If one looks retrospectively at the history of dopamine, from its present status to its discovery, there is no doubt it has come quite a long way. Following the early studies by Sir Henry Dale in 1910, dopamine was labeled as a weak sympathomimetic amine, without a function of its own, and was left in this neglected state for nearly half a century, until its presence in the brain was discovered by Arvid Carlsson in 1959 and its depletion in the putamen of Parkinson's patients was reported by Oleh Hornykiewicz in 1960. Then, the dopamine precursor l-DOPA was introduced as a treatment of Parkinson's disease, gaining the reputation of an outstanding example of rational therapy directly derived from pathophysiological knowledge. Thus, on the wings of this success, the next 10 years saw dopamine as the transmitter of extrapy-ramidal motor functions. Dopamine was so much linked to motor functions that when in the 1970s Roy Wise, with his anhedonia hypothesis, attributed to dopamine the role of a substrate of all rewards, a hot debate ensued that persists until now. Although debated, the relationship of dopamine with reward has been so fruitful that initiated its second life, that of dopamine's role in incentive learning, motivation, and impulse control and in the mechanism of drug addiction. In the background is the role of dopamine in the therapeutic action of fundamental drugs, such as antipsychotics, that gave the impetus for the study of the role of dopamine in executive functions and working memory, another success story of its own.
That of dopamine has been an ideal field of study for neuroscientists and probably the greatest contribution of modern neuroscience to the dopamine field has been the demonstration that dopamine has different anatomical, biochemical, physiological, and pharmacological substrates. Thus, from the idea of a dopamine system working "en masse" and circumscribed to the neostriatum, we went through the notion of ventral and dorsal striatum and the distinction of nonstriatal, including cortical, dopamine, and shell and core accumbens subdivisions, up to the present dissection of distinct subpopulations of dopamine neurons projecting to different subdivisions of the terminal dopamine field, talking through other transmitters beside dopamine and eventually playing opposite motivational functions.
This book provides a number of examples of the revolution carried by neuroscience in the dopamine field, a revolution that might well mark dopamine's third life. The success of the Dopamine 2013 meeting, from which the contributions of this book are taken, indicates that this third life of dopamine will not be less rewarding than the previous ones. Gaetano Di Chiara; Marco Diana; Pierfranco Spano

Contributors v

Preface ix

CHAPTER 1 Thalamostriatal Synapses—Another Substrate for Dopamine Action? 1

Gordon W. Arbuthnott

1. The "Other" Striatal Input 2

2. Thalamostriatal Targets 3

3. Formation and Function of Thalamostriatal Synapses 4

4. Impact of Thalamic Changes in Parkinson's Disease on the Motor System 5

5. Spine Loss in Striatal Neurons After Dopamine Removal 6

Acknowledgments 8

References 9

CHAPTER 2 Life-Long Consequences of Juvenile Exposure to Psychotropic Drugs on Brain and Behavior 13

Heinz Steiner, Brandon L. Warren, Vincent Van Waes, Carlos A. Bolanos-Guzman

1. Introduction 14

2. Effects of Juvenile Methylphenidate + Fluoxetine Treatment on Gene Regulation in the Striatum 15

      2.1. Effects of Acute and Repeated MPH+FLX Treatment on Striatal IEG Expression 16

      2.2. Effects of Acute and Repeated MPH+FLX Treatment on Striatal Neuropeptide Expression 19

3. Effects of Juvenile Methylphenidate+Fluoxetine Treatment on Molecular Signaling in the Midbrain and Behavior 19

      3.1. Effects of Juvenile MPH, FLX, and MPH+FLX Exposure on Responses to Aversive Stimuli 20

      3.2. Effects of Juvenile MPH, FLX, and MPH+FLX Exposure on ERK Signaling in the VTA 21

      3.3. Reversal of Combined MPH+FLX-Induced Behavioral Despair in Adulthood 22

4. Discussion and Conclusions 23

Acknowledgments 25

References 25

CHAPTER 3 The Role of Learning-Related Dopamine Signals in Addiction Vulnerability 31

Quentin J.M. Huys, Philippe N. Tobler, Gregor Hasler, Shelly B. Flagel

1. Background 32

      1.1. Overview 33

2. Model-Free and Model-Based Learning from Rewards 34

      2.1. Model-Based Learning 36

      2.2. Model-Free Prediction-Error Learning 36

3. Phasic Dopamine Signals Represent Model-free Prediction Errors 39

      3.1. Causal Role of (Dopamine-Mediated) Prediction Errors in Learning 42

      3.2. Phasic Dopamine Signals in Model-Based Learning 45

4. Behavioral Characteristics of Model-Free and Model-Based Choices 45

      4.1. Outcome Identity 46

      4.2. Pavlovian Approach and Consummatory Behaviors 46

      4.3. Instrumental Behavior 47

      4.4. Pavlovian-Instrumental Transfer (PIT) 48

      4.5. Motivational Shifts 48

      4.6. Unlearning 50

5. Individual Variability 50

      5.1. Sign-Tracking and Goal-Tracking 50

      5.2. Incentive Salience Accounts of the Sign-Tracking/Goal-Tracking Variability 53

      5.3. Reinforcement Learning Accounts of the Sign-Tracking/Goal-Tracking Variability 54

6. Addiction 58

      6.1. Phasic Dopaminergic Signals in Addiction 58

      6.2. Individual Variability in Addiction Vulnerability 59

      6.3. Shifts Toward Model-Free Learning in Addiction 61

      6.4. Conclusions 63

Acknowledgments 64

References 64

CHAPTER 4 Dopaminergic Function in Relation to Genes Associated with Risk for Schizophrenia: Translational Mutant Mouse Models 79

Paula M. Moran, Colm M.P. O'Tuatliaigh, Francesco Papaleo, John L. Waddington C2\1. Introduction 80

2. Mice Mutant for Dopamine Related Genes 80

      2.1. DAergic Function and Schizophrenia 80

      2.2. Dopamine-Releasing Drugs and Dopamine Transporter Mutants 81

      2.3. D2 Antagonists and D2 Mutants 82

      2.4. Overview 84

3. Mice Mutant for DTNBP1 (dysbindin-1) 85

      3.1. Dysbindin-1 and Schizophrenia 85

      3.2. Dysbindin-1 and DAergic Cell Biology 86

      3.3. Dysbindin 1 and DAergic Function 87

      3.4. Overview 88

4. Mice Mutant for NRG1/ErbB 89

      4.1. Neuregulin-1/ErbB Signaling and Schizophrenia 89

      4.2. Neuregulin 1/ErbB Signaling and DAergic Cell Biology 90

      4.3. Neuregulin-1/ErbB Signaling and DAergic Function 91

      4.4. Overview 94

5. Gene x Environment and Gene x Gene Interactions 94

      5.1. Gene x Environment Interactions and DAergic Function 94

      5.2. Gene x Gene Interactions and DAergic Function 96

      5.3. Overview 97

6. Conclusions 98

Acknowledgments 98

References 98

CHAPTER 5 Dopamine D2 Heteroreceptor Complexes and their Receptor-Receptor Interactions in Ventral Striatum: Novel Targets for Antipsychotic Drugs 113

Kjell Fuxe, Dasiel O. Borroto-Escuela, Alexander O. Tarakanov, Wilber Romero-Fernandez, Luca Ferraro, Sergio Tanganelli, Mileidys Perez-Alea, Michael Di Palma, Luigi F. Agnati

1. Introduction 114

2. Allosteric Receptor-Receptor Interactions in Heteroreceptor Complexes 115

3. On the Interface of Receptor Heteromers 115

4. Adenosine A2AR—DA D2R Heteroreceptor Complexes 117

      4.1. Receptor Interface 120

      4.2. Brain Circuits and Behavioral Role 122

      4.3. On the Possible Existence of A2A-D2-FGFR1 Heteroreceptor Complexes 122

5. DA D2-Neurotensin NTS 1 Heteroreceptor Complexes 123

      5.1. Receptor-Receptor Interactions 123

      5.2. Transmitter Effects In Vivo in Brain Circuits 124

6. DA D2-5-HT2A Heteroreceptor Complexes 125

      6.1. RET Techniques and Proximity Ligation Assays 125

      6.2. Signaling and Recognition 126

7. 5-HT2A-mGluR2 Heteroreceptor Complexes 127

8. D2-Oxytocinr Heteroreceptor Complexes 128

      8.1. Structure 129

      8.2. Recognition and Signaling 129

9. Summary and Future Directions 130

Acknowledgments 131

References 131

CHAPTER 6 The Multilingual Nature of Dopamine Neurons 141

Louis-Eric Trudeau, Thomas S. Hnasko, Asa Wallen-Mackenzie, Marisela Morales, Steven Rayport, David Sulzer

1. The Particular Nature of Dopamine Neurons 142

2. Discovery of Cotransmitters in DA Neurons 143

3. Localization of Glutamatergic and Mixed Phenotype DA Neurons in the Brain 147

4. Synaptic Connectivity and Plasticity of Glutamate Release by DA Neurons 149

5. Developmental Role of Glutamate Release by DA Neurons 151

6. Possible Contribution of VGLUT2 in DA Neurons to Vesicular Synergy 153

7. Does Glutamate Corelease Mediate a Reward-Relevant Signal? 155

Acknowledgments 156

References 157

CHAPTER 7 Imaging Dopamine Neurotransmission in Live Human Brain 165

Rajendra D. Badgaiyan

1. Molecular Imaging Techniques 167

2. Basic Principles and Receptor Kinetic Models 168

3. Single-Scan Dynamic Molecular Imaging Technique 171

4. Use of Multiple Kinetic Models 172

5. Study of Pathophysiology of Psychiatric Conditions 174

6. Limitations and Future Directions 178

7. Summary 179

Acknowledgments 179

References 179

CHAPTER 8 Dopamine Receptor Heteromeric Complexes and their Emerging Functions 183

Susan R. George, Andras Kern, Roy G. Smith, Rafael Franco

1. Introduction 183

2. The Dopamine D1 Receptor and D2 Receptor Heteromer 184

      2.1. A Dopamine Receptor Complex Linked to Calcium Signaling 184

      2.2. Coexpression and Interaction of D\1 and D2 Dopamine Receptors 184

      2.3. Consequences of Increased Intracellular Calcium Release 185

      2.4. Anatomical Distribution of Neurons Expressing the D1-D2 Heteromer 186

      2.5. Regulation of the D1-D2 Heteromer 187

      2.6. Interaction Interface Between the D1 and D2 Receptors 187

3. The Dopamine D2 Receptor and Ghrelin Receptor Heteromer 188

      3.1. GHSR1a and DRD2 Are Coexpressed in Hypothalamic Neurons Resulting in the Modification of Canonical Dopamine Signaling 189

      3.2. GHSR1a and DRD2 Allosterically Interact via Heteromer Formation 190

      3.3. GHSR1a:DRD2 Heteromers Regulate Food Intake 191

4. The Dopamine D2 Receptor and Adenosine Receptor Heteromer 193

      4.1. Functional and Pharmacological Consequences of D2 Receptor-Containing Heteromers 193

      4.2. Relevance of Heteromer Quaternary Structure 194

      4.3. Presence of Heteromers in a Parkinsonian Model of Parkinson's Disease 195

      4.4. Loss of Heteromers in L-DOPA-Induced Dyskinetic Primates 195

      4.5. l-DOPA Treatment Disrupts A_2A-CB_1-D2 Receptor Heteromers 196

References 196

CHAPTER 9 Alcohol: Mechanisms Along the Mesolimbic Dopamine System 201

Jorgen A. Engel, Elisabet Jerlhag

1. The Reward Systems in the Brain 202

2. The Mesolimbic Dopamine System 202

3. The Cholinergic-Dopaminergic Reward Link 204

4. Addictive Behaviors 204

5. The Role of Dopamine in Reward 205

6. The Effects of the Dopamine Stabilizer (-)-OSU6162 on Alcohol Consumption in Rodents 206

7. The Role of Different Reward Nodes for Alcohol Reward 207

8. The Role of the Cholinergic-Dopaminergic Reward Link for Reward Induced by Addictive Drugs and Behavior 209

9. Alcohol and Ligand-Gated Ion Channels 209

      9.1. nACHRs and Alcohol 210

      9.2. Glycine Receptors and Alcohol 211

      9.3. Other Ligand-Gated Ion Channels and Alcohol 211

10. A Possible Role of Gut brain Peptides for Drug Dependence 212

      10.1. The Orexigenic Peptide Ghrelin Activates the ChoIinergic—Dopaminergic Reward Link 212

      10.2. The Role for Ghrelin Signaling in Drug-Induced Reward 213

      10.3. The Role for Glucagon-Like Peptide 1 in Drug-Induced Reward 216

11. Conclusions 216

Acknowledgments 217

References 217

CHAPTER 10 The Role of Dopamine in Huntington's Disease 235

Carlos Cepeda, Kerry P.S. Murphy, Martin Parent, Michael S. Levine

1. Introduction 236

2. Striatal DA Innervation in the HD Postmortem Brain 236

3. Neurochemistry 238

4. DA Receptors 238

5. DA in Genetic Animal Models of HD 239

6. Synaplic Electrophysiology in HD Models 240

7. DA and Synaptic Plasticity in HD 240

8. DA and Excitotoxicity 242

9. Mechanisms of DA Dysregulation 243

10. DA Agonists and Antagonists as Treatments for HD 244

11. Conclusions and Future Directions 245

Acknowledgments 246

References 246

CHAPTER 11 Dopamine D_3 Receptor Ligands for Drug Addiction Treatment: Update on Recent Findings 255

Bernard Le Foll, Ginetta Collo, Eugenii A. Rabiner, Isabelle Boileau, Emilia Merlo Pich, Pierre Sokoloff

1. Introduction 256

      1.1. Novel Findings Related to D_3 Receptor Signaling 257

2. Behavioral Effects of D_3 Blockade in Animal Model of Drug Addiction 259

      2.1. Imaging D_3 Receptor In Vivo 261

      2.2. Recent Imaging Studies Using (~11C)-(+)-PHNO in Drug Addiction 264

3. Translating the D3 Hypothesis into Clinical Intervention 265

4. Conclusion 268

References 268

CHAPTER 12 Effects of Prenatal Exposure to Cocaine on Brain Structure and Function 277

Deirdre M. McCarthy, Zeeba D. Kabir, Pradeep G. Bhide, Barry E. Kosofsky

1. Introduction 278

2. Results 279

      2.1. Delayed Tangential Migration of GABA Neurons Following Prenatal Cocaine Exposure 279

      2.2. Persistent Deficits in the Numerical Density of GABA Neurons in the mPFC 281

      2.3. BDNF: A Molecular Mediator of Cocaine's Effects on Tangential Migration of GABA Neurons 281

      2.4. Long-Term Effects on BDNF Expression 282

      2.5. BDNF: A Molecular Mediator of Cocaine's Effects on Cognitive Function 284

3. Conclusions 286

References 287

Index 291

Other volumes in PROGRESS IN BRAIN RESEARCH 299

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