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Author (up) Albuquerque, E.X.; Pereira, E.F.R.; Alkondon, M.; Rogers, S.W.
Title Mammalian nicotinic acetylcholine receptors: from structure to function Type Journal Article
Year 2009 Publication Physiological Reviews Abbreviated Journal Physiol Rev
Volume 89 Issue 1 Pages 73-120
Keywords Alzheimer Disease/physiopathology; Animals; Brain/physiology; Disease Models, Animal; Gene Expression Regulation/physiology; Humans; Parkinson Disease/physiopathology; Receptors, Nicotinic/*chemistry/*physiology
Abstract The classical studies of nicotine by Langley at the turn of the 20th century introduced the concept of a “receptive substance,” from which the idea of a “receptor” came to light. Subsequent studies aided by the Torpedo electric organ, a rich source of muscle-type nicotinic receptors (nAChRs), and the discovery of alpha-bungarotoxin, a snake toxin that binds pseudo-irreversibly to the muscle nAChR, resulted in the muscle nAChR being the best characterized ligand-gated ion channel hitherto. With the advancement of functional and genetic studies in the late 1980s, the existence of nAChRs in the mammalian brain was confirmed and the realization that the numerous nAChR subtypes contribute to the psychoactive properties of nicotine and other drugs of abuse and to the neuropathology of various diseases, including Alzheimer's, Parkinson's, and schizophrenia, has since emerged. This review provides a comprehensive overview of these findings and the more recent revelations of the impact that the rich diversity in function and expression of this receptor family has on neuronal and nonneuronal cells throughout the body. Despite these numerous developments, our understanding of the contributions of specific neuronal nAChR subtypes to the many facets of physiology throughout the body remains in its infancy.
Call Number Serial 1876
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Author (up) Andersson, D.R.; Bjornsson, E.; Bergquist, F.; Nissbrandt, H.
Title Motor activity-induced dopamine release in the substantia nigra is regulated by muscarinic receptors Type Journal Article
Year 2010 Publication Experimental Neurology Abbreviated Journal Exp Neurol
Volume 221 Issue 1 Pages 251-259
Keywords Analysis of Variance; Animals; Area Under Curve; Brain Injuries/chemically induced/*pathology; Chromatography, High Pressure Liquid/methods; Dendrites/drug effects/metabolism; Disease Models, Animal; Dopamine/*metabolism; Dose-Response Relationship, Drug; Electrochemistry/methods; Female; Functional Laterality; Mecamylamine/pharmacology; Microdialysis/methods; Motor Activity/drug effects/*physiology; Muscarinic Antagonists/pharmacology; Nicotinic Antagonists/pharmacology; Oxidopamine; Rats; Rats, Sprague-Dawley; Receptors, Muscarinic/*physiology; Rotarod Performance Test/methods; Scopolamine Hydrobromide/pharmacology; Substantia Nigra/drug effects/*metabolism/pathology; gamma-Aminobutyric Acid/metabolism
Abstract Nigro-striatal neurons release dopamine not only from their axon terminals in the striatum, but also from somata and dendrites in the substantia nigra. Somatodendritic dopamine release in the substantia nigra can facilitate motor function by mechanisms that may act independently of axon terminal dopamine release in the striatum. The dopamine neurons in the substantia nigra receive a cholinergic input from the pedunculopontine nucleus. Despite recent efforts to introduce this nucleus as a potential target for deep brain stimulation to treat motor symptoms in Parkinson's disease; and the well-known antiparkinsonian effects of anticholinergic drugs; the cholinergic influence on somatodendritic dopamine release is not well understood. The aim of this study was to investigate the possible regulation of locomotor-induced dopamine release in the substantia nigra by endogenous acetylcholine release. In intact and 6-OHDA hemi-lesioned animals alike, the muscarinic antagonist scopolamine, when perfused in the substantia nigra, amplified the locomotor-induced somatodendritic dopamine release to approximately 200% of baseline, compared to 120-130% of baseline in vehicle-treated animals. A functional importance of nigral muscarinic receptor activation was demonstrated in hemi-lesioned animals, where motor performance was significantly improved by scopolamine to 82% of pre-lesion performance, as compared to 56% in vehicle-treated controls. The results indicate that muscarinic activity in the substantia nigra is of functional importance in an animal Parkinson's disease model, and strengthen the notion that nigral dopaminergic regulation of motor activity/performance is independent of striatal dopamine release.
Call Number Serial 308
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Author (up) Bencan, Z.; Sledge, D.; Levin, E.D.
Title Buspirone, chlordiazepoxide and diazepam effects in a zebrafish model of anxiety Type Journal Article
Year 2009 Publication Pharmacology, Biochemistry, and Behavior Abbreviated Journal Pharmacol Biochem Behav
Volume 94 Issue 1 Pages 75-80
Keywords Animals; Anti-Anxiety Agents/*therapeutic use; Anxiety/*drug therapy; Behavior, Animal/drug effects; Benzodiazepines/administration & dosage/therapeutic use; Buspirone/administration & dosage/*therapeutic use; Chlordiazepoxide/administration & dosage/*therapeutic use; Cholinergic Agents/administration & dosage/therapeutic use; Diazepam/administration & dosage/*therapeutic use; *Disease Models, Animal; Diving; Dose-Response Relationship, Drug; Exploratory Behavior/drug effects; Imaging, Three-Dimensional/methods; Serotonin Agents/administration & dosage/therapeutic use; Stress, Psychological; Time Factors; *Zebrafish
Abstract Zebrafish are becoming more widely used to study neurobehavioral pharmacology. We have developed a method to assess novel environment diving behavior of zebrafish as a model of stress response and anxiolytic drug effects. In a novel tank, zebrafish dwell in the bottom of the tank initially and then increase their swimming exploration to higher levels over time. We previously found that nicotine, which has anxiolytic effects in rodents and humans, significantly lessens the novel tank diving response in zebrafish. The specificity of the diving effect was validated with a novel vs. non-novel test tank. The novel tank diving response of zebrafish was tested when given three anxiolytic drugs from two different chemical and pharmacological classes: buspirone, chlordiazepoxide and diazepam. When the test tank was novel the diving response was clearly seen whereas it was significantly reduced when the test tank was not novel. Buspirone, a serotonergic (5HT(1A) receptor agonist) anxiolytic drug with some D(2) dopaminergic effect, had a pronounced anxiolytic-like effect in the zebrafish diving model at doses that did not have sedative effects. In contrast, chlordiazepoxide, a benzodiazepine anxiolytic drug, which is an effective agonist at GABA-A receptors, did not produce signs of anxiolysis in zebrafish over a broad dose range up to those that caused sedation. Diazepam another benzodiazepine anxiolytic drug did produce an anxiolytic effect at doses that did not cause sedation. The zebrafish novel tank diving task can be useful in discriminating anxiolytic drugs of several classes (serotonergic, benzodiazepines and nicotinic).
Call Number Serial 209
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Author (up) Bi, L.-L.; Wang, J.; Luo, Z.-Y.; Chen, S.-P.; Geng, F.; Chen, Y.-hua; Li, S.-J.; Yuan, C.-hua; Lin, S.; Gao, T.-M.
Title Enhanced excitability in the infralimbic cortex produces anxiety-like behaviors Type Journal Article
Year 2013 Publication Neuropharmacology Abbreviated Journal Neuropharmacology
Volume 72 Issue Pages 148-156
Keywords 6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology/therapeutic use; Animals; Animals, Newborn; Anxiety/chemically induced/drug therapy/*pathology; Bicuculline/toxicity; Disease Models, Animal; Excitatory Amino Acid Antagonists/pharmacology/therapeutic use; Excitatory Postsynaptic Potentials/drug effects/*physiology; Exploratory Behavior/drug effects; GABA-A Receptor Antagonists/toxicity; In Vitro Techniques; Inhibitory Postsynaptic Potentials/drug effects; Injections, Intraventricular; Male; Maze Learning/drug effects; Mice; Mice, Inbred C57BL; Patch-Clamp Techniques; Prefrontal Cortex/drug effects/*physiopathology
Abstract The medial prefrontal cortex (mPFC) has been implicated in modulating anxiety. However, it is unknown whether excitatory or inhibitory neurotransmission in the infralimbic (IL) subregion of the mPFC underlies the pathology of anxiety-related behavior. To address this issue, we infused the GABAA receptor (GABAAR) antagonist bicuculline to temporarily activate the IL cortex. IL cortex activation decreased the time spent in the center area in the open field test, decreased exploration of the open-arms in the elevated plus maze test, and increased the latency to bite food in the novelty-suppressed feeding test. These findings substantiate the GABAergic system's role in anxiety-related behaviors. IL cortex inactivation with the AMPA receptor (AMPAR) antagonist CNQX produced opposite, anxiolytic effects. However, infusion of the NMDA receptor (NMDAR) antagonist AP5 into the IL cortex had no significant effect. Additionally, we did not observe motor activity deficits or appetite deficits following inhibition of GABAergic or glutamatergic neurotransmission. Interestingly, we found parallel and corresponding electrophysiological changes in anxious mice; compared to mice with relatively low anxiety, the relatively high anxiety mice exhibited smaller evoked inhibitory postsynaptic currents (eIPSCs) and larger AMPA-mediated evoked excitatory postsynaptic currents (eEPSCs) in pyramidal neurons in the IL cortex. The changes of eIPSCs and eEPSCs were due to presynaptic mechanisms. Our results suggest that imbalances of neurotransmission in the IL cortex may cause a net increase in excitatory inputs onto pyramidal neurons, which may underlie the pathogenic mechanism of anxiety disorders.
Call Number Serial 1045
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Author (up) Carpenter, K.J.; Sen, S.; Matthews, E.A.; Flatters, S.L.; Wozniak, K.M.; Slusher, B.S.; Dickenson, A.H.
Title Effects of GCP-II inhibition on responses of dorsal horn neurones after inflammation and neuropathy: an electrophysiological study in the rat Type Journal Article
Year 2003 Publication Neuropeptides Abbreviated Journal Neuropeptides
Volume 37 Issue 5 Pages 298-306
Keywords Animals; Carrageenan; Dipeptides/*metabolism; Disease Models, Animal; Electric Stimulation; Glutamate Carboxypeptidase II/*antagonists & inhibitors; Ligation; Male; Nerve Fibers, Myelinated/physiology; Nerve Fibers, Unmyelinated/physiology; Neuralgia/chemically induced/immunology/*physiopathology; Neuritis/chemically induced/immunology/*physiopathology; Nociceptors/physiology; Organophosphorus Compounds/pharmacology; Posterior Horn Cells/drug effects/immunology/*physiopathology; Rats; Rats, Sprague-Dawley; Spinal Nerves/physiopathology
Abstract N-Acetylaspartylglutamate (NAAG) is a peptide neurotransmitter present in the brain and spinal cord. It is hydrolysed by glutamate carboxypeptidase II (GCPII); thus, the GCP-II inhibitor 2-[phosphono-methyl]-pentanedioic acid (2-PMPA) protects endogenous NAAG from degradation, allowing its effects to be studied in vivo. We recorded the effect of spinal 2-PMPA (50-1000 microg) on the electrical-evoked activity of dorsal horn neurones in normal and carrageenan-inflamed animals, and in the spinal nerve ligation (SNL) model of neuropathy and sham-operated animals. In normal animals, 1000 microg 2-PMPA selectively inhibited noxious-evoked activity (input, post-discharge and C- and Adelta-fibre-evoked responses), and not low threshold Abeta-fibre-evoked responses. After carrageenan inflammation, the lower dose of 100 microg 2-PMPA inhibited input, post-discharge, C- and Adelta-fibre-evoked responses by a significantly greater amount than the same dose in normal animals. 2-PMPA inhibited neuronal responses less consistently in sham-operated and SNL animals, and effects were not significantly different from those seen in normal animals. NAAG is an agonist at the inhibitory metabotropic glutamate receptor mGluR3, and 2-PMPA may inhibit nociceptive transmission in normal animals by elevating synaptic NAAG levels, allowing it to activate mGluR3 and thus reducing transmitter release from afferent nerve terminals. mGluR3 expression in the superficial dorsal horn is upregulated after peripheral inflammation, perhaps explaining the greater inhibition of neuronal responses we observed after carrageenan inflammation. These results support an important role of endogenous NAAG in the spinal processing of noxious information.
Call Number Serial 104
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Author (up) Citron, M.
Title Alzheimer's disease: treatments in discovery and development Type Journal Article
Year 2002 Publication Nature Neuroscience Abbreviated Journal Nat Neurosci
Volume 5 Suppl Issue Pages 1055-1057
Keywords Alzheimer Disease/metabolism/physiopathology/*therapy; Amyloid beta-Peptides/*antagonists & inhibitors/biosynthesis; Animals; Brain/*drug effects/metabolism/physiopathology; Disease Models, Animal; *Drug Design; Drug Evaluation/trends; Drug Industry/trends; Enzyme Inhibitors/pharmacology/therapeutic use; Humans
Abstract Alzheimer's disease is the single biggest unmet medical need in neurology. Current drugs are safe, but of limited benefit to most patients. This review discusses the scientific basis and current status of promising disease-modifying therapies in the discovery and development stages. I describe the major targets of anti-amyloid therapy and the main focus of disease modification approaches. In addition, two new potential treatment approaches supported by retrospective epidemiology are outlined.
Call Number Serial 137
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Author (up) Conrad, K.L.; Louderback, K.M.; Gessner, C.P.; Winder, D.G.
Title Stress-induced alterations in anxiety-like behavior and adaptations in plasticity in the bed nucleus of the stria terminalis Type Journal Article
Year 2011 Publication Physiology & Behavior Abbreviated Journal Physiol Behav
Volume 104 Issue 2 Pages 248-256
Keywords Adaptation, Physiological/drug effects/*physiology; Analysis of Variance; Animals; Anxiety/*etiology/*pathology; Behavior, Animal/drug effects; Biophysics; Corticosterone/adverse effects; Disease Models, Animal; Electric Stimulation; Exploratory Behavior/drug effects/physiology; Long-Term Potentiation/drug effects/*physiology; Male; Maze Learning/drug effects; Mice; Mice, Inbred C57BL; Patch-Clamp Techniques/methods; Septal Nuclei/drug effects/*physiopathology; Social Isolation/psychology; Time Factors
Abstract In vulnerable individuals, exposure to stressors can result in chronic disorders such as generalized anxiety disorder (GAD), major depressive disorder (MDD), and post-traumatic stress disorder (PTSD). The extended amygdala is critically implicated in mediating acute and chronic stress responsivity and anxiety-like behaviors. The bed nucleus of the stria terminalis (BNST), a subregion of the extended amygdala, serves as a relay of corticolimbic information to the paraventricular nucleus of the hypothalamus (PVN) to directly influence the stress response. To investigate the influence of the corticosteroid milieu and housing conditions on BNST function, adult C57Bl/6J were either acutely or chronically administered corticosterone (CORT, 25mg/kg in sesame oil) or vehicle (sesame oil) or were group housed or socially isolated for 1 day (acute) or 6-8 weeks (chronic). To ascertain whether these stressors could influence anxiety-like behavior, studies were performed using the novel open-field (NOF) and the elevated zero maze (EZM) tests. To investigate potential associated changes in plasticity, alterations in BNST function were assessed using ex vivo extracellular field potential recordings in the (dorsal-lateral) dlBNST and a high frequency stimulus protocol to induce long-term potentiation (LTP). Our results suggest that chronic CORT injections and chronic social isolation housing conditions lead to an increase in anxiety-like behavior on the EZM and NOF. Chronically stressed mice also displayed a parallel blunting of LTP in the dlBNST. Conversely, acute social isolation housing had no effect on anxiety-like behavior but still resulted in a blunting of LTP in the dlBNST. Collectively, our results suggest acute and chronic stressors can have a distinct profile on plasticity in the BNST that is not uniformly associated with an increase in anxiety-like behavior.
Call Number Serial 85
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Author (up) D'Hooge, R.; De Deyn, P.P.
Title Applications of the Morris water maze in the study of learning and memory Type Journal Article
Year 2001 Publication Brain Research. Brain Research Reviews Abbreviated Journal Brain Res Brain Res Rev
Volume 36 Issue 1 Pages 60-90
Keywords Animals; Behavior, Animal/*physiology; Brain/cytology/*physiology; Denervation/adverse effects; Disease Models, Animal; Maze Learning/*physiology; Memory/*physiology; Mice; Nerve Net/cytology/*physiology; Neurotransmitter Agents/metabolism; Rats; Rodentia/anatomy & histology/*physiology; Space Perception/*physiology
Abstract The Morris water maze (MWM) was described 20 years ago as a device to investigate spatial learning and memory in laboratory rats. In the meanwhile, it has become one of the most frequently used laboratory tools in behavioral neuroscience. Many methodological variations of the MWM task have been and are being used by research groups in many different applications. However, researchers have become increasingly aware that MWM performance is influenced by factors such as apparatus or training procedure as well as by the characteristics of the experimental animals (sex, species/strain, age, nutritional state, exposure to stress or infection). Lesions in distinct brain regions like hippocampus, striatum, basal forebrain, cerebellum and cerebral cortex were shown to impair MWM performance, but disconnecting rather than destroying brain regions relevant for spatial learning may impair MWM performance as well. Spatial learning in general and MWM performance in particular appear to depend upon the coordinated action of different brain regions and neurotransmitter systems constituting a functionally integrated neural network. Finally, the MWM task has often been used in the validation of rodent models for neurocognitive disorders and the evaluation of possible neurocognitive treatments. Through its many applications, MWM testing gained a position at the very core of contemporary neuroscience research.
Call Number Serial 1556
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Author (up) El Amki, M.; Lerouet, D.; Coqueran, B.; Curis, E.; Orset, C.; Vivien, D.; Plotkine, M.; Marchand-Leroux, C.; Margaill, I.
Title Experimental modeling of recombinant tissue plasminogen activator effects after ischemic stroke Type Journal Article
Year 2012 Publication Experimental Neurology Abbreviated Journal Exp Neurol
Volume 238 Issue 2 Pages 138-144
Keywords Analysis of Variance; Animals; Brain Edema/etiology/prevention & control; Brain Infarction/etiology/prevention & control; *Disease Models, Animal; Drug Administration Schedule; Fibrinolytic Agents/*therapeutic use; Hemorrhage/drug therapy/etiology; Humans; Infarction, Middle Cerebral Artery/*complications; Male; Mice; Nervous System Diseases/etiology; Random Allocation; Stroke/complications/*drug therapy/*etiology; Time Factors; Tissue Plasminogen Activator/*therapeutic use; Treatment Outcome
Abstract Recombinant tissue plasminogen activator (rt-PA) is currently the only approved drug for ischemic stroke treatment, with a dose of 0.9 mg/kg. Since the fibrinolytic activity of rt-PA has been reported in vitro to be 10-fold less potent in rodent than in human, in most in vivo experimental models of cerebral ischemia rt-PA is used at 10 mg/kg. The purpose of this study was to compare the effects of the “human” (0.9 mg/kg) and “rodent” (10 mg/kg) doses of rt-PA given at an early or a delayed time point in a mouse model of cerebral ischemia. Cerebral ischemia was induced by thrombin injection into the left middle cerebral artery of mice. Rt-PA (0.9 or 10 mg/kg) was intravenously administered 30 min or 4 h after the onset of ischemia. The degree of reperfusion after rt-PA was followed for 90 min after its injection. The neurological deficit, infarct volumes, edema and hemorrhagic transformations (HT) were assessed at 24 h. Reperfusion was complete after early administration of rt-PA at 10 mg/kg but partial with rt-PA at 0.9 mg/kg. Both doses given at 4 h induced partial reperfusion. Early administration of both doses of rt-PA reduced the neurological deficit, lesion volume and brain edema, without modifying post-ischemic HT. Injected at 4 h, rt-PA at 0.9 and 10 mg/kg lost its beneficial effects and worsened HT. In conclusion, in the mouse thrombin stroke model, the “human” dose of rt-PA exhibits effects close to those observed in clinic.
Call Number Serial 925
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Author (up) File, S.E.; Seth, P.
Title A review of 25 years of the social interaction test Type Journal Article
Year 2003 Publication European Journal of Pharmacology Abbreviated Journal Eur J Pharmacol
Volume 463 Issue 1-3 Pages 35-53
Keywords Animals; Anti-Anxiety Agents/pharmacology; Anxiety/chemically induced/metabolism/*psychology; Behavior, Animal/drug effects; Brain/physiopathology; *Disease Models, Animal; Environment; Neuropeptides/metabolism/pharmacology; Neurotransmitter Agents/*metabolism/pharmacology; *Social Behavior; Substance Withdrawal Syndrome/etiology/psychology
Abstract The social interaction test of anxiety was developed 25 years ago to provide an ethologically based test that was sensitive to both anxiolytic and anxiogenic effects. It is sensitive to a number of environmental and physiological factors that can affect anxiety. It has detected anxiogenic effects of peptides such as corticotropin-releasing factor (CRF) and adrenocorticotropic hormone (ACTH), and anxiolytic effects of neuropeptide Y and substance P receptor antagonists. It has successfully identified neuropharmacological sites of action of anxiogenic compounds and drug withdrawal. Effects of compounds acting on the gamma-aminobutyric acid (GABA) and 5-hydroxytryptamine (5-HT) systems have been extensively investigated after both systemic administration and microinjection into specific brain regions. The use of this test has, thus, played a crucial role in unravelling the neural basis of anxiety. It is hoped that in the next 25 years, the test will play a crucial role in determining the genetic basis of anxiety disorders.
Call Number Serial 1187
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