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Author (up) Amici, M.; Eusebi, F.; Miledi, R. file  url
openurl 
  Title Effects of the antibiotic gentamicin on nicotinic acetylcholine receptors Type Journal Article
  Year 2005 Publication Neuropharmacology Abbreviated Journal Neuropharmacology  
  Volume 49 Issue 5 Pages 627-637  
  Keywords Animals; Anti-Bacterial Agents--pharmacology; Cochlea--drug effects; DNA, Complementary--biosynthesis; Electrophysiology; Gentamicins--pharmacology; Humans; Membrane Potentials--drug effects, physiology; Mice; Nicotinic Antagonists; Oocytes--metabolism; Patch-Clamp Techniques; RNA, Complementary--biosynthesis; Receptors, Nicotinic--biosynthesis, drug effects, genetics; Torpedo; Vestibule, Labyrinth--drug effects; Xenopus; alpha7 Nicotinic Acetylcholine Receptor  
  Abstract Medical treatment with the aminoglycosidic antibiotic gentamicin may produce side effects that include neuromuscular blockage and ototoxicity; which are believed to result from a dysfunction of nicotinic acetylcholine receptors (AChRs). Gentamicin is known to reversibly block ACh-currents generated by the activation of muscle-type alphabetagammadelta-AChR and neuronal alpha9-AChR. We studied the effects of gentamicin on heteromeric alphabetagammadelta-AChR and homomeric alpha7-AChR expressed in Xenopus oocytes. Prolonged treatment with gentamicin, and other antibiotics, differentially altered alphabetagammadelta- and alpha7-AChR responses. Specifically, gentamicin accelerated desensitization and did not reduce ACh-currents in oocytes expressing alphabetagammadelta-AChRs, whereas ACh-currents were reduced and desensitization was unaltered in oocytes expressing alpha7-AChRs. Moreover, acutely applied gentamicin acted as a competitive antagonist on both types of receptors and increased the rate of desensitization in alphabetagammadelta-AChR while reducing the rate of desensitization in alpha7-AChR. This data helps to better understand the action of gentamicin on muscle and nervous tissues, providing mechanistic insights that could eventually lead to improving the medical use of aminoglycosides.  
  Call Number Serial 445  
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Author (up) Bayer, L.; Eggermann, E.; Serafin, M.; Grivel, J.; Machard, D.; Muhlethaler, M.; Jones, B.E. file  url
doi  openurl
  Title Opposite effects of noradrenaline and acetylcholine upon hypocretin/orexin versus melanin concentrating hormone neurons in rat hypothalamic slices Type Journal Article
  Year 2005 Publication Neuroscience Abbreviated Journal Neuroscience  
  Volume 130 Issue 4 Pages 807-811  
  Keywords Acetylcholine/pharmacology/*physiology; Action Potentials/drug effects/physiology; Animals; Arousal/drug effects/physiology; Cholinergic Agonists/pharmacology; Hypothalamic Area, Lateral/cytology/drug effects/*metabolism; Hypothalamic Hormones/*metabolism; Intracellular Signaling Peptides and Proteins/*metabolism; Locus Coeruleus/physiology; Melanins/*metabolism; Models, Neurological; Neural Inhibition/drug effects/physiology; Neural Pathways/cytology/drug effects/metabolism; Neurons/drug effects/*metabolism; Neuropeptides/*metabolism; Norepinephrine/pharmacology/*physiology; Organ Culture Techniques; Patch-Clamp Techniques; Pedunculopontine Tegmental Nucleus/physiology; Pituitary Hormones/*metabolism; Rats; Rats, Sprague-Dawley; Sleep/physiology; Synaptic Transmission/drug effects/physiology  
  Abstract Hypocretin/orexin (Hcrt/Orx) and melanin concentrating hormone (MCH) are peptides contained in overlapping cell groups of the lateral hypothalamus and commonly involved in regulating sleep-wake states and energy balance, though likely in different ways. To see if these neurons are similarly or differentially modulated by neurotransmitters of the major brainstem arousal systems, the effects of noradrenaline (NA) and carbachol, a cholinergic agonist, were examined on identified Hcrt/Orx and MCH neurons in rat hypothalamic slices. Whereas both agonists depolarized and excited Hcrt/Orx neurons, they both hyperpolarized MCH neurons by direct postsynaptic actions. According to the activity profiles of the noradrenergic locus coeruleus and cholinergic pontomesencephalic neurons across the sleep-waking cycle, the Hcrt/Orx neurons would be excited by NA and acetylcholine (ACh) and thus active during arousal, whereas the MCH neurons would be inhibited by NA and ACh and thus inactive during arousal while disinhibited and possibly active during slow wave sleep. According to the present pharmacological results, Hcrt/Orx neurons may thus stimulate arousal in tandem with other arousal systems, whereas MCH neurons may function in opposition with other arousal systems and thus potentially dampen arousal to promote sleep.  
  Call Number Serial 331  
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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. file  url
openurl 
  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) Conrad, K.L.; Louderback, K.M.; Gessner, C.P.; Winder, D.G. file  url
doi  openurl
  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) de Groat, W.C.; Yoshimura, N. file  url
openurl 
  Title Changes in afferent activity after spinal cord injury Type Journal Article
  Year 2010 Publication Neurourology and Urodynamics Abbreviated Journal Neurourol Urodyn  
  Volume 29 Issue 1 Pages 63-76  
  Keywords Afferent Pathways/metabolism/*physiopathology; Animals; Central Nervous System/metabolism/*physiopathology; Ganglia, Spinal/metabolism/*physiopathology; Genetic Therapy/methods; Humans; Mechanotransduction, Cellular; Nerve Fibers, Myelinated; Nerve Fibers, Unmyelinated; Nerve Growth Factor/metabolism; Neuroanatomical Tract-Tracing Techniques; Neuronal Plasticity; Patch-Clamp Techniques; Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism; Potassium Channels/metabolism; Recovery of Function; Reflex; Sodium Channels/metabolism; Spinal Cord Injuries/complications/metabolism/*physiopathology/therapy; Urinary Bladder/*innervation; Urinary Bladder, Neurogenic/etiology/metabolism/*physiopathology/therapy; *Urination; gamma-Aminobutyric Acid/metabolism  
  Abstract AIMS: To summarize the changes that occur in the properties of bladder afferent neurons following spinal cord injury. METHODS: Literature review of anatomical, immunohistochemical, and pharmacologic studies of normal and dysfunctional bladder afferent pathways. RESULTS: Studies in animals indicate that the micturition reflex is mediated by a spinobulbospinal pathway passing through coordination centers (periaqueductal gray and pontine micturition center) located in the rostral brain stem. This reflex pathway, which is activated by small myelinated (Adelta) bladder afferent nerves, is in turn modulated by higher centers in the cerebral cortex involved in the voluntary control of micturition. Spinal cord injury at cervical or thoracic levels disrupts voluntary voiding, as well as the normal reflex pathways that coordinate bladder and sphincter function. Following spinal cord injury, the bladder is initially areflexic but then becomes hyperreflexic due to the emergence of a spinal micturition reflex pathway. The recovery of bladder function after spinal cord injury is dependent in part on the plasticity of bladder afferent pathways and the unmasking of reflexes triggered by unmyelinated, capsaicin-sensitive, C-fiber bladder afferent neurons. Plasticity is associated with morphologic, chemical, and electrical changes in bladder afferent neurons and appears to be mediated in part by neurotrophic factors released in the spinal cord and the peripheral target organs. CONCLUSIONS: Spinal cord injury at sites remote from the lumbosacral spinal cord can indirectly influence properties of bladder afferent neurons by altering the function and chemical environment in the bladder or the spinal cord.  
  Call Number Serial 2147  
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Author (up) Hage, T.A.; Khaliq, Z.M. file  url
doi  openurl
  Title Tonic firing rate controls dendritic Ca2+ signaling and synaptic gain in substantia nigra dopamine neurons Type Journal Article
  Year 2015 Publication The Journal of Neuroscience : the Official Journal of the Society for Neuroscience Abbreviated Journal J Neurosci  
  Volume 35 Issue 14 Pages 5823-5836  
  Keywords Action Potentials/*physiology; Animals; Animals, Newborn; Calcium/*metabolism; Calcium Signaling/drug effects/*physiology; Dopaminergic Neurons/*cytology; Female; Glutamic Acid/pharmacology; In Vitro Techniques; Male; Mice; Microscopy, Confocal; Neurotransmitter Agents/pharmacology; Patch-Clamp Techniques; Substantia Nigra/*cytology; Synapses/drug effects/*physiology; action potential; backpropagation; calcium imaging; dendrite; dopamine; substantia nigra  
  Abstract Substantia nigra dopamine neurons fire tonically resulting in action potential backpropagation and dendritic Ca(2+) influx. Using Ca(2+) imaging in acute mouse brain slices, we find a surprisingly steep relationship between tonic firing rate and dendritic Ca(2+). Increasing the tonic rate from 1 to 6 Hz generated Ca(2+) signals up to fivefold greater than predicted by linear summation of single spike-evoked Ca(2+)-transients. This “Ca(2+) supralinearity” was produced largely by depolarization of the interspike voltage leading to activation of subthreshold Ca(2+) channels and was present throughout the proximal and distal dendrites. Two-photon glutamate uncaging experiments show somatic depolarization enhances NMDA receptor-mediated Ca(2+) signals >400 mum distal to the soma, due to unusually tight electrotonic coupling of the soma to distal dendrites. Consequently, we find that fast tonic firing intensifies synaptically driven burst firing output in dopamine neurons. These results show that modulation of background firing rate precisely tunes dendritic Ca(2+) signaling and provides a simple yet powerful mechanism to dynamically regulate the gain of synaptic input.  
  Call Number Serial 1135  
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Author (up) Hall, A.C.; Stevens, R.J.N.; Betts, B.A.; Yeung, W.-Y.; Kelley, J.C.; Harrison, N.L. file  url
doi  openurl
  Title Subunit-dependent block by isoflurane of wild-type and mutant alpha(1)S270H GABA(A) receptor currents in Xenopus oocytes Type Journal Article
  Year 2005 Publication Neuroscience Letters Abbreviated Journal Neurosci Lett  
  Volume 382 Issue 3 Pages 332-337  
  Keywords Anesthetics, Inhalation/*pharmacology; Animals; Bicuculline/pharmacology; Dose-Response Relationship, Drug; Excitatory Postsynaptic Potentials/drug effects/physiology; GABA Antagonists/pharmacology; Isoflurane/*pharmacology; Membrane Potentials/*drug effects/physiology; Mutation; Oocytes/drug effects; Patch-Clamp Techniques; Picrotoxin/pharmacology; Protein Subunits/*drug effects/metabolism; Receptors, GABA-A/*drug effects/genetics/metabolism; Recombinant Proteins/drug effects; Substrate Specificity; Xenopus  
  Abstract The volatile anesthetic isoflurane both prolongs and reduces the amplitude of GABA-mediated inhibitory postsynaptic currents (IPSCs) recorded in neurons. To explore the latter effect, we investigated isoflurane-induced inhibition of steady-state desensitized GABA currents in Xenopus oocytes expressing wild-type alpha(1)beta(2), alpha(1)beta(2)gamma(2s), mutant alpha(1)(S270H)beta(2) (serine to histidine at residue 270) or alpha(1)(S270H)beta(2)gamma(2s) receptors. The alpha(1) serine 270 site in TM2 (second transmembrane domain of the subunit) is postulated as a binding site for some volatile agents and is critical for positive modulation of sub-maximal GABA responses by isoflurane. For all receptor combinations, at < or =0.6 mM isoflurane (< or =2 minimum alveolar concentration (MAC)) current inhibitions were not pronounced ( approximately 10%) with block reaching half-maximal levels at supraclinical concentrations ( approximately 2 mM isoflurane, 6 MAC). Comparisons with other GABA(A) receptor blockers indicated that isoflurane blocks in a similar manner to picrotoxin, possibly via the pore of the receptor. The extent of isoflurane-induced inhibition was significantly attenuated by inclusion of the gamma(2s)-subunit but was unaffected by introduction of the S270H mutation in the alpha(1)-subunit. In conclusion, isoflurane binds with low affinity and with subunit-specificity to an inhibitory site on the GABA(A) receptor that is distinct from the site that facilitates positive modulation at the extracellular end of the pore.  
  Call Number Serial 507  
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Author (up) Hall, A.C.; Turcotte, C.M.; Betts, B.A.; Yeung, W.-Y.; Agyeman, A.S.; Burk, L.A. file  url
doi  openurl
  Title Modulation of human GABAA and glycine receptor currents by menthol and related monoterpenoids Type Journal Article
  Year 2004 Publication European Journal of Pharmacology Abbreviated Journal Eur J Pharmacol  
  Volume 506 Issue 1 Pages 9-16  
  Keywords Animals; Dose-Response Relationship, Drug; Drug Synergism; Female; Gene Expression; Glycine/pharmacology; Humans; Membrane Potentials/drug effects; Menthol/chemistry/*pharmacology; Monoterpenes/*pharmacology; Oocytes/drug effects/physiology; Patch-Clamp Techniques; Receptors, GABA-A/genetics/*physiology; Receptors, Glycine/genetics/*physiology; Stereoisomerism; Xenopus; gamma-Aminobutyric Acid/pharmacology  
  Abstract Effects of common monoterpenoid alcohols and ketones were investigated on recombinant human gamma-aminobutyric acid A (GABAA; alpha1beta2gamma2s) and glycine (alpha1 homomers) receptors expressed in Xenopus oocytes. GABA currents were enhanced by coapplications of 10-300 microM: (+)-menthol>(-)-menthol>(-)-borneol>>(-)-menthone=camphor enantiomers>carvone enantiomers, with menthol acting stereoselectively. By contrast, thujone diastereomers inhibited GABAA receptor currents while glycine currents were only markedly potentiated by menthol. Positive modulation by (+)-menthol was explored given its pronounced effects (e.g., at 100 microM, GABA and glycine EC20 responses increased by 496+/-113% and 135+/-56%, respectively). (+)-Menthol, 100 microM, reduced EC50 values for GABA and glycine from 82.8+/-9.9 to 25.0+/-1.8 microM, and from 98.7+/-8.6 to 75.7+/-9.4 microM respectively, with negligible effects on maximal currents. This study reveals a novel neuroactive role for menthol as a stereoselective modulator of inhibitory ligand-gated channels.  
  Call Number Serial 505  
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Author (up) Pfeffer, C.K.; Xue, M.; He, M.; Huang, Z.J.; Scanziani, M. file  url
openurl 
  Title Inhibition of inhibition in visual cortex: the logic of connections between molecularly distinct interneurons Type Journal Article
  Year 2013 Publication Nature Neuroscience Abbreviated Journal Nat Neurosci  
  Volume 16 Issue 8 Pages 1068-1076  
  Keywords Animals; Biomarkers; Channelrhodopsins; Female; Genes, Reporter; Inhibitory Postsynaptic Potentials/radiation effects; Interneurons/chemistry/classification/*physiology; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins/analysis; Neural Inhibition/*physiology; Optogenetics; Organophosphorus Compounds/pharmacology; Parvalbumins/analysis; Patch-Clamp Techniques; Photic Stimulation; Principal Component Analysis; Pyramidal Cells/physiology; Quinoxalines/pharmacology; Recombinant Fusion Proteins/physiology; Somatostatin/analysis; Synaptic Transmission/physiology/radiation effects; Vasoactive Intestinal Peptide/analysis; Visual Cortex/*physiology  
  Abstract Cortical inhibitory neurons contact each other to form a network of inhibitory synaptic connections. Our knowledge of the connectivity pattern underlying this inhibitory network is, however, still incomplete. Here we describe a simple and complementary interaction scheme between three large, molecularly distinct interneuron populations in mouse visual cortex: parvalbumin-expressing interneurons strongly inhibit one another but provide little inhibition to other populations. In contrast, somatostatin-expressing interneurons avoid inhibiting one another yet strongly inhibit all other populations. Finally, vasoactive intestinal peptide-expressing interneurons preferentially inhibit somatostatin-expressing interneurons. This scheme occurs in supragranular and infragranular layers, suggesting that inhibitory networks operate similarly at the input and output of the visual cortex. Thus, as the specificity of connections between excitatory neurons forms the basis for the cortical canonical circuit, the scheme described here outlines a standard connectivity pattern among cortical inhibitory neurons.  
  Call Number Serial 2151  
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