Skolnick Glutamate-based Therapies for Psychiatric Disorders

1. Auflage 2010
ISBN: 978-3-0346-0241-9
Verlag: Springer
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 178 Seiten

Reihe: Milestones in Drug Therapy

Both metabotropic and ionotropic glutamate receptors present attractive 'druggable' targets in treating disorders of the central nervous system. There has been a dramatic shift in the focus of glutamate-based therapies away from neurologic disorders such as stroke and traumatic brain injury to the treatment of psychiatric disorders. This 'Milestones in Drug Therapy' volume offers a unique, contemporary overview of preclinical and clinical evidence that modulating glutamatergic tone is an effective means of treating psychiatric disorders ranging from depression and anxiety to schizophrenia and drug abuse. The ability to treat diseases such as depression and schizophrenia through multiple, glutamate-based mechanisms offers a unique therapeutic opportunity, as described in this book.

Autoren/Hrsg.

Skolnick, Phil

Inhaltsverzeichnis

1;Glutamate-based Therapies for Psychiatric Disorders;3
1.1;Introduction;5
1.1.1;Glutamate and Psychiatric Disorders: Evolution Over Five Decades;5
1.1.2;Current Approaches to Modulate Glutamatergic Neurotransmission;6
1.1.3;Glutamate-Based Therapeutics in Psychiatry;6
1.1.4;References;8
1.2;Contents;11
1.3;Contributors;13
1.4;N-Methyl-d-Aspartate (NMDA) Antagonists for the Treatment of Depression;15
1.4.1;1 Introduction;16
1.4.2;2 Preclinical Studies;17
1.4.2.1;2.1 NMDA Antagonists Exhibit AD-Like Actions in Preclinical Tests with High Predictive Validity;17
1.4.2.2;2.2 NMDA Receptors Are Altered by Chronic AD Treatment;19
1.4.2.2.1;2.2.1 Neurochemical Studies;20
1.4.2.2.2;2.2.2 Behavioral and Electrophysiological Studies Confirm That Chronic AD Treatment Blunts NMDA Receptor Function;21
1.4.3;3 Clinical Studies with NMDA Antagonists in Depression;22
1.4.3.1;3.1 Multiple Reports Demonstrate a Rapid and Robust AD Response in Patients ``Resistant´´ to Biogenic Amine-Based Agents;22
1.4.3.2;3.2 Studies with Memantine in Depression Are Equivocal;24
1.4.3.3;3.3 A Selective NR2B Antagonist (Traxoprodil) Exhibits AD Activity;25
1.4.4;4 Why Did It Take So Long to Develop NMDA Antagonists for the Treatment of Depression?;26
1.4.5;5 Is It Feasible to Develop an NMDA Antagonist for the Treatment of Depression?;26
1.4.6;6 Why Are NMDA Antagonists AD?: Developing Drugs That Circumvent the Monoaminergic Synapse;28
1.4.7;References;30
1.5;Ionic Glutamate Modulators in Depression (Zinc, Magnesium);35
1.5.1;1 Zinc;35
1.5.1.1;1.1 Physiological Functions of Zinc;35
1.5.1.2;1.2 Zinc and Depression;36
1.5.1.2.1;1.2.1 Human Study (Table1);36
1.5.1.2.2;1.2.2 Preclinical Studies (Table1);38
1.5.1.3;1.3 Mechanism of Antidepressant Activity of Zinc;40
1.5.1.3.1;1.3.1 Involvement of the Glutamate System;40
1.5.1.3.2;1.3.2 Involvement of the Serotonergic System;41
1.5.1.3.3;1.3.3 Involvement of BDNF;42
1.5.1.3.4;1.3.4 Involvement of the GSK-3 Enzyme;42
1.5.2;2 Magnesium;42
1.5.2.1;2.1 Physiological Functions of Magnesium;42
1.5.2.2;2.2 Magnesium and Depression;43
1.5.2.2.1;2.2.1 Human Study (Table2);43
1.5.2.2.2;2.2.2 Preclinical Studies (Table2);44
1.5.2.3;2.3 Mechanism of Antidepressant Activity of Magnesium;45
1.5.2.3.1;2.3.1 Involvement of the Glutamate System;45
1.5.2.3.2;2.3.2 Involvement of Serotonergic System;45
1.5.2.3.3;2.3.3 Involvement of the Catecholaminergic System;46
1.5.2.3.4;2.3.4 Involvement of the GSK-3 Enzyme;46
1.5.3;3 Conclusions;46
1.5.4;References;46
1.6;Positive Allosteric Modulation of AMPA Receptors: A Novel Potential Antidepressant Therapy;53
1.6.1;1 Overview;54
1.6.2;2 AMPA Receptors;55
1.6.3;3 AMPA Receptor Potentiators;58
1.6.4;4 AMPA Receptor Potentiators Modulate Antidepressant-Related Biochemistry and Structural Biology;59
1.6.5;5 AMPA Receptors Are Modulated in Depression and by Antidepressant Treatment;61
1.6.6;6 AMPA Receptor Potentiators Engender Antidepressant-Like Behavioral Effects;63
1.6.7;7 Conclusions;64
1.6.8;References;66
1.7;Glutamatergic Modulators for the Treatment of Major Depressive Disorder: Metabotropic Glutamate Receptors;71
1.7.1;1 Introduction;72
1.7.2;2 Glutamate Modulation;73
1.7.3;3 Metabotropic Glutamate Receptors;73
1.7.4;4 Group I mGlu Receptors;74
1.7.4.1;4.1 Antidepressants Modify mGlu Receptors;74
1.7.4.2;4.2 Antidepressant-Like Behavioral Effects of Antagonists;79
1.7.5;5 Group II mGlu Receptors;79
1.7.5.1;5.1 Antidepressants Modify mGlu Receptors;79
1.7.5.2;5.2 Antidepressant-Like Neurochemical Effects;80
1.7.5.3;5.3 Antidepressant-Like Behavioral Effects of Antagonists;80
1.7.6;6 Group III mGlu Receptors;81
1.7.6.1;6.1 Antidepressants Modify mGlu Receptors;81
1.7.6.2;6.2 Antidepressant-Like Behavioral Effects;81
1.7.7;7 mGlu Receptor Involvement in Mood Disorders;82
1.7.7.1;7.1 Group I mGlu Receptors;82
1.7.7.2;7.2 Group II mGlu Receptors;84
1.7.7.3;7.3 Group III mGlu Receptors;84
1.7.8;References;84
1.8;Positive Modulation of AMPA Receptors as a Broad-Spectrum Strategy for Treating Neuropsychiatric Disorders;89
1.8.1;1 Introduction;90
1.8.2;2 Working Hypotheses;91
1.8.2.1;2.1 Cortical Control of Biogenic Amine Systems;91
1.8.2.2;2.2 Defects in the Spine Cytoskeleton May Be a Common Element in Psychiatric Disorders;92
1.8.3;3 Ampakines and Abnormal Biogenic Amine Activity;96
1.8.3.1;3.1 Stimulant-Induced Hyperactivity;96
1.8.3.2;3.2 Schizophrenia and Attention Deficit/Hyperactivity Disorder (ADHD);97
1.8.3.3;3.3 Depression;98
1.8.3.4;3.4 Cortical Effects of Ampakines;98
1.8.4;4 Effects of Ampakines on Conditions in Which Spine Plasticity Is Impaired;99
1.8.4.1;4.1 Huntington´s Disease;99
1.8.4.2;4.2 Aging;101
1.8.4.3;4.3 Chronic Reductions in Circulating Estrogen;104
1.8.4.4;4.4 Fragile-X Mental Retardation Syndrome (FXS);105
1.8.5;5 Summary and Discussion;106
1.8.6;References;109
1.9;Activation of Group II Metabotropic Glutamate Receptors (mGluR2 and mGluR3) as a Novel Approach for Treatment of Schizophrenia;115
1.9.1;1 Introduction;115
1.9.2;2 The Glutamatergic Hypothesis of Schizophrenia;117
1.9.3;3 The Group II mGluRs as Therapeutics Targets for Schizophrenia;120
1.9.4;4 mGluR2 Positive Allosteric Modulators as Therapeutics for Schizophrenia;123
1.9.5;5 mGluR2 and 5-HT2A May Provide a Novel Heterocomplex to Target for Potential Antipsychotic Activity;124
1.9.6;6 Concluding Remarks;126
1.9.7;References;126
1.10;mGluR1 Negative Allosteric Modulators: An Alternative Metabotropic Approach for the Treatment of Schizophrenia;131
1.10.1;1 Introduction;132
1.10.2;2 Development of mGluR1 Negative Allosteric Modulators (NAMs);134
1.10.3;3 Effects on DA-Dependent Behavior in Animal Models;135
1.10.4;4 Effects on Glutamate (NMDA)-Dependent Behavior in Animal Models;137
1.10.5;5 Immunohistochemical Analysis of c-fos Expression in Rats;139
1.10.6;6 Potential Side Effects by mGluR1 NAMs;140
1.10.6.1;6.1 Motor Coordination;140
1.10.6.2;6.2 Cognitive Behaviors;141
1.10.7;7 Conclusion;142
1.10.8;References;142
1.11;Metabotropic Glutamate Receptors as Targets for the Treatment of Drug and Alcohol Dependence;146
1.11.1;1 Introduction;146
1.11.2;2 Neurosubstrates Involved in Drug Dependence and Relapse;147
1.11.3;3 Glutamatergic Transmission in Drug Dependence;148
1.11.4;4 Metabotropic Glutamate Receptors and Glutamatergic Neurotransmission;148
1.11.5;5 Role of mGluRs in Preclinical Models of Drug Dependence;150
1.11.5.1;5.1 Role of mGluRs in the Modulation of the Reinforcing and Motivational Effects of Drugs of Abuse;150
1.11.5.2;5.2 Role of mGluRs in the Modulation of the Reward-Enhancing Effects of Drugs of Abuse;153
1.11.5.3;5.3 Role of mGluRs in the Modulation of the Conditioned Rewarding Effects of Drugs of Abuse;153
1.11.5.4;5.4 Role of mGluRs in the Modulation of Different Aspects of Drug Withdrawal, Including Anhedonia, Depression, and Anxiety;154
1.11.5.5;5.5 Role of mGluRs in the Modulation of Drug-Seeking Behavior;157
1.11.6;6 Summary and Conclusions;159
1.11.7;References;160
1.12;Metabotropic Approaches to Anxiety;170
1.12.1;1 Introduction;170
1.12.2;2 The Circuit of Fear and Anxiety;171
1.12.3;3 Distribution of mGlu Receptors in the Synaptic Cleft;173
1.12.4;4 Amygdala and mGlu Receptors;174
1.12.5;5 Mechanism of Action of mGlu Ligands;175
1.12.5.1;5.1 Group I mGlu Receptors;176
1.12.5.1.1;5.1.1 Clinical Data;176
1.12.5.2;5.2 Group II mGlu Receptors;178
1.12.5.2.1;5.2.1 Clinical Studies;179
1.12.5.3;5.3 Group III mGlu Receptors;180
1.12.6;6 Conclusions;182
1.12.7;References;182
1.13;Index;187