| Section I: Physiology of the Neurotransmitters GABA and Glycine |
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Physiology of the GABA and Glycine Systems |
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3 | (76) |
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3 | (1) |
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4 | (6) |
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Electrophysiological Properties of Interneurons |
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5 | (1) |
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Voltage-Dependent Channels |
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6 | (2) |
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8 | (2) |
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Physiological Responses Mediated by Inhibitory Neurotransmitters |
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10 | (5) |
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Membrane Effects of GABA and Glycine |
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10 | (2) |
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Depolarizing GABA and Glycine Responses |
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12 | (1) |
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Depolarizing GABA and Glycine Responses in Young Tissue |
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12 | (1) |
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Depolarizing GABAA Responses in Adult Tissue |
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13 | (1) |
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Membrane Potential Changes Caused by GABA in Unimpaled Cells |
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14 | (1) |
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Miniature Inhibitory Postsynaptic Currents |
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15 | (9) |
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Saturation of Receptor Patches by Quantal Release |
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15 | (4) |
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Co-Release of GABA and Other Transmitters |
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19 | (1) |
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19 | (1) |
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Co-Release of GABA and ATP |
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19 | (1) |
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20 | (3) |
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23 | (1) |
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24 | (4) |
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Control of Dendritic Electroresponsiveness |
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24 | (1) |
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Dendrodendritic Inhibition |
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25 | (1) |
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Back-Propagating Action Potentials |
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26 | (2) |
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Control of Persistent Cation Currents |
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28 | (1) |
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Somatic-Axonal Inhibition |
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28 | (6) |
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Conduction Block Along the Preterminal Axon |
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28 | (2) |
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Depolarization-Induced Suppression of Inhibition (DSI) |
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30 | (3) |
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Autoreception and Inhibition |
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33 | (1) |
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33 | (1) |
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Preterminal Extrasynaptic Receptors |
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33 | (1) |
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34 | (5) |
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34 | (2) |
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36 | (1) |
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GABAB Autoreceptor Activation |
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36 | (1) |
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Mechanism of Presynaptic GABAB Inhibition |
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37 | (1) |
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GABAB Enhancement of Synaptic Activity |
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38 | (1) |
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Response Plasticity and IPSPs |
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39 | (10) |
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Short-Term Plasticity of Interneuron Output |
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39 | (2) |
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Balance Between Excitation and Inhibition |
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41 | (1) |
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The Roles of IPSPs in Regulating Plasticity at Excitatory Synapses |
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42 | (1) |
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LTD of GABAAergic IPSPs in Hippocampus |
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42 | (1) |
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LTD of GABAAergic IPSPs in Cerebellum |
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43 | (2) |
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Long-Lasting Enhancement of GABAA IPSPs |
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45 | (1) |
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45 | (1) |
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46 | (1) |
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Long-Lasting Enhancement of IPSPs - Not LTP |
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47 | (1) |
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Target-Cell Specificity of Action |
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47 | (1) |
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Facilitation of LTD Induction at Other Synapses by IPSP Depression |
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48 | (1) |
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Synaptic Inhibition and the Generation of Rhythmic Firing Patterns in Populations of Cells |
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49 | (7) |
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50 | (1) |
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51 | (1) |
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Single-Unit Studies In Vivo |
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51 | (1) |
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52 | (1) |
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Depolarizing GABAA Responses and Rhythmic Firing |
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53 | (1) |
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Hypersynchrony and Pathology |
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54 | (1) |
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Control of Rhythmic Firing Through Inhibition of Gap Junctional Connections |
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55 | (1) |
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The Role of Inhibition in Sensory Processing |
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56 | (4) |
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56 | (1) |
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Dynamic Modulation of Receptive Fields |
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57 | (1) |
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Deafferentation Plasticity |
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57 | (1) |
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Activity-Dependent Receptive Field Modifications |
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58 | (1) |
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Glycine and Motor Reorganization |
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59 | (1) |
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60 | (19) |
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60 | (19) |
| Section II: Pharmacology of the GABA System |
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The Molecular Architecture of GABAA Receptors |
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79 | (22) |
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Repertoire of Subunit Types |
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79 | (4) |
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Structural Diversity and Uniformity |
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79 | (3) |
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82 | (1) |
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The Subunit Number per Receptor Molecule |
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83 | (1) |
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Subunits Within the Pentamer |
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84 | (4) |
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Two Subunit Pools for Receptor Assembly |
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84 | (1) |
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A Constrained Combinatorial System for the Receptor Compositions |
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85 | (3) |
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Stoichiometry Within the Pentamer |
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88 | (1) |
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Co-occurrence of Two Isoforms of One Subunit Type |
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88 | (1) |
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Possibilities for Subunit Stoichiometry |
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89 | (1) |
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GABAA Receptors Containing Other Types of Subunits |
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89 | (2) |
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90 | (1) |
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90 | (1) |
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91 | (1) |
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91 | (1) |
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91 | (1) |
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Conclusions on the Subtypes |
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92 | (9) |
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94 | (7) |
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Functions of GABAA -Receptors: Pharmacology and Pathophysiology |
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101 | (16) |
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101 | (1) |
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Pharmacology of GABAA -Receptor Subtypes |
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101 | (5) |
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Benzodiazepine Actions at GABAA-Receptor Subtypes |
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101 | (1) |
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Distinction of Receptor Subtypes by Point Mutations |
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101 | (2) |
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Sedation and Receptor Subtypes |
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103 | (1) |
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Amnesia and Receptor Subtypes |
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103 | (1) |
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Anticonvulsant Activity and Receptor Subtypes |
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104 | (1) |
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Myorelaxation, Potentiation and Receptor Subtypes |
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104 | (1) |
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Anxiolytic Activity and Receptor Subtypes |
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104 | (1) |
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Strategies for Drug Design |
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105 | (1) |
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Ethanol and GABAA Receptor Subtypes |
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105 | (1) |
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Anaesthetics and Pentobarbital |
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106 | (1) |
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GABAA -Receptor Mutants as Models for Disease |
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106 | (4) |
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Anxiety-Behaviour and Bias for Threat Cues |
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106 | (1) |
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Genetically Defined Animal Model of Anxiety |
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107 | (1) |
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Enhanced Reactivity to Natural Aversive Stimuli |
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107 | (1) |
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108 | (1) |
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Pathophysiology of Anxiety Disorders |
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108 | (2) |
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110 | (1) |
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110 | (1) |
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Desynchrony of Neuronal Oscillations |
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110 | (1) |
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Limitations of the Gene Inactivation Approach |
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110 | (7) |
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111 | (1) |
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111 | (1) |
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111 | (1) |
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112 | (1) |
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112 | (5) |
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Steroid Modulation of GABAA Receptors |
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117 | (24) |
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117 | (3) |
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Structure Activity Relationship for Steroids at the GABAA Receptor |
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120 | (8) |
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Enantioselectivity of Steroid Action |
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122 | (1) |
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122 | (1) |
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122 | (2) |
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124 | (2) |
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C5, C10 or C11 Substitution |
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126 | (1) |
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126 | (1) |
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127 | (1) |
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127 | (1) |
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127 | (1) |
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Neurosteroid Binding Site Heterogeneity and the Influence of GABAA Receptor Subunit Composition upon Neurosteroid Action |
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128 | (3) |
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128 | (2) |
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130 | (1) |
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130 | (1) |
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130 | (1) |
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130 | (1) |
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131 | (1) |
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Molecular Mechanism of Neurosteroid Action |
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131 | (1) |
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Neurosteroid Effects on Synaptic Transmission |
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132 | (2) |
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134 | (7) |
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135 | (6) |
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Allosteric Modulation of GABAA Receptor Function by General Anesthetics and Alcohols |
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141 | (32) |
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141 | (1) |
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What is a General Anesthetic? |
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141 | (2) |
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Special Considerations for Alcohol |
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143 | (1) |
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Overview of Ligand-Gated Ion Channels |
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143 | (1) |
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GABAA and Glycine Receptors |
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144 | (2) |
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Pharmacological Criteria for a Reasonable General Anesthetic/Alcohol Target Site |
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146 | (5) |
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What is the ``Clinically Relevant Concentration'' for a General Anesthetic? |
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147 | (1) |
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148 | (1) |
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148 | (2) |
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150 | (1) |
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150 | (1) |
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Experimental Approaches to Studying General Anesthetic and Alcohol Actions at the GABAA Receptors |
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151 | (1) |
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Actions of General Anesthetics at GABAA Receptors |
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152 | (3) |
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Volatile Anesthetics and Anesthetic Gases |
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155 | (2) |
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Intravenous Anesthetic Agents |
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157 | (1) |
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158 | (1) |
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GABAA and Glycine Receptors and Ethanol Action |
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158 | (2) |
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160 | (1) |
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Discussion and Future Directions |
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161 | (12) |
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162 | (11) |
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Anticonvulsants Acting on the GABA System |
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173 | (22) |
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173 | (2) |
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Role of GABA and GABA Receptors in Epilepsy |
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173 | (1) |
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Developmental Changes in GABAA Receptor Effects |
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174 | (1) |
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Mechanism of Action of Antiepileptic Drugs |
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175 | (1) |
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GABA Transporters and Tiagabine |
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175 | (4) |
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Effects of Other Anti-Epileptic Drugs on GABA-Transporters |
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178 | (1) |
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Changes in GABA Transporters in Epilepsy |
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179 | (1) |
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Vigabatrin and Inhibition of GABA-Transaminase |
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179 | (1) |
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Anticonvulsants Acting Through the GABAA Receptor |
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180 | (3) |
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181 | (1) |
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181 | (1) |
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182 | (1) |
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182 | (1) |
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183 | (1) |
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183 | (1) |
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Alterations in GABA Receptors in Epilepsy |
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183 | (4) |
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Alterations in the Expression of GABAA Receptors in Animal Models of Seizure |
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183 | (3) |
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GABAA Receptors and Absence Epilepsy |
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186 | (1) |
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Alternations in GABA Levels and GABAA Receptors in Human Epilepsy |
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187 | (1) |
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GABAergic Agents in Status Epilepticus |
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187 | (1) |
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Conclusions: Future Prospects for Anti-Epileptic Drugs Acting on GABAergic Transmission |
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188 | (7) |
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188 | (7) |
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Heterologous Regulation of GABAA Receptors: Protein Phosphorylation |
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195 | (32) |
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195 | (1) |
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Physiological Role of GABAA Receptors |
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196 | (1) |
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Molecular Structure of GABAA Receptors |
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196 | (2) |
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GABAA Receptor Subunit Families |
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196 | (1) |
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Domain Structures and Alternative Splicing |
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197 | (1) |
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Subunit Heterogeneity and Co-Assembly |
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198 | (1) |
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Consensus Sites for Protein Phosphorylation |
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198 | (1) |
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Identifying Phosphorylation Sites Within GABAA Receptor Subunits |
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199 | (3) |
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Phosphorylation of Neuronal GABAA Receptors |
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199 | (1) |
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Consensus Phosphorylation Sites in the Large Intracellular Domains |
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200 | (1) |
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Phosphorylation of Recombinant GABAA Receptors |
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201 | (1) |
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201 | (1) |
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201 | (1) |
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GABAA Receptor Phosphorylation: Consequences for Ion Channel Function |
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202 | (12) |
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cAMP-Dependent Protein Kinase |
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202 | (1) |
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202 | (1) |
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203 | (4) |
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cGMP-Dependent Protein Kinase |
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207 | (1) |
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Ca2+/Phospholipid Dependent Protein Kinase |
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207 | (3) |
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Ca2+/Calmodulin-Dependent Protein Kinase II and Ca2+ -Dependent Phosphatases |
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210 | (2) |
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212 | (1) |
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GABAA Receptor: Response Rundown and Washout |
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213 | (1) |
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Regulation of GABAA Receptor Cell Surface Expression |
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214 | (3) |
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217 | (10) |
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218 | (9) |
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Tolerance and Dependence to Ligands of the Benzodiazepine Recognition Sites Expressed by GABAA Receptors |
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227 | (24) |
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A Mechanistic Hypothesis on the Tolerance and Dependence to the Ligands of Benzodiazepine Recognition Sites (BZ-RS) Expressed by GABAA Receptors |
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227 | (1) |
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Tools to study changes in GABAA receptor subunit assembly |
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228 | (1) |
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Limitations in Interpreting Studies of GABAA Receptor Chimerae With and Without Single Amino Acid Mutations |
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229 | (1) |
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Characterization of BZ-RS Ligands Endowed with Anxiolytic and Anticonvulsant Actions |
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230 | (5) |
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Can the Subunit Expression Modification Associated with BZ Tolerance Explain the Decreased Intrinsic Activity of Full Positive-Allosteric Modulators at GABAA Receptors? |
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235 | (5) |
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Changes in GABA Receptor Subunit Assembly |
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235 | (1) |
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Studies on Ligand Binding to BZ-RS |
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235 | (1) |
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Changes in GABAA Receptor Subunit mRNA Expression |
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236 | (2) |
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Changes in GABAA Receptor Subunit Expression |
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238 | (1) |
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GABAA Receptor Subunit Allosteric Uncoupling |
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239 | (1) |
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Are Changes in GABAA Receptor Subunit Assembly Relevant to BZ Dependence? |
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240 | (2) |
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Development of Tolerance and Dependence Liability After Long- Term Treatment with Selective-Positive-Allosteric Modulators of GABAA Receptors |
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242 | (1) |
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242 | (1) |
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242 | (1) |
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Lack of Tolerance or Dependence Following Long Term Treatment with Partial-Positive-Allosteric BZ-RS Ligands |
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243 | (8) |
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Imidazenil is Devoid of Tolerance and Dependence Liability in Rodents |
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244 | (1) |
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Imidazenil is Devoid of Tolerance and Dependence Liability in Monkeys |
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245 | (2) |
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247 | (4) |
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GABAA Receptors and Disease |
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251 | (20) |
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251 | (1) |
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Diseases of Development and GABAA Receptors |
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252 | (2) |
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Diseases of Adult and GABAA Receptors |
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254 | (6) |
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GABAA Receptor Function in Adult Epilepsy |
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254 | (3) |
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GABAA Receptor Function in Anxiety |
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257 | (1) |
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GABAA Receptor Function in Alcoholism |
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258 | (2) |
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260 | (11) |
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261 | (10) |
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GABAc Receptors: Structure, Function and Pharmacology |
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271 | (28) |
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271 | (1) |
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Structure of GABAc Receptors |
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272 | (1) |
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Cloning of Vertebrate ρ-Subunits |
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272 | (1) |
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Subunit Composition of GABAc Receptors |
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272 | (1) |
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272 | (2) |
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Functional Properties of GABAc Receptors |
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274 | (4) |
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Identification of GABAc Receptors |
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274 | (1) |
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GABA Affinity and Ion Selectivity |
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274 | (2) |
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Single Channel Characteristics |
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276 | (1) |
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276 | (1) |
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277 | (1) |
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278 | (5) |
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278 | (2) |
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280 | (3) |
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Modulation of GABAc Receptors |
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283 | (4) |
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283 | (1) |
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Intracellular Modulation by Protein Kinases |
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284 | (3) |
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Physiological Function of GABAc Receptors |
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287 | (3) |
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Terminology for GABAc Receptors |
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290 | (1) |
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290 | (9) |
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291 | (8) |
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Structure of GABAB Receptors |
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299 | (12) |
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Physiological Evidence for GABAB Receptors Subtypes |
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299 | (1) |
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Pharmacology, Structure and Distribution of Cloned GABAB Receptors |
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300 | (3) |
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300 | (2) |
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302 | (1) |
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Molecular Determinants of Ligand Binding |
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302 | (1) |
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Functional Studies with Recombinant GABAB Receptors |
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303 | (3) |
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Individually Expressed BR1 and BR2 Receptors |
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303 | (2) |
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Heteromeric BR1 + BR2 Receptors |
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305 | (1) |
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Temporal and Spatial Distribution of Cloned GABAB Receptors |
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306 | (1) |
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Concluding Remarks and Future Directions |
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307 | (4) |
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307 | (4) |
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Pharmacology of GABAB Receptors |
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311 | (18) |
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311 | (1) |
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312 | (1) |
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GABAB Receptor Distribution and Localization in CNS |
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313 | (1) |
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GABAB Receptor Coupling to Adenylate Cyclase |
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314 | (1) |
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Ca++ and K+ Channel Coupling to GABAB Sites |
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315 | (1) |
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Pharmacological Effects - GABAB Receptor Agonists |
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316 | (3) |
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Pharmacological Effects - GABAB Receptor Antagonists |
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319 | (2) |
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321 | (8) |
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321 | (8) |
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GABAB Receptor Signaling Pathways |
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329 | (16) |
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329 | (1) |
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Second Messenger Production |
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330 | (6) |
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330 | (1) |
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330 | (4) |
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334 | (2) |
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336 | (1) |
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337 | (1) |
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338 | (7) |
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339 | (6) |
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Structure and Function of GABA Transporters |
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345 | (10) |
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345 | (1) |
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346 | (1) |
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Reconstitution and Purification |
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346 | (1) |
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Biochemical Characterisation of the GABA Transporter |
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347 | (1) |
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A New Superfamily of Na-Dependent Neurotransmitter Transporters |
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348 | (1) |
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348 | (1) |
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Structure-Function Relationships |
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349 | (2) |
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351 | (4) |
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352 | (3) |
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Pharmacology of GABA Transporters |
|
|
355 | (20) |
|
|
|
|
|
|
|
|
|
|
|
|
|
355 | (1) |
|
Physiological Relevance of GABA Transporters |
|
|
356 | (1) |
|
`Neuronal'- and `Glial'- Specific GABA Transport Inhibitors |
|
|
357 | (2) |
|
GABA Transporter Heterogeneity |
|
|
359 | (2) |
|
Lipophilic GABA Transporter Inhibitors |
|
|
361 | (3) |
|
|
|
361 | (1) |
|
Prodrugs of Nipecotic Acid, Hydroxynipecotic Acid, and Isoguvacine |
|
|
361 | (1) |
|
Nipecotic Acid and Guvacine Derivatives |
|
|
362 | (2) |
|
Specific GABA Transport Inhibitors |
|
|
364 | (2) |
|
Compounds Selective for GAT-1 |
|
|
364 | (1) |
|
Compounds Selective for GAT-2, GAT-3, and BGT-1 |
|
|
365 | (1) |
|
GABA Uptake Inhibitors as Experimental Tools |
|
|
366 | (1) |
|
GABA Transport Inhibition and Sleep |
|
|
366 | (1) |
|
Depolarizing Effects of GABA and Inhibition of GABA Uptake |
|
|
367 | (1) |
|
|
|
367 | (8) |
|
|
|
368 | (7) |
| Section III: Pharmacology of the Glycine System |
|
|
Structures, Diversity and Pharmacology of Glycine Receptors and Transporters |
|
|
375 | (28) |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
375 | (1) |
|
The Neurotransmitter Glycine |
|
|
375 | (1) |
|
Structure and Diversity of Glycine Transporters |
|
|
376 | (6) |
|
Structure of Plasma Membrane Glycine Transporters |
|
|
376 | (2) |
|
Diversity and Regulation of Plasma Membrane Glycine Transporters |
|
|
378 | (2) |
|
Distribution of Plasma Membrane Glycine Transporters and Possible Physiological Function |
|
|
380 | (1) |
|
The Vesicular Glycine/GABA Transporter |
|
|
381 | (1) |
|
Structure and Diversity of Glycine Receptor Channels |
|
|
382 | (11) |
|
GlyRs are Ligand-Gated Ion Channels of the nAChR Superfamily |
|
|
382 | (2) |
|
Glycine Receptor Isoforms |
|
|
384 | (1) |
|
Ligand-Binding Determinants |
|
|
385 | (2) |
|
|
|
387 | (1) |
|
The Peripheral Membrane Protein Gephyrin |
|
|
387 | (2) |
|
|
|
389 | (1) |
|
Antagonism of GlyR Function by Strychnine |
|
|
389 | (1) |
|
Amino Acids and Piperidine Carboxylic Acid Compounds |
|
|
390 | (1) |
|
Picrotoxinin, Cyanotriphenylborate, and Quinolinic Acid Derivatives |
|
|
390 | (1) |
|
Potentiation of GlyR Function by Anesthetics, Alcohol, and Zn2+ |
|
|
391 | (2) |
|
|
|
393 | (10) |
|
|
|
393 | (10) |
| Subject Index |
|
403 | |
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