Research Interests:
Research Interests: Engineering, Physics, Chemistry, Kinetics, Biology, and 18 moreMedicine, Multidisciplinary, Patch-clamp and imaging techniques, Cell line, Humans, Mice, Animals, PLoS one, Atypical Antipsychotics, Side Effect, Amino Acid Sequence, Individual Difference, Recombinant Proteins, Binding Site, Clozapine, Dissociation Constant, Binding affinity, and Molecular Sequence Data
Research Interests:
Steroid hormone action involves binding to cognate intracellular receptors that, in turn, bind to respective response elements and thus modulate gene expression. The present study shows that the gonadal steroids, 17beta-estradiol and... more
Steroid hormone action involves binding to cognate intracellular receptors that, in turn, bind to respective response elements and thus modulate gene expression. The present study shows that the gonadal steroids, 17beta-estradiol and progesterone, may also act as functional antagonists at the 5-hydroxytryptamine type 3 (5-HT3) receptor in whole-cell voltage-clamp recordings of HEK 293 cells stably expressing the 5-HT3 receptor. Functional antagonistic properties at this ligand-gated ion channel could also be shown for 17alpha-estradiol, 17alpha-ethinyl-17beta-estradiol, mestranol, R 5020, testosterone, and allopregnanolone but not for pregnenolone sulfate and cholesterol. An antagonism at the 5-HT3 receptor could further be observed with the aromatic alcohol 4-dodecylphenol but not with phenol or ethanol. Thus, the modulation of 5-HT3 receptor function by steroids or alcohols is dependent on their respective molecule structure. The antagonistic action of steroids at the 5-HT3 receptor is not mediated via the serotonin binding site because the steroids did not alter the binding affinity of [3H]GR65630 to the 5-HT3 receptor, and kinetic experiments revealed a quite different response pattern to 17beta-estradiol when compared with the competitive antagonist metoclopramide. BSA-conjugated gonadal steroids labeled with fluorescein isothiocyanate bound to membranes of HEK 293 cells expressing the 5-HT3 receptor in contrast to native HEK 293 cells. However, there was no dose-dependent displacement of the binding of gonadal steroids to membranes of cells expressing the 5-HT3 receptor in binding experiments or fluorescence studies. Thus, gonadal steroids probably interact allosterically with the 5-HT3 receptor at the receptor-membrane interface. The functional antagonism of gonadal steroids at the 5-HT3 receptor may play a role for the development and course of nausea during pregnancy and of psychiatric disorders.
Research Interests: Kinetics, Molecular endocrinology, Gene expression, Biological Sciences, Molecular, and 16 moreSerotonin, Cell line, Evoked Potentials, Pregnancy, Progesterone, Humans, Kidney, Female, Serotonin Receptors, Transfection, Imidazoles, Voltage Clamp, Binding Site, Serotonin antagonists, Estradiol, and Binding affinity
Merz Pharmaceuticals GmbH and Forest Laboratories Inc are developing neramexane, an oral N-methyl-D-aspartate antagonist, as a potential neuroprotectant for various central nervous system disorders, including Alzheimer's disease, and... more
Merz Pharmaceuticals GmbH and Forest Laboratories Inc are developing neramexane, an oral N-methyl-D-aspartate antagonist, as a potential neuroprotectant for various central nervous system disorders, including Alzheimer's disease, and for the potential treatment of drug and alcohol dependence, and pain.
Research Interests:
Research Interests:
... Brown, SM, Peet, E., Manuck, SB, Williamson, DE, Dahl, RE, Ferrell, RE & Hariri, AR (2005) A regulatory variant of the human tryptophan hydroxylase-2 gene biases amygdala reactivity. Mol Psychiatry 10, 884888. ...... more
... Brown, SM, Peet, E., Manuck, SB, Williamson, DE, Dahl, RE, Ferrell, RE & Hariri, AR (2005) A regulatory variant of the human tryptophan hydroxylase-2 gene biases amygdala reactivity. Mol Psychiatry 10, 884888. ... Domenici, MR, Azad, SC, Marsicano, G., Schierloh, A., Wotjak ...
Research Interests:
Research Interests:
Manipulating the function of neurons and circuits that translate electrical and chemical signals into behavior represents a major challenges in neuroscience. In addition to optogenetic methods using light-activatable channels,... more
Manipulating the function of neurons and circuits that translate electrical and chemical signals into behavior represents a major challenges in neuroscience. In addition to optogenetic methods using light-activatable channels, pharmacogenetic methods with ligand induced modulation of cell signaling and excitability have been developed. However, they are largely based on ectopic expression of exogenous or chimera proteins. Now, we describe the remote and reversible expression of a Kir2.1 type potassium channel using the chemogenetic technique of small molecule induced protein stabilization. Based on shield1-mediated shedding of a destabilizing domain fused to a protein of interest and inhibition of protein degradation, this principle has been adopted for biomedicine, but not in neuroscience so far. Here, we apply this chemogenetic approach in brain research for the first time in order to control a potassium channel in a remote and reversible manner. We could show that shield1-mediated ectopic Kir2.1 stabilization induces neuronal silencing in vitro and in vivo in the mouse brain. We also validated this novel pharmacogenetic method in different neurobehavioral paradigms.The DD-Kir2.1 may complement the existing portfolio of pharmaco- and optogenetic techniques for specific neuron manipulation, but it may also provide an example for future applications of this principle in neuroscience research.
N-methyl-D-aspartate (NMDA) receptor antagonists have a potentially wide range of therapeutic applications. Unfortunately, potent NMDA receptor channel blockers produce phencyclidine-like psychotropic symptoms in humans and rodents, and... more
N-methyl-D-aspartate (NMDA) receptor antagonists have a potentially wide range of therapeutic applications. Unfortunately, potent NMDA receptor channel blockers produce phencyclidine-like psychotropic symptoms in humans and rodents, and thereby produce numerous side effects. However, recent data indicate that moderate-affinity, voltage-dependent, open-channel blockers, such as memantine and neramexane (MRZ 2/579) are useful therapeutics as they prevent the pathological activation of NMDA receptors but allow their physiological activity and should prove to be useful therapeutics in a wide range of CNS disorders. Indeed, memantine was recently registered in both Europe and the USA for the treatment of moderate-to-severe Alzheimer's disease (AD). Neramexane is under development as a potential neuroprotectant against various CNS disorders. Although the predicted therapeutic doses of neramexane were very well tolerated in male volunteers, unfortunately, recent Phase II/III clinical trials for moderate-to-severe AD delivered contradictory results. Neramexane also failed in a recent randomized controlled Phase II trial against drug abuse and depression. Although Phase Ib clinical trials for the indications of chronic pain showed positive results, Phase II results indicate no superiority to existing treatments. However, positive study results have been presented recently in a Phase IIb study on the treatment of tinnitus. A Phase III study for this indication is presently ongoing. Another promising application for neramexane as a neuroprotectant might be chronic neurodegeneration, such as Parkinson's disease, Huntington's disease, vascular dementia, frontal lobe dementia, Down's syndrome and AD.
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Despite the overt need for improved treatment modalities in depression, efforts to develop conceptually novel antidepressants have been relatively unsuccessful so far. Here we present a translational approach combining results from... more
Despite the overt need for improved treatment modalities in depression, efforts to develop conceptually novel antidepressants have been relatively unsuccessful so far. Here we present a translational approach combining results from hypothesis-free animal experiments with data from a genetic association study in depression. Comparing genes regulated by chronic paroxetine treatment in the mouse hippocampus with genes showing nominally significant association with antidepressant treatment response in two pharmacogenetic studies, the activin pathway was the only one to show this dual pattern of association and therefore selected as a candidate. We examined the regulation of activin A and activin receptor type IA mRNA following antidepressant treatment. We investigated the effects of stereotaxic infusion of activin into the hippocampus and the amygdala in a behavioural model of depression. To analyse whether variants in genes in the activin signalling pathway predict antidepressant treat...
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Research Interests:
An in vitro excitatory post-synaptic potential stimulation technique was used to examine the effects of asiatic acid (a. acid), an isolated compound of Centella asiatica on excitatory postsynaptic potential (EPSP) in the rat hippocampal... more
An in vitro excitatory post-synaptic potential stimulation technique was used to examine the effects of asiatic acid (a. acid), an isolated compound of Centella asiatica on excitatory postsynaptic potential (EPSP) in the rat hippocampal slices. Hippocampal slices 350 μrn thick were perfused with oxygenated artificial cerebrospinal fluid, and electrodes were placed in the cornu ammonis (CA1) region to record EPSP responses to stimulation of Schaffer collateral/commissural fibers. Gamma-aminobutyric acid (GABA) receptors ...
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Research Interests:
There is a relation between stress and alcohol drinking. We show that the corticotropin-releasing hormone (CRH) system that mediates endocrine and behavioral responses to stress plays a role in the control of long-term alcohol drinking.... more
There is a relation between stress and alcohol drinking. We show that the corticotropin-releasing hormone (CRH) system that mediates endocrine and behavioral responses to stress plays a role in the control of long-term alcohol drinking. In mice lacking a functional CRH1 receptor, stress leads to enhanced and progressively increasing alcohol intake. The effect of repeated stress on alcohol drinking behavior appeared with a delay and persisted throughout life. It was associated with an up-regulation of the N-methyl-d-aspartate receptor subunit NR2B. Alterations in the CRH1 receptor gene and adaptional changes in NR2B subunits may constitute a genetic risk factor for stress-induced alcohol drinking and alcoholism.
Research Interests: Genetics, Science, Multidisciplinary, Corticotropin Releasing Hormone, Signal Transduction, and 15 moreHippocampus, Brain, Mutation, Mice, Alcoholism, Female, Animals, Alcohol Drinking, Male, Ethanol, Risk factors, Behavioral Animal Models, Risk Factors, Physiological Stress Markers, and Action Potentials
Research Interests: Engineering, Physics, Chemistry, Kinetics, Biology, and 18 moreMedicine, Multidisciplinary, Patch-clamp and imaging techniques, Cell line, Humans, Mice, Animals, PLoS one, Atypical Antipsychotics, Side Effect, Amino Acid Sequence, Individual Difference, Recombinant Proteins, Binding Site, Clozapine, Dissociation Constant, Binding affinity, and Molecular Sequence Data
The present study investigated the functional antagonism of different antidepressants on 5-HT (3) receptor function and the role of lipid rafts for these modulatory effects. Electrophysiological recordings of 5-HT evoked cation currents... more
The present study investigated the functional antagonism of different antidepressants on 5-HT (3) receptor function and the role of lipid rafts for these modulatory effects. Electrophysiological recordings of 5-HT evoked cation currents were recorded with N1E-115 and HEK-5-HT (3A) cells and hippocampal neurons. The characterization of the antagonism of antidepressants was made by the displacement of [ (3)H]GR65630 binding. For membrane fractionation, sucrose density gradient centrifugation was used. Gradient fractions were assayed for antidepressant concentrations by HPLC; 5-HT (3) receptor membrane distribution was determined by Western blot. Colocalization experiments were performed by means of immunocytochemistry. Most antidepressants acted as non-competitive antagonists at the 5-HT (3) receptor. Moreover, some of these compounds were enriched within lipid rafts. Cholesterol depletion impaired lipid raft integrity thereby affecting 5-HT (3) receptor function, whereas the antagonistic effects of antidepressants were not altered.In conclusion, most antidepressants directly antagonize 5-HT (3) receptor activity. 5-HT (3) receptor function PER SE appears to depend on lipid raft integrity, which is, however, not a prerequisite for the modulatory potency of antidepressants at this receptor.
Research Interests:
Research Interests:
Research Interests: Psychology, Cognitive Science, Long Term Potentiation, Synaptic Plasticity, Patch-clamp and imaging techniques, and 16 moreHippocampus, Mice, GABA receptors, Female, Animals, Male, Neuronal Plasticity, Synaptic Transmission, Associative learning, Long Term Depression, SYNAPSES, Neurosciences, Gamma-Aminobutyric Acid, GABA receptor, Excitatory Postsynaptic Potentials, and Corticotropin-releasing factor
Research Interests:
Research Interests:
Research Interests: Psychology, Neuropharmacology, Xenopus, Cell line, Brain, and 13 moreHumans, Alcohol, Female, Animals, Male, Ethanol, Memantine, Neurons, Rats, Protein Expression, Wistar Rats, Taurine, and Neurosciences
Research Interests:
Research Interests:
Research Interests:
Steroid hormone action involves binding to cognate intracellular receptors that, in turn, bind to respective response elements and thus modulate gene expression. The present study shows that the gonadal steroids, 17beta-estradiol and... more
Steroid hormone action involves binding to cognate intracellular receptors that, in turn, bind to respective response elements and thus modulate gene expression. The present study shows that the gonadal steroids, 17beta-estradiol and progesterone, may also act as functional antagonists at the 5-hydroxytryptamine type 3 (5-HT3) receptor in whole-cell voltage-clamp recordings of HEK 293 cells stably expressing the 5-HT3 receptor. Functional antagonistic properties at this ligand-gated ion channel could also be shown for 17alpha-estradiol, 17alpha-ethinyl-17beta-estradiol, mestranol, R 5020, testosterone, and allopregnanolone but not for pregnenolone sulfate and cholesterol. An antagonism at the 5-HT3 receptor could further be observed with the aromatic alcohol 4-dodecylphenol but not with phenol or ethanol. Thus, the modulation of 5-HT3 receptor function by steroids or alcohols is dependent on their respective molecule structure. The antagonistic action of steroids at the 5-HT3 receptor is not mediated via the serotonin binding site because the steroids did not alter the binding affinity of [3H]GR65630 to the 5-HT3 receptor, and kinetic experiments revealed a quite different response pattern to 17beta-estradiol when compared with the competitive antagonist metoclopramide. BSA-conjugated gonadal steroids labeled with fluorescein isothiocyanate bound to membranes of HEK 293 cells expressing the 5-HT3 receptor in contrast to native HEK 293 cells. However, there was no dose-dependent displacement of the binding of gonadal steroids to membranes of cells expressing the 5-HT3 receptor in binding experiments or fluorescence studies. Thus, gonadal steroids probably interact allosterically with the 5-HT3 receptor at the receptor-membrane interface. The functional antagonism of gonadal steroids at the 5-HT3 receptor may play a role for the development and course of nausea during pregnancy and of psychiatric disorders.
Research Interests: Kinetics, Molecular endocrinology, Gene expression, Biological Sciences, Molecular, and 16 moreSerotonin, Cell line, Evoked Potentials, Pregnancy, Progesterone, Humans, Kidney, Female, Serotonin Receptors, Transfection, Imidazoles, Voltage Clamp, Binding Site, Serotonin antagonists, Estradiol, and Binding affinity
Research Interests:
Research Interests: Animal Behavior, Long Term Potentiation, Transgenic Mice, Neuroplasticity, Hippocampus, and 13 moreMice, Animals, Transgenic Animals, Neuronal Plasticity, Transgenesis, Spatial Learning, Spatial Behavior, Time Factors, Spatial navigation, Psychiatric, Maze Learning, Monoamine oxidase, and Glucocorticoids
Research Interests:
Research Interests:
... Brown, SM, Peet, E., Manuck, SB, Williamson, DE, Dahl, RE, Ferrell, RE & Hariri, AR (2005) A regulatory variant of the human tryptophan hydroxylase-2 gene biases amygdala reactivity. Mol Psychiatry 10, 884888. ...... more
... Brown, SM, Peet, E., Manuck, SB, Williamson, DE, Dahl, RE, Ferrell, RE & Hariri, AR (2005) A regulatory variant of the human tryptophan hydroxylase-2 gene biases amygdala reactivity. Mol Psychiatry 10, 884888. ... Domenici, MR, Azad, SC, Marsicano, G., Schierloh, A., Wotjak ...
Research Interests:
ABSTRACT The classical mechanisms of action of antidepressants suggest that they act through inhibition of monoamine transporters. There is evidence that antipressants indirectly modulate GABA-A receptors through neurosteroids. We showed... more
ABSTRACT The classical mechanisms of action of antidepressants suggest that they act through inhibition of monoamine transporters. There is evidence that antipressants indirectly modulate GABA-A receptors through neurosteroids. We showed that antidepressants may also directly modulate the function of the serotonin type 3 (5-HT3) receptor in an allosteric fashion. This non-competitive inhibition of receptor function occurred with different classes of antidepressants including tricyclic antidepressants, SSRIs and NARIs. Moreover, these antidepressants were differentially accumulated in lipid rafts. Their concentartions in lipid rafts were related to their ability to allosterically modulate this ligand gated ion channel. However, lipid raft integrity was not a prerequisite for the allosteric modulation of this ion channel by antidepressants. Morover, differential results were observed with regard to NMDA and GABA-A receptors. Our data show that the allosteric modulation of ligand gated ion channels is an underestimated pharmacologcical principle which challenges the concept of target specificty of antidepressants for monoamine transporters.
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Research Interests:
Research Interests: Electrophysiology, Anesthesiology, Long Term Potentiation, Aging, Synaptic Plasticity, and 12 morePatch-clamp and imaging techniques, Hippocampus, In Vitro, Mice, Animals, Neuronal Plasticity, Synaptic Transmission, Clinical Sciences, SYNAPSES, Isoflurane, Glutamate Receptor, and Excitatory Postsynaptic Potentials
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Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests: Signal Processing, Kinetics, Photochemistry, Patch-clamp and imaging techniques, Glutamate, and 16 moreLasers, Animals, Male, Astrocyte, The, Dendrites, Synaptic Transmission, Infrared, Rats, SYNAPSES, Neocortex, Infrared Rays, Whole cell Patch-Clamp, Glutamate Receptor, Glutamate release, and Cell Membrane
The gaseous anaesthetic N2O displays analgesic, anxiolytic, and amnesic properties and has addictive psychedelic effects. N2O can further act as a neuroprotective agent, but may also become neurotoxic under certain conditions. Here, we... more
The gaseous anaesthetic N2O displays analgesic, anxiolytic, and amnesic properties and has addictive psychedelic effects. N2O can further act as a neuroprotective agent, but may also become neurotoxic under certain conditions. Here, we employed whole-cell patch-clamp techniques in acute brain slices, and electrical afferent and infrared-guided laser stimulation to examine how N2O (65%) can affect NMDA receptor (NMDAR)-mediated synaptic transmission to principal neurons (PNs) of the adult murine basolateral amygdala (BLA). The BLA plays a critical role in anaesthetic-induced amnesia, the formation of aversive memories, as well as in fear and addictive behaviour. We evoked NMDAR-mediated excitatory postsynaptic currents (NMDAR-EPSCs) in PNs of the BLA (BLA-PNs). We found these currents to be markedly decreased by N2O via pre- and postsynaptic actions: Without changing their kinetics and open probability, N2O impeded the voltage-dependent channel opening of NMDARs in BLA-PNs and diminished their unitary conductance as estimated by non-stationary fluctuation analysis. In addition, our data speak in favour of a N2O-produced reduction in the probability of glutamate release at the synapses generating the NMDAR-EPSCs. It is conceivable that these effects not only contribute to anaesthesia and anxiolysis, but also have bearings on learning and memory as well as excitotoxicity in the amygdala.
Research Interests: Psychology, Kinetics, Neuropharmacology, Patch-clamp and imaging techniques, Learning and Memory, and 16 moreLasers, Mice, Animals, Male, Amygdala, Synaptic Transmission, Infrared, Oxygen, Nitrous Oxide, SYNAPSES, Neurosciences, Patch Clamp, Whole cell Patch-Clamp, Basolateral Amygdala, Excitatory Postsynaptic Potentials, and Glutamate release
The rapid application of solutions containing the volatile anaesthetics isoflurane or sevoflurane induced inward currents in human embryonic kidney (HEK293) cells carrying rat recombinant alpha(1)beta(2)gamma(2L) GABA(A) receptor... more
The rapid application of solutions containing the volatile anaesthetics isoflurane or sevoflurane induced inward currents in human embryonic kidney (HEK293) cells carrying rat recombinant alpha(1)beta(2)gamma(2L) GABA(A) receptor assemblies. The responses evoked by the anaesthetics applied via a fast delivery system were recorded using the patch-clamp technique in the whole-cell mode. The anaesthetics induced a fast inward current which was followed by a prominent tail current upon the rapid withdrawal of the agent. These currents were simulated using a kinetic scheme embodying two agonist-like binding steps required for receptor activation, and one binding step by which the anaesthetic induces an open-channel block. According to this model of a biphasic receptor modulation, the open-channel block delays the ion flux through the ligand-gated receptors and, thus, prolongs the overall duration of the current response. Open-channel blocks might also be operative in other ligand-gated ion channels to modulate synaptic strength.