Glutamate-based Therapies for Psychiatric Disorders (eBook)

Glutamate-based Therapies for Psychiatric Disorders 3
Introduction 5
Glutamate and Psychiatric Disorders: Evolution Over Five Decades 5
Current Approaches to Modulate Glutamatergic Neurotransmission 6
Glutamate-Based Therapeutics in Psychiatry 6
References 8
Contents 11
Contributors 13
N-Methyl-d-Aspartate (NMDA) Antagonists for the Treatment of Depression 15
1 Introduction 16
2 Preclinical Studies 17
2.1 NMDA Antagonists Exhibit AD-Like Actions in Preclinical Tests with High Predictive Validity 17
2.2 NMDA Receptors Are Altered by Chronic AD Treatment 19
2.2.1 Neurochemical Studies 20
2.2.2 Behavioral and Electrophysiological Studies Confirm That Chronic AD Treatment Blunts NMDA Receptor Function 21
3 Clinical Studies with NMDA Antagonists in Depression 22
3.1 Multiple Reports Demonstrate a Rapid and Robust AD Response in Patients ``Resistant´´ to Biogenic Amine-Based Agents 22
3.2 Studies with Memantine in Depression Are Equivocal 24
3.3 A Selective NR2B Antagonist (Traxoprodil) Exhibits AD Activity 25
4 Why Did It Take So Long to Develop NMDA Antagonists for the Treatment of Depression? 26
5 Is It Feasible to Develop an NMDA Antagonist for the Treatment of Depression? 26
6 Why Are NMDA Antagonists AD?: Developing Drugs That Circumvent the Monoaminergic Synapse 28
References 30
Ionic Glutamate Modulators in Depression (Zinc, Magnesium) 35
1 Zinc 35
1.1 Physiological Functions of Zinc 35
1.2 Zinc and Depression 36
1.2.1 Human Study (Table1) 36
1.2.2 Preclinical Studies (Table1) 38
1.3 Mechanism of Antidepressant Activity of Zinc 40
1.3.1 Involvement of the Glutamate System 40
1.3.2 Involvement of the Serotonergic System 41
1.3.3 Involvement of BDNF 42
1.3.4 Involvement of the GSK-3 Enzyme 42
2 Magnesium 42
2.1 Physiological Functions of Magnesium 42
2.2 Magnesium and Depression 43
2.2.1 Human Study (Table2) 43
2.2.2 Preclinical Studies (Table2) 44
2.3 Mechanism of Antidepressant Activity of Magnesium 45
2.3.1 Involvement of the Glutamate System 45
2.3.2 Involvement of Serotonergic System 45
2.3.3 Involvement of the Catecholaminergic System 46
2.3.4 Involvement of the GSK-3 Enzyme 46
3 Conclusions 46
References 46
Positive Allosteric Modulation of AMPA Receptors: A Novel Potential Antidepressant Therapy 53
1 Overview 54
2 AMPA Receptors 55
3 AMPA Receptor Potentiators 58
4 AMPA Receptor Potentiators Modulate Antidepressant-Related Biochemistry and Structural Biology 59
5 AMPA Receptors Are Modulated in Depression and by Antidepressant Treatment 61
6 AMPA Receptor Potentiators Engender Antidepressant-Like Behavioral Effects 63
7 Conclusions 64
References 66
Glutamatergic Modulators for the Treatment of Major Depressive Disorder: Metabotropic Glutamate Receptors 71
1 Introduction 72
2 Glutamate Modulation 73
3 Metabotropic Glutamate Receptors 73
4 Group I mGlu Receptors 74
4.1 Antidepressants Modify mGlu Receptors 74
4.2 Antidepressant-Like Behavioral Effects of Antagonists 79
5 Group II mGlu Receptors 79
5.1 Antidepressants Modify mGlu Receptors 79
5.2 Antidepressant-Like Neurochemical Effects 80
5.3 Antidepressant-Like Behavioral Effects of Antagonists 80
6 Group III mGlu Receptors 81
6.1 Antidepressants Modify mGlu Receptors 81
6.2 Antidepressant-Like Behavioral Effects 81
7 mGlu Receptor Involvement in Mood Disorders 82
7.1 Group I mGlu Receptors 82
7.2 Group II mGlu Receptors 84
7.3 Group III mGlu Receptors 84
References 84
Positive Modulation of AMPA Receptors as a Broad-Spectrum Strategy for Treating Neuropsychiatric Disorders 89
1 Introduction 90
2 Working Hypotheses 91
2.1 Cortical Control of Biogenic Amine Systems 91
2.2 Defects in the Spine Cytoskeleton May Be a Common Element in Psychiatric Disorders 92
3 Ampakines and Abnormal Biogenic Amine Activity 96
3.1 Stimulant-Induced Hyperactivity 96
3.2 Schizophrenia and Attention Deficit/Hyperactivity Disorder (ADHD) 97
3.3 Depression 98
3.4 Cortical Effects of Ampakines 98
4 Effects of Ampakines on Conditions in Which Spine Plasticity Is Impaired 99
4.1 Huntington´s Disease 99
4.2 Aging 101
4.3 Chronic Reductions in Circulating Estrogen 104
4.4 Fragile-X Mental Retardation Syndrome (FXS) 105
5 Summary and Discussion 106
References 109
Activation of Group II Metabotropic Glutamate Receptors (mGluR2 and mGluR3) as a Novel Approach for Treatment of Schizophrenia 115
1 Introduction 115
2 The Glutamatergic Hypothesis of Schizophrenia 117
3 The Group II mGluRs as Therapeutics Targets for Schizophrenia 120
4 mGluR2 Positive Allosteric Modulators as Therapeutics for Schizophrenia 123
5 mGluR2 and 5-HT2A May Provide a Novel Heterocomplex to Target for Potential Antipsychotic Activity 124
6 Concluding Remarks 126
References 126
mGluR1 Negative Allosteric Modulators: An Alternative Metabotropic Approach for the Treatment of Schizophrenia 131
1 Introduction 132
2 Development of mGluR1 Negative Allosteric Modulators (NAMs) 134
3 Effects on DA-Dependent Behavior in Animal Models 135
4 Effects on Glutamate (NMDA)-Dependent Behavior in Animal Models 137
5 Immunohistochemical Analysis of c-fos Expression in Rats 139
6 Potential Side Effects by mGluR1 NAMs 140
6.1 Motor Coordination 140
6.2 Cognitive Behaviors 141
7 Conclusion 142
References 142
Metabotropic Glutamate Receptors as Targets for the Treatment of Drug and Alcohol Dependence 146
1 Introduction 146
2 Neurosubstrates Involved in Drug Dependence and Relapse 147
3 Glutamatergic Transmission in Drug Dependence 148
4 Metabotropic Glutamate Receptors and Glutamatergic Neurotransmission 148
5 Role of mGluRs in Preclinical Models of Drug Dependence 150
5.1 Role of mGluRs in the Modulation of the Reinforcing and Motivational Effects of Drugs of Abuse 150
5.2 Role of mGluRs in the Modulation of the Reward-Enhancing Effects of Drugs of Abuse 153
5.3 Role of mGluRs in the Modulation of the Conditioned Rewarding Effects of Drugs of Abuse 153
5.4 Role of mGluRs in the Modulation of Different Aspects of Drug Withdrawal, Including Anhedonia, Depression, and Anxiety 154
5.5 Role of mGluRs in the Modulation of Drug-Seeking Behavior 157
6 Summary and Conclusions 159
References 160
Metabotropic Approaches to Anxiety 170
1 Introduction 170
2 The Circuit of Fear and Anxiety 171
3 Distribution of mGlu Receptors in the Synaptic Cleft 173
4 Amygdala and mGlu Receptors 174
5 Mechanism of Action of mGlu Ligands 175
5.1 Group I mGlu Receptors 176
5.1.1 Clinical Data 176
5.2 Group II mGlu Receptors 178
5.2.1 Clinical Studies 179
5.3 Group III mGlu Receptors 180
6 Conclusions 182
References 182
Index 187