PMID:21106907

Capsaicin and regulation of respiration: interaction with central substance P mechanisms.

PubMed

Hedner, J; Hedner, T; Jonason, J

1985-01-01

The neuropharmacological effects of capsaicin (CAPS) (8-methyl-N-vanillyl-6-nonenamide) have been closely linked to the peptide neurotransmitter substance P (SP). In order to elucidate SP mechanisms in peripheral and central control of breathing we have studied the respiratory effects of CAPS and SP administration to neonatal and adult rats using a whole body plethysmographic method. CAPS (3 and 30 micrograms) induced an immediate apnea after intravenous injection. This effect could be reduced by vagotomy but not further changed by combined vagotomy and glossopharyngectomy. The apnoic periods were followed by periods of tachypnea. Intracerebroventricular (i.c.v.) administration of CAPS resulted in an increased tidal volume (VT) and a decreased respiratory frequency (f), i.e. a respiratory response similar to that seen after i.c.v. SP. No apnoic episodes were seen after i.c.v. injection. The respiratory pattern after acute i.c.v. CAPS administration was not significantly changed by neonatal CAPS pretreatment. However, while saline pretreated control animals responded to an i.c.v. injection of SP with an increase in VT and inspiratory drive (VT/TI), animals pretreated with CAPS responded with a shortening of inspiratory and expiratory time in combination with an increase in VT. Similar changes have been observed in vagotomized animals after SP administration. It is concluded that CAPS elicits apnea via mechanisms located outside the CNS, which cannot be fully deafferented by combined vagotomy and glossopharyngectomy. Furthermore, CAPS i.c.v. induces a stimulation of respiration by a central mechanism of action, possibly due to a release of SP. Neonatal pretreatment with CAPS modifies the respiratory response to i.c.v. SP. This effect might be due to an impairment in tonical afferent SP mechanisms to the central respiratory regulating system and possibly also to an impairment of central SP mechanisms involved in respiration.

Chemical profiling with HPLC-FTMS of exogenous and endogenous chemicals susceptible to the administration of chotosan in an animal model of type 2 diabetes-induced dementia.

PubMed

Niu, Yimin; Li, Feng; Inada, Chikako; Tanaka, Ken; Watanabe, Shiro; Fujiwara, Hironori; Sasaki-Hamada, Sachie; Oka, Jun-Ichiro; Matsumoto, Kinzo

2015-02-01

In our previous study, the daily administration of chotosan (CTS), a Kampo formula consisting of Uncaria and other 10 different crude drugs, ameliorated cognitive deficits in several animal models of dementia including type 2 diabetic db/db mice in a similar manner to tacrine, an acetylcholinesterase inhibitor. The present study investigated the metabonomics of CTS in db/db mice, a type 2 diabetes model, and m/m mice, a non-diabetes control strain, to identify the exogenous and endogenous chemicals susceptible to the administration of CTS using high performance liquid chromatography equipped with an orbitrap hybrid Fourier transform mass spectrometer. The results obtained revealed that the systemic administration of CTS for 20 days led to the distribution of Uncalia plant-derived alkaloids such as rhynchophylline, hirsuteine, and corynoxeine in the plasma and brains of db/db and m/m mice and induced alterations in four major metabolic pathways; i.e., (1) purine, (2) tryptophan, (3) cysteine and methionine, (4) glycerophospholipids in db/db mice. Moreover, glycerophosphocholine (GPC) levels in the plasma and brain were significantly higher in CTS-treated db/db mice than in vehicle-treated control animals. The results of the in vitro experiment using organotypic hippocampal slice cultures demonstrated that GPC (10-30 μM), as well as tacrine, protected hippocampal cells from N-methyl-d-aspartate-induced excitotoxicity in a manner that was reversible with the muscarinic receptor antagonist scopolamine, whereas GPC had no effect on the activity of acetylcholinesterase in vitro. Our results demonstrated that some CTS constituents with neuropharmacological activity were distributed in the plasma and brain tissue following the systemic administration of CTS and may subsequently have affected some metabolic pathways including glycerophospholipid metabolism and cognitive function in db/db mice. Moreover, the present metabonomic analysis suggested that GPC is a putative endogenous chemical that may be involved in the tacrine-like actions of CTS in the present diabetic animal model. Copyright © 2014 Elsevier B.V. All rights reserved.

Brain Imaging Studies on the Cognitive, Pharmacological and Neurobiological Effects of Cannabis in Humans: Evidence from Studies of Adult Users.

PubMed

Weinstein, Aviv; Livny, Abigail; Weizman, Abraham

2016-01-01

Cannabis is the most widely used illicit drug worldwide. Regular cannabis use has been associated with a range of acute and chronic mental health problems, such as anxiety, depression, psychotic symptoms and neurocognitive impairments and their neural mechanisms need to be examined. This review summarizes and critically evaluates brain-imaging studies of cannabis in recreational and regular cannabis users between January 2000 and January 2016. The search has yielded eligible 103 structural and functional studies. Regular use of cannabis results in volumetric, gray matter and white matter structural changes in the brain, in particular in the hippocampus and the amygdala. Regular use of cannabis affects cognitive processes such as attention, memory, inhibitory control, decision-making, emotional processing, social cognition and their associated brain areas. There is evidence that regular cannabis use leads to altered neural function during attention and working memory and that recruitment of activity in additional brain regions can compensate for it. Similar to other drugs of abuse, cannabis cues activated areas in the reward pathway. Pharmacological studies showed a modest increase in human striatal dopamine transmission after administration of THC in healthy volunteers. Regular cannabis use resulted in reduced dopamine transporter occupancy and reduced dopamine synthesis but not in reduced striatal D2/D3 receptor occupancy compared with healthy control participants. Studies also showed different effects of Δ-9 tetrahydrocannabinol (THC) and cannabidiol (CBD) on emotion, cognition and associated brain regions in healthy volunteers, whereby CBD protects against the psychoactive effects of THC. Brain imaging studies using selective high-affinity radioligands for the imaging of cannabinoid CB1 receptor availability in Positron Emission Tomography (PET) showed downregulation of CB1 in regular users of cannabis. In conclusion, regular use of the cannabinoids exerts structural and functional changes in the human brain. These changes have profound implications for our understanding of the neuropharmacology of cannabis and its effects on cognition, mental health and the brain. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

[Nanopsychiatry. The potential role of nanotechnologies in the future of psychiatry. A systematic review].

PubMed

Fond, G; Miot, S

2013-09-01

Nanomedicine is defined as the area using nanotechnology's concepts for the benefit of human beings, their health and well being. The field of nanotechnology opened new unsuspected fields of research a few years ago. To provide an overview of nanotechnology application areas that could affect care for psychiatric illnesses. We conducted a systematic review using the PRISMA criteria (preferred reporting items for systematic reviews and meta-analysis). Inclusion criteria were specified in advance: all studies describing the development of nanotechnology in psychiatry. The research paradigm was: "(nanotechnology OR nanoparticles OR nanomedicine) AND (central nervous system)" Articles were identified in three research bases, Medline (1966-present), Web of Science (1975-present) and Cochrane (all articles). The last search was carried out on April 2, 2012. Seventy-six items were included in this qualitative review. The main applications of nanotechnology in psychiatry are (i) pharmacology. There are two main difficulties in neuropharmacology. Drugs have to pass the blood brain barrier and then to be internalized by targeted cells. Nanoparticles could increase drugs' bioavailability and pharmacokinetics, especially improving safety and efficacy of psychotropic drugs. Liposomes, nanosomes, nanoparticle polymers, nanobubbles are some examples of this targeted drug delivery. Nanotechnologies could also add new pharmacological properties, like nanohells and dendrimers; (ii) living analysis. Nanotechnology provides technical assistance to in vivo imaging or metabolome analysis; (iii) central nervous system modeling. Research teams have modelized inorganic synapses and mimicked synaptic behavior, essential for further creation of artificial neural systems. Some nanoparticle assemblies present the same small world and free-scale network architecture as cortical neural networks. Nanotechnologies and quantum physics could be used to create models of artificial intelligence and mental illnesses. Even if nanotechnologies are promising, their safety is still tricky and this must be kept in mind. We are not about to see a concrete application of nanomedicine in daily psychiatric practice. However, it seems essential that psychiatrists do not forsake this area of research the perspectives of which could be decisive in the field of mental illness. Copyright © 2013 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

Alterations in pharmacological and behavioural responses in recombinant mouse line with an increased predisposition to catalepsy: role of the 5-HT1A receptor.

PubMed

Kulikova, E A; Bazovkina, D V; Akulov, A E; Tsybko, A S; Fursenko, D V; Kulikov, A V; Naumenko, V S; Ponimaskin, E; Kondaurova, E M

2016-07-01

One important syndrome of psychiatric disorders in humans is catalepsy. Here, we created mice with different predispositions to catalepsy and analysed their pharmacological and behavioural properties. Two mouse lines, B6-M76C and B6-M76B, were created by transfer of the main locus of catalepsy containing the 5-HT1A receptor gene to the C57BL/6 genetic background. Behaviour, brain morphology, expression of key components of the serotoninergic system, and pharmacological responses to acute and chronic stimulation of the 5-HT1A receptor were compared. B6-M76B mice were not cataleptic, whereas 14% of B6-M76C mice demonstrated catalepsy and decreased depressive-like behaviour. Acute administration of the 5-HT1A receptor agonist 8-OH-DPAT resulted in dose-dependent hypothermia and in decreased locomotion in both lines. Chronic 8-OH-DPAT administration abolished the 5-HT1A receptor-mediated hypothermic response in B6-M76C mice and increased locomotor activity in B6-M76B mice. In addition, 5-HT metabolism was significantly reduced in the hippocampus of B6-M76C mice, and this effect was accompanied by an increased expression of the 5-HT1A receptor. Our findings indicate that transfer of the main locus of hereditary catalepsy containing the 5-HT1A receptor from CBA mice to the C57BL/6 genetic background led to increased postsynaptic and decreased presynaptic functional responses of the 5-HT1A receptor. This characteristic establishes the B6-M76C line as an attractive model for the pharmacological screening of 5-HT1A receptor-related drugs specifically acting on either pre- or postsynaptic receptors. This article is part of a themed section on Updating Neuropathology and Neuropharmacology of Monoaminergic Systems. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.13/issuetoc. © 2016 The British Pharmacological Society.

The D1CT-7 mouse model of Tourette syndrome displays sensorimotor gating deficits in response to spatial confinement.

PubMed

Godar, Sean C; Mosher, Laura J; Strathman, Hunter J; Gochi, Andrea M; Jones, Cori M; Fowler, Stephen C; Bortolato, Marco

2016-07-01

The D1CT-7 mouse is one of the best known animal models of Tourette syndrome (TS), featuring spontaneous tic-like behaviours sensitive to standard TS therapies; these characteristics ensure a high face and predictive validity of this model, yet its construct validity remains elusive. To address this issue, we studied the responses of D1CT-7 mice to two critical components of TS pathophysiology: the exacerbation of tic-like behaviours in response to stress and the presence of sensorimotor gating deficits, which are thought to reflect the perceptual alterations causing the tics. D1CT-7 and wild-type (WT) littermates were subjected to a 20 min session of spatial confinement (SC) within an inescapable, 10 cm wide cylindrical enclosure. Changes in plasma corticosterone levels, tic-like behaviours and other spontaneous responses were measured. SC-exposed mice were also tested for the prepulse inhibition (PPI) of the startle response (a sensorimotor gating index) and other TS-related behaviours, including open-field locomotion, novel object exploration and social interaction and compared with non-confined counterparts. SC produced a marked increase in corticosterone concentrations in both D1CT-7 and WT mice. In D1CT-7, but not WT mice, SC exacerbated tic-like and digging behaviours, and triggered PPI deficits and aggressive responses. Conversely, SC did not modify locomotor activity or novel object exploration in D1CT-7 mice. Both tic-like behaviours and PPI impairments in SC-exposed D1CT-7 mice were inhibited by standard TS therapies and D1 dopamine receptor antagonism. These findings collectively support the translational and construct validity of D1CT-7 mice with respect to TS. This article is part of a themed section on Updating Neuropathology and Neuropharmacology of Monoaminergic Systems. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.13/issuetoc. © 2015 The British Pharmacological Society.

A fluorescent approach for identifying P2X1 ligands.

PubMed

Ruepp, Marc-David; Brozik, James A; de Esch, Iwan J P; Farndale, Richard W; Murrell-Lagnado, Ruth D; Thompson, Andrew J

2015-11-01

There are no commercially available, small, receptor-specific P2X1 ligands. There are several synthetic derivatives of the natural agonist ATP and some structurally-complex antagonists including compounds such as PPADS, NTP-ATP, suramin and its derivatives (e.g. NF279, NF449). NF449 is the most potent and selective ligand, but potencies of many others are not particularly high and they can also act at other P2X, P2Y and non-purinergic receptors. While there is clearly scope for further work on P2X1 receptor pharmacology, screening can be difficult owing to rapid receptor desensitisation. To reduce desensitisation substitutions can be made within the N-terminus of the P2X1 receptor, but these could also affect ligand properties. An alternative is the use of fluorescent voltage-sensitive dyes that respond to membrane potential changes resulting from channel opening. Here we utilised this approach in conjunction with fragment-based drug-discovery. Using a single concentration (300 μM) we identified 46 novel leads from a library of 1443 fragments (hit rate = 3.2%). These hits were independently validated by measuring concentration-dependence with the same voltage-sensitive dye, and by visualising the competition of hits with an Alexa-647-ATP fluorophore using confocal microscopy; confocal yielded kon (1.142 × 10(6) M(-1) s(-1)) and koff (0.136 s(-1)) for Alexa-647-ATP (Kd = 119 nM). The identified hit fragments had promising structural diversity. In summary, the measurement of functional responses using voltage-sensitive dyes was flexible and cost-effective because labelled competitors were not needed, effects were independent of a specific binding site, and both agonist and antagonist actions were probed in a single assay. The method is widely applicable and could be applied to all P2X family members, as well as other voltage-gated and ligand-gated ion channels. This article is part of the Special Issue entitled 'Fluorescent Tools in Neuropharmacology'. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Looking for the Self: Phenomenology, Neurophysiology and Philosophical Significance of Drug-induced Ego Dissolution

PubMed Central

Millière, Raphaël

2017-01-01

There is converging evidence that high doses of hallucinogenic drugs can produce significant alterations of self-experience, described as the dissolution of the sense of self and the loss of boundaries between self and world. This article discusses the relevance of this phenomenon, known as “drug-induced ego dissolution (DIED)”, for cognitive neuroscience, psychology and philosophy of mind. Data from self-report questionnaires suggest that three neuropharmacological classes of drugs can induce ego dissolution: classical psychedelics, dissociative anesthetics and agonists of the kappa opioid receptor (KOR). While these substances act on different neurotransmitter receptors, they all produce strong subjective effects that can be compared to the symptoms of acute psychosis, including ego dissolution. It has been suggested that neuroimaging of DIED can indirectly shed light on the neural correlates of the self. While this line of inquiry is promising, its results must be interpreted with caution. First, neural correlates of ego dissolution might reveal the necessary neurophysiological conditions for the maintenance of the sense of self, but it is more doubtful that this method can reveal its minimally sufficient conditions. Second, it is necessary to define the relevant notion of self at play in the phenomenon of DIED. This article suggests that DIED consists in the disruption of subpersonal processes underlying the “minimal” or “embodied” self, i.e., the basic experience of being a self rooted in multimodal integration of self-related stimuli. This hypothesis is consistent with Bayesian models of phenomenal selfhood, according to which the subjective structure of conscious experience ultimately results from the optimization of predictions in perception and action. Finally, it is argued that DIED is also of particular interest for philosophy of mind. On the one hand, it challenges theories according to which consciousness always involves self-awareness. On the other hand, it suggests that ordinary conscious experience might involve a minimal kind of self-awareness rooted in multisensory processing, which is what appears to fade away during DIED. PMID:28588463

N-Acetyl-S-(N,N-diethylcarbamoyl) cysteine in rat nucleus accumbens, medial prefrontal cortex, and in RAT and human plasma after disulfiram administration

PubMed Central

Winefield, Robert D.; Heemskerk, Anthonius A.M.; Kaul, Swetha; Williams, Todd D.; Caspers, Michael J.; Prisinzano, Thomas E.; McCance-Katz, Elinore F.; Lunte, Craig E.

2015-01-01

Disulfiram (DSF), a treatment for alcohol use disorders, has shown some clinical effectiveness in treating addiction to cocaine, nicotine, and pathological gambling. The mechanism of action of DSF for treating these addictions is unclear but it is unlikely to involve the inhibition of liver aldehyde dehydrogenase (ALDH2). DSF is a pro-drug and forms a number of metabolites, one of which is N-acetyl-S-(N,N-diethylcarbamoyl) cysteine (DETC-NAC). Here we describe a LCMS/MS method on a QQQ type instrument to quantify DETC-NAC in plasma and intracellular fluid from mammalian brain. An internal standard, the N,N-di-isopropylcarbamoyl homolog (MIM: 291 > 128) is easily separable from DETC-NAC (MIM: 263 > 100) on C18 RP media with a methanol gradient. The method's linear range is 0.5–500 nM from plasma and dialysate salt solution with all precisions better than 10% RSD. DETC-NAC and internal standards were recovered at better than 95% from all matrices, perchloric acid precipitation (plasma) or formic acid addition (salt) and is stable in plasma or salt at low pH for up to 24 h. Stability is observed through three freeze-thaw cycles per day for 7 days. No HPLC peak area matrix effect was greater than 10%. A human plasma sample from a prior analysis for S-(N,N-diethylcarbamoyl) glutathione (CARB) was found to have DETC NAC as well. In other human plasma samples from 62.5 mg/d and 250mg/d dosing, CARB concentration peaks at 0.3 and 4 nM at 3 h followed by DETC-NAC peaks of 11 and 70 nM 2 h later. Employing microdialysis sampling, DETC-NAC levels in the nucleus accumbens (NAc), medial prefrontal cortex (mPFC), and plasma of rats treated with DSF reached 1.1, 2.5 and 80 nM at 6 h. The correlation between the appearance and long duration of DETC-NAC concentration in rat brain and the persistence of DSF-induced changes in neurotransmitters observed by Faiman et al. (Neuropharmacology, 2013, 75C, 95–105) is discussed. PMID:25720821

Ethnopharmacology—A Bibliometric Analysis of a Field of Research Meandering Between Medicine and Food Science?

PubMed Central

Yeung, Andy Wai Kan; Heinrich, Michael; Atanasov, Atanas G.

2018-01-01

Background: The research into bioactive natural products of medicinal plants has a long tradition, but ethnopharmacology as a well-defined field of research has a relatively short history, only dating back 50 years. Aims: With the fast development of this field and its global importance especially in the fast developing economies of Asia it is timely to assess the most influential articles (as measured by citations) and to identify important drivers and research trends in this field. Methods: Scopus was searched to identify relevant articles which were assessed by all three authors. The 100 most cited articles were identified and analyzed. Bibliometric software (VOSviewer) was utilized to supplement the analysis and to generate a term map that visualized the citation patterns of the 100 articles containing different terms. Results: Forty-four of the 100 articles are reviews. On average, each of the 100 articles had 632 citations and since publication was cited 43 times annually. The four core journals were Journal of Ethnopharmacology (n = 17), Food Chemistry (n = 7), Life Sciences (n = 5), and Journal of Agricultural and Food Chemistry (n = 4). Anti-oxidant effects appeared to be a recurring and highly cited topic, whereas the links into drug discovery and neuropharmacology seemed to be less strong. Numerous medicinal plants and functional foods were the foci of research, and the foci shifted when comparing pre-2000 and post-2000 publications (with the later involving a broader spectrum of plants and foods and a wider range of biological effects). Contributions largely came from Asia, and also from the Americas, Africa, and Oceania, besides Europe. Conclusion: We have identified and analyzed the 100 most-cited articles in ethnopharmacology. Within 50 years the field has gained a profile and while conventionally often linked to “traditional knowledge,” drug discovery and some areas of pharmacology, this analysis highlights its emerging importance in the context of disease prevention (food science), but also the development of research driven by the needs and interests of the fast developing economies most notably of Asia. PMID:29599720

Ethnopharmacology-A Bibliometric Analysis of a Field of Research Meandering Between Medicine and Food Science?

PubMed

Yeung, Andy Wai Kan; Heinrich, Michael; Atanasov, Atanas G

2018-01-01

Background: The research into bioactive natural products of medicinal plants has a long tradition, but ethnopharmacology as a well-defined field of research has a relatively short history, only dating back 50 years. Aims: With the fast development of this field and its global importance especially in the fast developing economies of Asia it is timely to assess the most influential articles (as measured by citations) and to identify important drivers and research trends in this field. Methods: Scopus was searched to identify relevant articles which were assessed by all three authors. The 100 most cited articles were identified and analyzed. Bibliometric software (VOSviewer) was utilized to supplement the analysis and to generate a term map that visualized the citation patterns of the 100 articles containing different terms. Results: Forty-four of the 100 articles are reviews. On average, each of the 100 articles had 632 citations and since publication was cited 43 times annually. The four core journals were Journal of Ethnopharmacology ( n = 17), Food Chemistry ( n = 7), Life Sciences ( n = 5), and Journal of Agricultural and Food Chemistry ( n = 4). Anti-oxidant effects appeared to be a recurring and highly cited topic, whereas the links into drug discovery and neuropharmacology seemed to be less strong. Numerous medicinal plants and functional foods were the foci of research, and the foci shifted when comparing pre-2000 and post-2000 publications (with the later involving a broader spectrum of plants and foods and a wider range of biological effects). Contributions largely came from Asia, and also from the Americas, Africa, and Oceania, besides Europe. Conclusion: We have identified and analyzed the 100 most-cited articles in ethnopharmacology. Within 50 years the field has gained a profile and while conventionally often linked to "traditional knowledge," drug discovery and some areas of pharmacology, this analysis highlights its emerging importance in the context of disease prevention (food science), but also the development of research driven by the needs and interests of the fast developing economies most notably of Asia.

Development of Micro-Electrode Array Based Tests for Neurotoxicity: Assessment of Interlaboratory Reproducibility with Neuroactive Chemicals

PubMed Central

Novellino, A.; Scelfo, Bibiana; Palosaari, T.; Price, A.; Sobanski, Tomasz; Shafer, T. J.; Johnstone, A. F. M.; Gross, G. W.; Gramowski, A.; Schroeder, O.; Jügelt, K.; Chiappalone, M.; Benfenati, F.; Martinoia, S.; Tedesco, M. T.; Defranchi, E.; D’Angelo, P.; Whelan, M.

2011-01-01

Neuronal assemblies within the nervous system produce electrical activity that can be recorded in terms of action potential patterns. Such patterns provide a sensitive endpoint to detect effects of a variety of chemical and physical perturbations. They are a function of synaptic changes and do not necessarily involve structural alterations. In vitro neuronal networks (NNs) grown on micro-electrode arrays (MEAs) respond to neuroactive substances as well as the in vivo brain. As such, they constitute a valuable tool for investigating changes in the electrophysiological activity of the neurons in response to chemical exposures. However, the reproducibility of NN responses to chemical exposure has not been systematically documented. To this purpose six independent laboratories (in Europe and in USA) evaluated the response to the same pharmacological compounds (Fluoxetine, Muscimol, and Verapamil) in primary neuronal cultures. Common standardization principles and acceptance criteria for the quality of the cultures have been established to compare the obtained results. These studies involved more than 100 experiments before the final conclusions have been drawn that MEA technology has a potential for standard in vitro neurotoxicity/neuropharmacology evaluation. The obtained results show good intra- and inter-laboratory reproducibility of the responses. The consistent inhibitory effects of the compounds were observed in all the laboratories with the 50% Inhibiting Concentrations (IC50s) ranging from: (mean ± SEM, in μM) 1.53 ± 0.17 to 5.4 ± 0.7 (n = 35) for Fluoxetine, 0.16 ± 0.03 to 0.38 ± 0.16 μM (n = 35) for Muscimol, and 2.68 ± 0.32 to 5.23 ± 1.7 (n = 32) for Verapamil. The outcome of this study indicates that the MEA approach is a robust tool leading to reproducible results. The future direction will be to extend the set of testing compounds and to propose the MEA approach as a standard screen for identification and prioritization of chemicals with neurotoxicity potential. PMID:21562604

DOE Office of Scientific and Technical Information (OSTI.GOV)

Heusinkveld, Harm J.; Westerink, Remco H.S., E-mail: R.Westerink@uu.nl

Calcium plays a crucial role in virtually all cellular processes, including neurotransmission. The intracellular Ca{sup 2+} concentration ([Ca{sup 2+}]{sub i}) is therefore an important readout in neurotoxicological and neuropharmacological studies. Consequently, there is an increasing demand for high-throughput measurements of [Ca{sup 2+}]{sub i}, e.g. using multi-well microplate readers, in hazard characterization, human risk assessment and drug development. However, changes in [Ca{sup 2+}]{sub i} are highly dynamic, thereby creating challenges for high-throughput measurements. Nonetheless, several protocols are now available for real-time kinetic measurement of [Ca{sup 2+}]{sub i} in plate reader systems, though the results of such plate reader-based measurements have beenmore » questioned. In view of the increasing use of plate reader systems for measurements of [Ca{sup 2+}]{sub i} a careful evaluation of current technologies is warranted. We therefore performed an extensive set of experiments, using two cell lines (PC12 and B35) and two fluorescent calcium-sensitive dyes (Fluo-4 and Fura-2), for comparison of a linear plate reader system with single cell fluorescence microscopy. Our data demonstrate that the use of plate reader systems for high-throughput real-time kinetic measurements of [Ca{sup 2+}]{sub i} is associated with many pitfalls and limitations, including erroneous sustained increases in fluorescence, limited sensitivity and lack of single cell resolution. Additionally, our data demonstrate that probenecid, which is often used to prevent dye leakage, effectively inhibits the depolarization-evoked increase in [Ca{sup 2+}]{sub i}. Overall, the data indicate that the use of current plate reader-based strategies for high-throughput real-time kinetic measurements of [Ca{sup 2+}]{sub i} is associated with caveats and limitations that require further investigation. - Research Highlights: > The use of plate readers for high-throughput screening of intracellular Ca{sup 2+} is associated with many pitfalls and limitations. > Single cell fluorescent microscopy is recommended for measurements of intracellular Ca{sup 2+}. > Dual-wavelength dyes (Fura-2) are preferred over single-wavelength dyes (Fluo-4) for measurements of intracellular Ca{sup 2+}. > Probenecid prevents dye leakage but abolishes depolarization-evoked Ca{sup 2+} influx, severely hampering measurements of Ca{sup 2+}. > In general, care should be taken when interpreting data from high-throughput kinetic measurements.« less

Neuropharmacology of New Psychoactive Substances (NPS): Focus on the Rewarding and Reinforcing Properties of Cannabimimetics and Amphetamine-Like Stimulants

PubMed Central

Miliano, Cristina; Serpelloni, Giovanni; Rimondo, Claudia; Mereu, Maddalena; Marti, Matteo; De Luca, Maria Antonietta

2016-01-01

New psychoactive substances (NPS) are a heterogeneous and rapidly evolving class of molecules available on the global illicit drug market (e.g smart shops, internet, “dark net”) as a substitute for controlled substances. The use of NPS, mainly consumed along with other drugs of abuse and/or alcohol, has resulted in a significantly growing number of mortality and emergency admissions for overdoses, as reported by several poison centers from all over the world. The fact that the number of NPS have more than doubled over the last 10 years, is a critical challenge to governments, the scientific community, and civil society [EMCDDA (European Drug Report), 2014; UNODC, 2014b; Trends and developments]. The chemical structure (phenethylamines, piperazines, cathinones, tryptamines, synthetic cannabinoids) of NPS and their pharmacological and clinical effects (hallucinogenic, anesthetic, dissociative, depressant) help classify them into different categories. In the recent past, 50% of newly identified NPS have been classified as synthetic cannabinoids followed by new phenethylamines (17%) (UNODC, 2014b). Besides peripheral toxicological effects, many NPS seem to have addictive properties. Behavioral, neurochemical, and electrophysiological evidence can help in detecting them. This manuscript will review existing literature about the addictive and rewarding properties of the most popular NPS classes: cannabimimetics (JWH, HU, CP series) and amphetamine-like stimulants (amphetamine, methamphetamine, methcathinone, and MDMA analogs). Moreover, the review will include recent data from our lab which links JWH-018, a CB1 and CB2 agonist more potent than Δ9-THC, to other cannabinoids with known abuse potential, and to other classes of abused drugs that increase dopamine signaling in the Nucleus Accumbens (NAc) shell. Thus the neurochemical mechanisms that produce the rewarding properties of JWH-018, which most likely contributes to the greater incidence of dependence associated with “Spice” use, will be described (De Luca et al., 2015a). Considering the growing evidence of a widespread use of NPS, this review will be useful to understand the new trends in the field of drug reward and drug addiction by revealing the rewarding properties of NPS, and will be helpful to gather reliable data regarding the abuse potential of these compounds. PMID:27147945

Effect of root-extracts of Ficus benghalensis (Banyan) in memory, anxiety, muscle co-ordination and seizure in animal models.

PubMed

Panday, Dipesh Raj; Rauniar, G P

2016-11-03

Ficus benghalensis L. (Banyan) is a commonly found tree in Eastern Nepal. Its different plant parts are used for various neurological ailments. This study was performed in mice to see its effects in various neuropharmacological parameters. Passive-avoidance (memory), Open-field (anxiety), Pentobarbital-induced Sleep potentiation (sleep), Rota-rod (muscle-co-ordination), Pentylenetetrazol-Induced and Maximal Electroshock Seizure Tests were performed. Sample size was calculated using G*Power 3.1.9.2. Aqueous root extracts (Soxhlet method) of Ficus benghalensis 100 mg/kg and 200 mg/kg with negative and positive controls were used. The experimental results were represented as Mean ± SD. P-value was set at <0.05. Oneway analysis of variance (ANOVA) or Mann-Whitney U test was appropriately used. Passive-avoidance test showed 200 mg/kg group spent significantly less. Time (0.00s + 0.00s) in shock-zone than Normal Saline-group (9.67 s + 14.36 s, P = 0.000) or Diazepam-group (41.07 s + 88.24 s, P = 0.000). Open-field test showed 200 mg/kg group spent significantly longer Time (24.77 s + 12.23 s) in central-square than either Normal Saline group (15.08 s + 6.81 s, P = 0.000) or Diazepam-group (15.32 s + 5.12 s, P = 0.000). In Rota-rod test, 200 mg/kg group fell off the rod significantly (P = 0.000) earlier (33.01 s + 43.61 s) than both Normal Saline (>120 s) and Diazepam (62.07 s + 43.83 s) PTZ model showed that 100 mg/kg significantly (P = 0.004) delayed seizure-onset (184.40s + 36.36 s) compared to Normal Saline (101.79 s + 22.81 s), however, in MES model 200 mg/kg significantly (P = 0.000) prolonged tonic hind-limb extension (17.57 s + 2.15 s) compared to Normal Saline (13.55 s + 2.75 s) or Phenytoin (00.00s + 00.00s). Aerial roots of Ficus benghalensis have memory-enhancing, anxiolytic, musclerelaxant, and seizure-modifying effect.

Drugs of abuse that mediate advanced glycation end product formation: a chemical link to disease pathology.

PubMed

Treweek, Jennifer B; Dickerson, Tobin J; Janda, Kim D

2009-05-19

Nicotine and methamphetamine are frequently abused in modern society, despite the increasing evidence of their addictive, neuropharmacological, and toxic effects. Tobacco, the most widely abused substance, is the leading cause of preventable death in the United States, killing nearly half a million Americans annually. A methamphetamine epidemic has also spread during the past decade; severe neurotoxicity and addictiveness contribute to the drug's notoriety. Although the majority of research on these two drugs is of pharmacological and neurobiological motivation, further study of these molecules from a chemical perspective may provide novel mechanistic insight into either their addictive potential or their pathological effects. For example, nicotine and methamphetamine share a common structural feature, a secondary amine, suggesting that these molecules could possess similar (or analogous) in vivo reactivity. Discoveries concerning the synthetic requirements for aqueous aldol catalysis and the feasibility of the enamine mechanism under physiological conditions have given rise to the hypothesis that ingested molecules, such as abused drugs, could participate in reactions utilizing an enamine intermediate in vivo. The chemical reactivity of exogenous drugs with amine functionalities was initially examined in the context of the Maillard reaction, or nonenzymatic browning. The heating of reducing sugars with amino acids yields a brown solution; studies of this reaction were originally applied to food chemistry for the production of distinct flavors and aromas. Further research has since revealed numerous instances in which the in vivo production of advanced glycation end products (AGEs) through the Maillard reaction contribute to the pathology of disease states. Specifically, the modification of long-lived proteins by glycation and glycoxidation and the accumulation of these AGEs compromise the original function of such proteins and change the mechanical properties of affected tissue. In this Account, we summarize our investigations into the capacity for exogenous compounds to initiate the Maillard reaction and the corresponding physiological and immunological impact of the drug-conjugated AGEs that form. Many of the pathological components of diabetes, atherosclerosis, cancer, macular degeneration, Alzheimer's disease, and even the normal aging process are attributable to AGEs and their potential for aggregate formation in the vasculature. A deeper understanding of AGEs, and particularly glycated proteins, will provide fundamental mechanistic insight into disease origins.

Role of Anterior Intralaminar Nuclei of Thalamus Projections to Dorsomedial Striatum in Incubation of Methamphetamine Craving.

PubMed

Li, Xuan; Witonsky, Kailyn R; Lofaro, Olivia M; Surjono, Felicia; Zhang, Jianjun; Bossert, Jennifer M; Shaham, Yavin

2018-02-28

Relapse to methamphetamine (Meth) seeking progressively increases after withdrawal from drug self-administration (incubation of Meth craving). We previously demonstrated a role of dorsomedial striatum (DMS) dopamine D1 receptors (D1Rs) in this incubation. Here, we studied the role of afferent glutamatergic projections into the DMS and local D1R-glutamate interaction in this incubation in male rats. We first measured projection-specific activation on day 30 relapse test by using cholera toxin b (retrograde tracer) + Fos (activity marker) double-labeling in projection areas. Next, we determined the effect of pharmacological reversible inactivation of lateral or medial anterior intralaminar nuclei of thalamus (AIT-L or AIT-M) on incubated Meth seeking on withdrawal day 30. We then used an anatomical asymmetrical disconnection procedure to determine whether an interaction between AIT-L→DMS glutamatergic projections and postsynaptic DMS D1Rs contributes to incubated Meth seeking. We also determined the effect of unilateral inactivation of AIT-L and D1R blockade of DMS on incubated Meth seeking, and the effect of contralateral disconnection of AIT-L→DMS projections on nonincubated Meth seeking on withdrawal day 1. Incubated Meth seeking was associated with selective activation of AIT→DMS projections; other glutamatergic projections to DMS were not activated. AIT-L (but not AIT-M) inactivation or anatomical disconnection of AIT-L→DMS projections decreased incubated Meth seeking. Unilateral inactivation of AIT-L or D1R blockade of the DMS had no effect on incubated Meth craving, and contralateral disconnection of AIT-L→DMS projections had no effect on nonincubated Meth seeking. Our results identify a novel role of AIT-L and AIT-L→DMS glutamatergic projections in incubation of drug craving and drug seeking. SIGNIFICANCE STATEMENT Methamphetamine seeking progressively increases after withdrawal from drug self-administration, a phenomenon termed incubation of methamphetamine craving. We previously found that D1R-mediated dopamine transmission in the dorsomedial striatum plays a critical role in this incubation phenomenon. Here, we used neuroanatomical and neuropharmacological methods in rats to demonstrate that an interaction between the glutamatergic projection from the lateral anterior intralaminar nuclei of the thalamus to the dorsomedial striatum and local dopamine D1 receptors plays a critical role in relapse to methamphetamine seeking after prolonged withdrawal. Our study identified a novel motivation-related thalamostriatal projection critical to relapse to drug seeking. Copyright © 2018 the authors 0270-6474/18/382270-13$15.00/0.

Role of the 5-HT2A Receptor in Self- and Other-Initiated Social Interaction in Lysergic Acid Diethylamide-Induced States: A Pharmacological fMRI Study.

PubMed

Preller, Katrin H; Schilbach, Leonhard; Pokorny, Thomas; Flemming, Jan; Seifritz, Erich; Vollenweider, Franz X

2018-04-04

Distortions of self-experience are critical symptoms of psychiatric disorders and have detrimental effects on social interactions. In light of the immense need for improved and targeted interventions for social impairments, it is important to better understand the neurochemical substrates of social interaction abilities. We therefore investigated the pharmacological and neural correlates of self- and other-initiated social interaction. In a double-blind, randomized, counterbalanced, crossover study 24 healthy human participants (18 males and 6 females) received either (1) placebo + placebo, (2) placebo + lysergic acid diethylamide (LSD; 100 μg, p.o.), or (3) ketanserin (40 mg, p.o.) + LSD (100 μg, p.o.) on three different occasions. Participants took part in an interactive task using eye-tracking and functional magnetic resonance imaging completing trials of self- and other-initiated joint and non-joint attention. Results demonstrate first, that LSD reduced activity in brain areas important for self-processing, but also social cognition; second, that change in brain activity was linked to subjective experience; and third, that LSD decreased the efficiency of establishing joint attention. Furthermore, LSD-induced effects were blocked by the serotonin 2A receptor (5-HT 2A R) antagonist ketanserin, indicating that effects of LSD are attributable to 5-HT 2A R stimulation. The current results demonstrate that activity in areas of the "social brain" can be modulated via the 5-HT 2A R thereby pointing toward this system as a potential target for the treatment of social impairments associated with psychiatric disorders. SIGNIFICANCE STATEMENT Distortions of self-representation and, potentially related to this, dysfunctional social cognition are central hallmarks of various psychiatric disorders and critically impact disease development, progression, treatment, as well as real-world functioning. However, these deficits are insufficiently targeted by current treatment approaches. The administration of lysergic acid diethylamide (LSD) in combination with functional magnetic resonance imaging and real-time eye-tracking offers the unique opportunity to study alterations in self-experience, their relation to social cognition, and the underlying neuropharmacology. Results demonstrate that LSD alters self-experience as well as basic social cognition processing in areas of the "social brain". Furthermore, these alterations are attributable to 5-HT 2A receptor stimulation, thereby pinpointing toward this receptor system in the development of pharmacotherapies for sociocognitive deficits in psychiatric disorders. Copyright © 2018 the authors 0270-6474/18/383603-09$15.00/0.

Role of Ventral Subiculum in Context-Induced Relapse to Alcohol Seeking after Punishment-Imposed Abstinence

PubMed Central

Campbell, Erin J.; Whitaker, Leslie R.; Harvey, Brandon K.; Kaganovsky, Konstantin; Adhikary, Sweta; Hope, Bruce T.; Heins, Robert C.; Prisinzano, Thomas E.; Vardy, Eyal; Bonci, Antonello; Bossert, Jennifer M.

2016-01-01

In many human alcoholics, abstinence is self-imposed because of the negative consequences of excessive alcohol use, and relapse is often triggered by exposure to environmental contexts associated with prior alcohol drinking. We recently developed a rat model of this human condition in which we train alcohol-preferring P rats to self-administer alcohol in one context (A), punish the alcohol-reinforced responding in a different context (B), and then test for relapse to alcohol seeking in Contexts A and B without alcohol or shock. Here, we studied the role of projections to nucleus accumbens (NAc) shell from ventral subiculum (vSub), basolateral amygdala, paraventricular thalamus, and ventral medial prefrontal cortex in context-induced relapse after punishment-imposed abstinence. First, we measured double-labeling of the neuronal activity marker Fos with the retrograde tracer cholera toxin subunit B (injected in NAc shell) and demonstrated that context-induced relapse is associated with selective activation of the vSub→NAc shell projection. Next, we reversibly inactivated the vSub with GABA receptor agonists (muscimol+baclofen) before the context-induced relapse tests and provided evidence for a causal role of vSub in this relapse. Finally, we used a dual-virus approach to restrict expression of the inhibitory κ opioid-receptor based DREADD (KORD) in vSub→NAc shell projection neurons. We found that systemic injections of the KORD agonist salvinorin B, which selectively inhibits KORD-expressing neurons, decreased context-induced relapse to alcohol seeking. Our results demonstrate a critical role of vSub in context-induced relapse after punishment-imposed abstinence and further suggest a role of the vSub→NAc projection in this relapse. SIGNIFICANCE STATEMENT In many human alcoholics, abstinence is self-imposed because of the negative consequences of excessive use, and relapse is often triggered by exposure to environmental contexts associated with prior alcohol use. Until recently, an animal model of this human condition did not exist. We developed a rat model of this human condition in which we train alcohol-preferring P rats to self-administer alcohol in one context (A), punish the alcohol-reinforced responding in a different context (B), and test for relapse to alcohol seeking in Contexts A and B. Here, we used neuroanatomical, neuropharmacological, and chemogenetic methods to demonstrate a role of ventral subiculum and potentially its projections to nucleus accumbens in context-induced relapse after punishment-imposed abstinence. PMID:26985037

Animal models of alcoholism: neurobiology of high alcohol-drinking behavior in rodents.

PubMed

McBride, W J; Li, T K

1998-01-01

This review discusses efforts to develop rodent models for the study of neurobiological mechanisms underlying chronic alcohol drinking, alcoholism, and abnormal alcohol-seeking behavior. Selective breeding has produced stable lines of rats that reliably exhibit high and (for comparison purposes) low voluntary alcohol consumption. In addition, animal models of chronic ethanol self-administration have been developed in rodents, who do not have a genetic predisposition for high alcohol-seeking behavior, to explore environmental influences in ethanol drinking and the effects of physical dependence on alcohol self-administration. The selectively bred high-preference animals reliably self-administer ethanol by free-choice drinking and operantly respond for oral ethanol in amounts that produce pharmacologically meaningful blood alcohol concentrations (50 to 200 mg% and higher). In addition, the alcohol-preferring rats will self-administer ethanol by intragastric infusion. With chronic free-choice drinking, the high alcohol-preferring rats develop tolerance to the high-dose effects of ethanol and show signs of physical dependence after the withdrawal of alcohol. Compared with nonpreferring animals, the alcohol-preferring rats are less sensitive to the sedative-hypnotic effects of ethanol and develop tolerance more quickly to high-dose ethanol. Nonselected common stock rats can be trained to chronically self-administer ethanol following its initial presentation in a palatable sucrose or saccharin solution, and the gradual replacement of the sucrose or saccharin with ethanol (the sucrose/saccharin-fade technique). Moreover, rats that are trained in this manner and then made dependent by ethanol-vapor inhalation or liquid diet increase their ethanol self-administration during the withdrawal period. Both the selectively bred rats and common-stock rats demonstrate "relapse" and an alcohol deprivation effect following 2 or more weeks of abstinence. Systemic administration of agents that (1) increase synaptic levels of serotonin (5-HT) or dopamine (DA); (2) activate 5-HT1A, 5-HT2, D2, D3, or GABA(A) receptors; or (3) block opioid and 5-HT3 receptors decrease ethanol intake in most animal models. Neurochemical, neuroanatomical, and neuropharmacological studies indicate innate differences exist between the high alcohol-consuming and low alcohol-consuming rodents in various CNS limbic structures. In addition, reduced mesolimbic DA and 5-HT function have been observed during alcohol withdrawal in common stock rats. Depending on the animal model under study, abnormalities in the mesolimbic dopamine pathway, and/or the serotonin, opioid, and GABA systems that regulate this pathway may underlie vulnerability to the abnormal alcohol-seeking behavior in the genetic animal models.

Role of Ventral Subiculum in Context-Induced Relapse to Alcohol Seeking after Punishment-Imposed Abstinence.

PubMed

Marchant, Nathan J; Campbell, Erin J; Whitaker, Leslie R; Harvey, Brandon K; Kaganovsky, Konstantin; Adhikary, Sweta; Hope, Bruce T; Heins, Robert C; Prisinzano, Thomas E; Vardy, Eyal; Bonci, Antonello; Bossert, Jennifer M; Shaham, Yavin

2016-03-16

In many human alcoholics, abstinence is self-imposed because of the negative consequences of excessive alcohol use, and relapse is often triggered by exposure to environmental contexts associated with prior alcohol drinking. We recently developed a rat model of this human condition in which we train alcohol-preferring P rats to self-administer alcohol in one context (A), punish the alcohol-reinforced responding in a different context (B), and then test for relapse to alcohol seeking in Contexts A and B without alcohol or shock. Here, we studied the role of projections to nucleus accumbens (NAc) shell from ventral subiculum (vSub), basolateral amygdala, paraventricular thalamus, and ventral medial prefrontal cortex in context-induced relapse after punishment-imposed abstinence. First, we measured double-labeling of the neuronal activity marker Fos with the retrograde tracer cholera toxin subunit B (injected in NAc shell) and demonstrated that context-induced relapse is associated with selective activation of the vSub→NAc shell projection. Next, we reversibly inactivated the vSub with GABA receptor agonists (muscimol+baclofen) before the context-induced relapse tests and provided evidence for a causal role of vSub in this relapse. Finally, we used a dual-virus approach to restrict expression of the inhibitory κ opioid-receptor based DREADD (KORD) in vSub→NAc shell projection neurons. We found that systemic injections of the KORD agonist salvinorin B, which selectively inhibits KORD-expressing neurons, decreased context-induced relapse to alcohol seeking. Our results demonstrate a critical role of vSub in context-induced relapse after punishment-imposed abstinence and further suggest a role of the vSub→NAc projection in this relapse. In many human alcoholics, abstinence is self-imposed because of the negative consequences of excessive use, and relapse is often triggered by exposure to environmental contexts associated with prior alcohol use. Until recently, an animal model of this human condition did not exist. We developed a rat model of this human condition in which we train alcohol-preferring P rats to self-administer alcohol in one context (A), punish the alcohol-reinforced responding in a different context (B), and test for relapse to alcohol seeking in Contexts A and B. Here, we used neuroanatomical, neuropharmacological, and chemogenetic methods to demonstrate a role of ventral subiculum and potentially its projections to nucleus accumbens in context-induced relapse after punishment-imposed abstinence. Copyright © 2016 the authors 0270-6474/16/363282-14$15.00/0.

Establishing a learned-helplessness effect paradigm in C57BL/6 mice: behavioural evidence for emotional, motivational and cognitive effects of aversive uncontrollability per se.

PubMed

Pryce, Christopher R; Azzinnari, Damiano; Sigrist, Hannes; Gschwind, Tilo; Lesch, Klaus-Peter; Seifritz, Erich

2012-01-01

Uncontrollability of major life events has been proposed to be central to depression onset and maintenance. The learned helplessness (LH) effect describes a deficit in terminating controllable aversive stimuli in individuals that experienced aversive stimuli as uncontrollable relative to individuals that experienced the same stimuli as controllable. The LH effect translates across species and therefore can provide an objective-valid readout in animal models of depression. Paradigms for a robust LH effect are established and currently applied in rat but there are few reports of prior and current study of the LH effect in mouse. This includes the C57BL/6 mouse, typically the strain of choice for application of molecular-genetic tools in pre-clinical depression research. The aims of this study were to develop a robust paradigm for the LH effect in BL/6 mice, provide evidence for underlying psychological processes, and study the effect of a depression-relevant genotype on the LH effect. The apparatus used for in/escapable electro-shock exposure and escape test was a two-way shuttle arena with continuous automated measurement of locomotion, compartment transfers, e-shock escapes, vertical activity and freezing. Brother-pairs of BL/6 mice were allocated to either escapable e-shocks (ES) or inescapable e-shocks (IS), with escape latencies of the ES brother used as e-shock durations for the IS brother. The standard two-way shuttle paradigm was modified: the central gate was replaced by a raised divider and e-shock escape required transfer to the distal part of the safe compartment. These refinements yielded reduced superstitious, pre-adaptive e-shock transfers in IS mice and thereby increased the LH effect. To obtain a robust LH effect in all brother pairs, pre-screening for minor between-brother ES differences was necessary and did not confound the LH effect. IS mice developed reduced motor responses to e-shock, consistent with a motivational deficit, and absence of a learning curve for escapes at escape test, consistent with a cognitive deficit. When a tone CS was used to predict e-shock, IS mice exhibited increased reactivity to the CS, consistent with hyper-emotionality. There was no ES-IS difference in pain sensitivity. Mice heterozygous knockout for the 5-HTT gene exhibited an increased LH effect relative to wildtype mice. This mouse model will allow for the detailed molecular study of the aetiology, psychology, neurobiology and neuropharmacology of uncontrollability of aversive stimuli, a potential major aetiological factor and state marker in depression. This article is part of a Special Issue entitled 'Anxiety and Depression'. Copyright © 2011 Elsevier Ltd. All rights reserved.

[Psychotic disorder induced by Fahr's syndrome: a case report].

PubMed

El Hechmi, S; Bouhlel, S; Melki, W; El Hechmi, Z

2014-06-01

Fahr's syndrome is a rare disorder characterized by abnormal deposits of calcium in areas of the brain that control movement, including the basal ganglia and the cerebral cortex associated with many neurological and psychiatric abnormalities such as a rigid hypokinetic syndrome, mood disorders and cognitive impairment. Fahr's syndrome is secondary to some disorders, such as hypoparathyroidism. We report the case of a 56 year-old man, with a history of cataract, who was admitted to our psychiatric hospital for the first time in his life because of psychotic symptoms associated with irritability and aggressiveness. Since the age of 38 the patient had become nervous, 10 years later he developed tonic-clonic seizures. Two months ago, he began expressing delusions of persecution against his wife and sons and making fugues. According to his family during this period, he was agitated, aggressive, and suffered from insomnia and anorexia. The general and psychiatric examination showed an upright and bronzed patient with neglected hygiene. He was indifferent to his environment and expressed poor mimics and gestures. He was anxious, suspicious and not very talkative. He was conscious but his attention was slightly decreased. Moreover, he was not aware of his problems. The neurological examination showed extrapyramidal syndrome with postural tremor and cerebellar ataxia. A cranial computed tomography brain scan found bilateral, symmetric basal ganglia calcifications, in favour of Fahr's syndrome. Phosphocalcic investigations revealed low concentration of serum calcium at 1.01mmol/L (normal 2.15 to 2.57mmol/L) and hyperphosphoremia at 2.69mmol/L (normal 0.81 to 1.55mmol/L). He also had low concentrations of 25-OH vitamin as well as decreased urinary levels of phosphate and calcium. The blood level of parathyroid hormone was 0ng/L. The diagnosis of Fahr's syndrome, revealing a hypoparathyroidism was posed. He was supplemented with calcium and alpha cholecalciferol and treated with clozapine (100mg per day). After four weeks, psychotic symptoms responded well to this treatment without expressing any side effects, notably seizures. Psychotic symptoms seen in Fahr's disease include auditory and visual hallucinations, complex perceptual distortions, delusions, and fugue state. Some of them were manifest in this patient. It is likely that the psychosis in both Fahr's disease and schizophrenia share a similar pathology. Positive psychotic symptoms, hallucinations, and paranoia are not necessarily generated by the classical hypothesis of dopamine-mediated attachment of salience to internally generated stimuli. Still, there is some evidence that disruption of the cortex involved in the pathophysiology of schizophrenia is also seen in Fahr's disease, particularly in areas of the limbic system. Psychiatrists should consider Fahr's syndrome as a differential diagnosis in the evaluation of psychosis associated with seizures. This case, along with others in the literature, further emphasizes the importance of the role of neuro-imaging and the search for disrupted phosphocalcic metabolism in patients with atypical psychotic symptoms. Moreover, further research should focus on pharmacologic interventions. The efficacy and risks of neuropharmacologic and psychopharmacologic interventions in Fahr's syndrome, and correlates of good and poor outcome with these interventions remain to be defined. Copyright © 2013. Published by Elsevier Masson SAS.

Marijuana poisoning.

PubMed

Fitzgerald, Kevin T; Bronstein, Alvin C; Newquist, Kristin L

2013-02-01

The plant Cannabis sativa has been used for centuries for the effects of its psychoactive resins. The term "marijuana" typically refers to tobacco-like preparations of the leaves and flowers. The plant contains more than 400 chemicals but the cannabinoid δ-9-tetrahydrocannabinol (THC) is the major psychoactive constituent. "Hashish" is the resin extracted from the tops of flowering plants and generally has a much higher THC concentration. Marijuana is the most commonly used illicit drug in the United States. Currently, several states have passed legislation to decriminalize possession of small amounts of marijuana for both medical and personal use and several other states have similar legislation under consideration. The most common form of marijuana use in humans is inhalation of the smoke of marijuana cigarettes, followed by ingestion. In animals, although secondhand smoke inhalation is possible, the most common source of exposure is through ingestion of the owner's marijuana supply. The minimum lethal oral dose for dogs for THC is more than 3 g/kg. Although the drug has a high margin of safety, deaths have been seen after ingestion of food products containing the more concentrated medical-grade THC butter. There are two specific cannabinoid receptors in humans and dogs, CB1 (primarily in central nervous system) and CB2 (peripheral tissues). In animals, following oral ingestion, clinical effects begin within 60 minutes. All of the neuropharmacologic mechanisms by which cannabinoids produce psychoactive effects have not been identified. However, CB1 activity is believed to be responsible for the majority of cannabinoid clinical effects. Highly lipid soluble, THC is distributed in fat, liver, brain, and renal tissue. Fifteen percent of THC is excreted into the urine and the rest is eliminated in the feces through biliary excretion. Clinical signs of canine intoxication include depression, hypersalivation, mydriasis, hypermetria, vomiting, urinary incontinence, tremors, hypothermia, and bradycardia. Higher dosages may additionally cause nystagmus, agitation, tachypnea, tachycardia, ataxia, hyperexcitability, and seizures. Treatment of marijuana ingestion in animals is largely supportive. Vital signs including temperature and heart rate and rhythm must be continually monitored. Stomach content and urine can be tested for cannabinoids. Gas chromatography and mass spectrometry can be utilized for THC detection but usually may take several days and are not practical for initiation of therapy. Human urine drug-screening tests can be unreliable for confirmation of marijuana toxicosis in dogs owing to the interference of a large number of the metabolites in canine urine. False negatives may also arise if testing occurs too recently following THC ingestion. Thus, the use of human urine drug-screening tests in dogs remains controversial. No specific antidote presently exists for THC poisoning. Sedation with benzodiazepines may be necessary if dogs are severely agitated. Intravenous fluids may be employed to counter prolonged vomiting and to help control body temperature. Recently, the use of intralipid therapy to bind the highly lipophilic THC has been utilized to help reduce clinical signs. The majority of dogs experiencing intoxication after marijuana ingestion recover completely without sequellae. Differential diagnoses of canine THC toxicosis include human pharmaceuticals with central nervous system stimulatory effects, drugs with central nervous system depressant effects, macrolide parasiticides, xylitol, and hallucinogenic mushrooms. Copyright © 2013 Elsevier Inc. All rights reserved.

Addiction and brain reward and antireward pathways.

PubMed

Gardner, Eliot L

2011-01-01

Addictive drugs have in common that they are voluntarily self-administered by laboratory animals (usually avidly), and that they enhance the functioning of the reward circuitry of the brain (producing the 'high' that the drug user seeks). The core reward circuitry consists of an 'in-series' circuit linking the ventral tegmental area, nucleus accumbens and ventral pallidum via the medial forebrain bundle. Although originally believed to simply encode the set point of hedonic tone, these circuits are now believed to be functionally far more complex, also encoding attention, expectancy of reward, disconfirmation of reward expectancy, and incentive motivation. 'Hedonic dysregulation' within these circuits may lead to addiction. The 'second-stage' dopaminergic component in this reward circuitry is the crucial addictive-drug-sensitive component. All addictive drugs have in common that they enhance (directly or indirectly or even transsynaptically) dop-aminergic reward synaptic function in the nucleus accumbens. Drug self-administration is regulated by nucleus accumbens dopamine levels, and is done to keep nucleus accumbens dopamine within a specific elevated range (to maintain a desired hedonic level). For some classes of addictive drugs (e.g. opiates), tolerance to the euphoric effects develops with chronic use. Postuse dysphoria then comes to dominate reward circuit hedonic tone, and addicts no longer use drugs to get high, but simply to get back to normal ('get straight'). The brain circuits mediating the pleasurable effects of addictive drugs are anatomically, neurophysiologically and neurochemically different from those mediating physical dependence, and from those mediating craving and relapse. There are important genetic variations in vulnerability to drug addiction, yet environmental factors such as stress and social defeat also alter brain-reward mechanisms in such a manner as to impart vulnerability to addiction. In short, the 'bio-psycho-social' model of etiology holds very well for addiction. Addiction appears to correlate with a hypodopaminergic dysfunctional state within the reward circuitry of the brain. Neuroimaging studies in humans add credence to this hypothesis. Credible evidence also implicates serotonergic, opioid, endocannabinoid, GABAergic and glutamatergic mechanisms in addiction. Critically, drug addiction progresses from occasional recreational use to impulsive use to habitual compulsive use. This correlates with a progression from reward-driven to habit-driven drug-seeking behavior. This behavioral progression correlates with a neuroanatomical progression from ventral striatal (nucleus accumbens) to dorsal striatal control over drug-seeking behavior. The three classical sets of craving and relapse triggers are (a) reexposure to addictive drugs, (b) stress, and (c) reexposure to environmental cues (people, places, things) previously associated with drug-taking behavior. Drug-triggered relapse involves the nucleus accumbens and the neurotransmitter dopamine. Stress-triggered relapse involves (a) the central nucleus of the amygdala, the bed nucleus of the stria terminalis, and the neurotransmitter corticotrophin-releasing factor, and (b) the lateral tegmental noradrenergic nuclei of the brain stem and the neurotransmitter norepinephrine. Cue-triggered relapse involves the basolateral nucleus of the amygdala, the hippocampus and the neurotransmitter glutamate. Knowledge of the neuroanatomy, neurophysiology, neurochemistry and neuropharmacology of addictive drug action in the brain is currently producing a variety of strategies for pharmacotherapeutic treatment of drug addiction, some of which appear promising. Copyright © 2011 S. Karger AG, Basel.

Introduction: Addiction and Brain Reward and Anti-Reward Pathways

PubMed Central

Gardner, Eliot L.

2013-01-01

Addictive drugs have in common that they are voluntarily self-administered by laboratory animals (usually avidly) and that they enhance the functioning of the reward circuitry of the brain (producing the “high” that the drug-user seeks). The core reward circuitry consists of an “in series” circuit linking the ventral tegmental area, nucleus accumbens, and ventral pallidum - via the medial forebrain bundle. Although originally believed to encode simply the set-point of hedonic tone, these circuits are now believed to be functionally far more complex - also encoding attention, expectancy of reward, disconfirmation of reward expectancy, and incentive motivation. “Hedonic dysregulation” within these circuits may lead to addiction. The “second-stage” dopaminergic component in this reward circuitry is the crucial addictive-drug-sensitive component. All addictive drugs have in common that they enhance (directly or indirectly or even transsynaptically) dopaminergic reward synaptic function in the nucleus accumbens. Drug self-administration is regulated by nucleus accumbens dopamine levels, and is done to keep nucleus accumbens dopamine within a specific elevated range (to maintain a desired hedonic level). For some classes of addictive drugs (e.g., opiates), tolerance to the euphoric effects develops with chronic use. Post-use dysphoria then comes to dominate reward circuit hedonic tone, and addicts no longer use drugs to get “high,” but simply to get back to normal (“get straight”). The brain circuits mediating the pleasurable effects of addictive drugs are anatomically, neurophysiologically, and neurochemically different from those mediating physical dependence, and from those mediating craving and relapse. There are important genetic variations in vulnerability to drug addiction, yet environmental factors such as stress and social defeat also alter brain-reward mechanisms in such a manner as to impart vulnerability to addiction. In short, the “bio-psycho-social” model of etiology holds very well for addiction. Addiction appears to correlate with a hypo-dopaminergic dysfunctional state within the reward circuitry of the brain. Neuroimaging studies in humans add credence to this hypothesis. Credible evidence also implicates serotonergic, opioid, endocannabinoid, GABAergic, and glutamatergic mechanisms in addiction. Critically, drug addiction progresses from occasional recreational use to impulsive use to habitual compulsive use. This correlates with a progression from reward-driven to habit-driven drug-seeking behavior. This behavioral progression correlates with a neuroanatomical progression from ventral striatal (nucleus accumbens) to dorsal striatal control over drug-seeking behavior. The three classical sets of craving and relapse triggers are a) re-exposure to addictive drugs, b) stress, and c) re-exposure to environmental cues (“people, places, things”) previously associated with drug-taking behavior. Drug-triggered relapse involves the nucleus accumbens and the neurotransmitter dopamine. Stress-triggered relapse involves a) the central nucleus of the amygdala, the bed nucleus of the stria terminalis, and the neurotransmitter CRF; and b) the lateral tegmental noradrenergic nuclei of the brain stem and the neurotransmitter norepinephrine. Cue-triggered relapse involves the basolateral nucleus of the amygdala, the hippocampus, and the neurotransmitter glutamate. Knowledge of the neuroanatomy, neurophysiology, neurochemistry, and neuropharmacology of addictive drug action in the brain is currently producing a variety of strategies for pharmacotherapeutic treatment of drug addiction, some of which appear promising. PMID:21508625

Animal models of Parkinson's disease: a source of novel treatments and clues to the cause of the disease

PubMed Central

Duty, Susan; Jenner, Peter

2011-01-01

Animal models of Parkinson's disease (PD) have proved highly effective in the discovery of novel treatments for motor symptoms of PD and in the search for clues to the underlying cause of the illness. Models based on specific pathogenic mechanisms may subsequently lead to the development of neuroprotective agents for PD that stop or slow disease progression. The array of available rodent models is large and ranges from acute pharmacological models, such as the reserpine- or haloperidol-treated rats that display one or more parkinsonian signs, to models exhibiting destruction of the dopaminergic nigro-striatal pathway, such as the classical 6-hydroxydopamine (6-OHDA) rat and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse models. All of these have provided test beds in which new molecules for treating the motor symptoms of PD can be assessed. In addition, the emergence of abnormal involuntary movements (AIMs) with repeated treatment of 6-OHDA-lesioned rats with L-DOPA has allowed for examination of the mechanisms responsible for treatment-related dyskinesia in PD, and the detection of molecules able to prevent or reverse their appearance. Other toxin-based models of nigro-striatal tract degeneration include the systemic administration of the pesticides rotenone and paraquat, but whilst providing clues to disease pathogenesis, these are not so commonly used for drug development. The MPTP-treated primate model of PD, which closely mimics the clinical features of PD and in which all currently used anti-parkinsonian medications have been shown to be effective, is undoubtedly the most clinically-relevant of all available models. The MPTP-treated primate develops clear dyskinesia when repeatedly exposed to L-DOPA, and these parkinsonian animals have shown responses to novel dopaminergic agents that are highly predictive of their effect in man. Whether non-dopaminergic drugs show the same degree of predictability of response is a matter of debate. As our understanding of the pathogenesis of PD has improved, so new rodent models produced by agents mimicking these mechanisms, including proteasome inhibitors such as PSI, lactacystin and epoximycin or inflammogens like lipopolysaccharide (LPS) have been developed. A further generation of models aimed at mimicking the genetic causes of PD has also sprung up. Whilst these newer models have provided further clues to the disease pathology, they have so far been less commonly used for drug development. There is little doubt that the availability of experimental animal models of PD has dramatically altered dopaminergic drug treatment of the illness and the prevention and reversal of drug-related side effects that emerge with disease progression and chronic medication. However, so far, we have made little progress in moving into other pharmacological areas for the treatment of PD, and we have not developed models that reflect the progressive nature of the illness and its complexity in terms of the extent of pathology and biochemical change. Only when this occurs are we likely to make progress in developing agents to stop or slow the disease progression. The overarching question that draws all of these models together in the quest for better drug treatments for PD is how well do they recapitulate the human condition and how predictive are they of successful translation of drugs into the clinic? This article aims to clarify the current position and highlight the strengths and weaknesses of available models. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21486284