Therapeutic Applications of Dopamine D3 Receptor Function: New Insight After 30 Years Of Research

Preface
Contents
A Historical Perspective on the Dopamine D3 Receptor
1 Molecular Cloning and Characterization of the D3 Receptor
2 Expression and Distribution of the D3 Receptors in the Brain
3 The Role of the D3 Receptor in Behavioral Sensitization
4 Hunting for D3 Receptor-Selective Compounds
5 Functional Role of D3 Receptors Elucidated in Preclinical Models with Selective Drugs
5.1 Motor Function
5.2 Addiction
5.3 Schizophrenia
5.4 Cognition
6 D3 Receptors in the Therapeutic Area
7 Conclusions
References
Location, Location, Location: The Expression of D3 Dopamine Receptors in the Nervous System
1 Introduction
2 The D3 Receptor Expression in the Mature Rodent Brain
3 The D3 Receptor Expression in the Mature Human Brain
4 The D3 Receptor Expression in the Developing Brain
5 Conclusion
References
Recent Advances in Dopamine D3 Receptor Heterodimers: Focus on Dopamine D3 and D1 Receptor-Receptor Interaction and Striatal F...
1 Introduction
2 G Protein-Coupled Receptors (GPCRs) and Receptor-Receptor Interactions
3 GPCRs Heterodimer´s Experimental Validation
4 Dopamine D3 Receptor (D3R) and Heterodimerization
5 D1R-D3R-Heterodimer in the Striatum
6 Functional Role of the D1R-D3R Heterodimer in the Striatum
7 Conclusions
References
Involvement of DA D3 Receptors in Structural Neuroplasticity of Selected Limbic Brain Circuits: Possible Role in Treatment-Res...
1 Introduction: Cellular and Molecular Mechanisms of Neuronal Structural Plasticity
2 Defective Neuronal Structural Plasticity in Brain of Patients with Mood Disorders
3 Dopamine D3 Receptors (D3R): Biological and Pharmacological Profile
3.1 D3R Role in Post-Synaptic Non-dopaminergic Neurons and Glia
3.2 D3R Role in Presynaptic DAergic Neurons
4 D3R Mediates Structural Plasticity in DAergic Neurons Engaging Neurotrophic Pathways
4.1 Studies in Mesencephalic DA Neurons of Rodents
5 Studies in Human DA Neurons Differentiated from Inducible Pluripotent Stem Cells (iPSC)
6 Effects on DA Neuron Structural Plasticity Produced by the Activation of D3R Could Be Beneficial in Patients with Treatment-...
7 D3R Signaling Is Involved in Structural Plasticity Produced by the Antidepressant Ketamine on Human and Mice Mesencephalic D...
8 Conclusions
References
Dopamine D3 Receptor in Parkinson Disease: A Prognosis Biomarker and an Intervention Target
1 Introduction
2 Dopamine and Dopamine Receptors
2.1 Dopamine
2.2 Dopamine Receptors
2.3 Differential Regulations of D2R and D3R
2.4 Development of [3H]WC-10 as a Novel D3R Radioligand
2.5 Quantitative Autoradiography Measure of Binding Affinity of [3H]WC-10 to D3R in Human Striatal Tissues
2.6 Quantitative Autoradiography Assay for D2R and D3R Densities
2.7 Striatal and Extrastriatal Distribution of D2R and D3R in Postmortem Human Brain
3 D3R in PD Intervention, Prognosis, and Progression
3.1 D3R Agonists Alleviate PD Symptoms
3.2 Possible Interventional Mechanisms of D3R Activation
3.3 Neuroimaging Biomarkers in PD Pathogenesis
3.4 D3R Changes for Predicting Prognosis of PD Treatment
3.5 D1R, D2R, and D3R Expression in Control, AD and LBD Brains
3.6 D1R + D3R Density Correlates with PD-Associated Symptomatic and Therapeutic Features
3.7 Impact of Striatal D3R Density on Overall Survival
4 Conclusions and Perspectives
References
Dopamine D3 Receptors: A Potential Target to Treat Motivational Deficits in Parkinson´s Disease
1 Beyond the Motor Symptoms of Parkinson´s Disease
2 Apathy as a Pivotal Symptom in PD
3 How to Define Apathy in PD?
4 Apathy and its Relation with the Dopaminergic State of PD Patient
5 Neurobiological Mechanisms Underlying Apathy: A Pivotal Role of the Dopaminergic System
6 How to Disentangle Potential Implication the Mesocorticolimbic and Nigrostriatal Dopaminergic Systems?
7 Bilateral and Partial Dopaminergic Lesion of the Nigrostriatal Projection Specifically Affects Motivated and Affective-Relat...
8 Pharmacological Reversion of the Behavioral Deficits of SNc-Lesioned Rats Highlights a Critical Involvement of Dopamine D3 R...
9 Autoradiographic Analysis Reveals Down-Regulation of D3R in the Dorsal Striatum of SNc-Lesioned Rats
10 Intracerebral Infusions of a D3R Antagonist Confirm the Causal Implication of Dorsostriatal D3R in the Motivational Deficit...
11 Distinct Functional Roles of D3R in the Dorsal Striatum and Nucleus Accumbens
12 Conclusion
References
Dopamine D3 Receptor, Cognition and Cognitive Dysfunctions in Neuropsychiatric Disorders: From the Bench to the Bedside
1 Introduction
2 Dopamine D3 Receptor, Cognition and Cognitive Dysfunctions: Preclinical Evidence
3 Dopamine D3 Receptor, Cognition and Cognitive Dysfunctions: Clinical Evidence
3.1 Dopamine D3 Receptor and Cognitive Functions in ADHD
3.2 Dopamine D3 Receptor and Cognitive Functions in Autism Spectrum Disorder (ASD)
3.3 Dopamine D3 Receptor and Cognitive Functions in Schizophrenia
3.4 Dopamine D3 Receptor and Cognitive Functions in Alzheimer Disease (AD)
3.5 Dopamine D3 Receptor and Cognitive Functions in Bipolar Disorder (BP)
4 The Potential Therapeutic Value of Drugs/Ligands Targeting the D3R for the Treatment of Cognitive Dysfunctions
4.1 D3R Antagonists in Preclinical Studies
4.2 Drugs Targeting D3R in Clinical Studies
4.3 Risperidone
4.4 Cariprazine
4.4.1 Blonanserin
4.4.2 Pramipexole
4.4.3 Buspirone
4.4.4 F17464
4.4.5 ABT-925
4.4.6 GSK598809
5 Conclusions
References
Current Perspectives on Selective Dopamine D3 Receptor Antagonists/Partial Agonists as Pharmacotherapeutics for Opioid and Psy...
1 Introduction: Brief Historical Perspective/Epidemiology
1.1 The Perfect Storm
1.2 Opioid Crisis
1.3 Psychostimulant Use Disorder: Cocaine and Methamphetamine
1.4 Polysubstance Use Highlighting Opioids/Methamphetamine
1.5 Co-Morbidities with Other Neuropsychiatric Disorders
2 D3R Neurocircuitry and Relationship to SUD
2.1 Rationale of D3R-Based Medication Development for the Treatment of Psychostimulant and Opioid Use Disorders
2.1.1 Dopamine Hypothesis of Drug Reward
2.1.2 Unique Profiles of D3R
High D3R Binding Affinity to DA
Restricted D3R Distribution
Cellular Distribution of D3R
2.2 Relationship to Neural Targets and Therapeutic Potential
2.2.1 Presynaptic D3R Mechanism
2.2.2 Postsynaptic D3R Mechanisms
NAc D3R Mechanism
VP D3R Mechanism
PFC D3R Mechanism
Insula D3R Mechanism
Amygdala (Amy) D3R Mechanism
2.3 D3R Neuroadaptations Due to SUD
2.3.1 Development Changes in D3R Expression
2.3.2 Tolerance and Desensitization after D3R Activation
2.3.3 Neuroadaptations after Exposure to Drugs of Abuse
2.4 Relationship of D3R to Pain
2.5 Relationship to Other Comorbid Neuropsychiatric Disorders
3 D3R Antagonists and Partial Agonists Currently under Preclinical Investigation for SUD
3.1 Past D3R Preferential and Selective Antagonists that Were Tested in Clinical Trials
3.1.1 GSK598809
3.1.2 Buspirone
3.1.3 Cariprazine
3.2 New and Promising D3R Selective Antagonists/Partial Agonists for SUD
3.2.1 (±)-VK4-116 and its R-Enantiomer
3.2.2 (±)-VK4-40 and its Enantiomers
3.2.3 Dual-Target Mu Opioid Receptor (MOR): D3R Partial Agonists
3.3 Potential Challenges: Cardiovascular Toxicity in the Presence of Cocaine
4 Perspective on Clinical Application as Treatments for SUD
4.1 Limitations and Advances in the Translational Value of Animal Models of SUD
4.2 Key Translational Medicine Questions Relevant to Clinical Development
4.3 Most Suitable Clinical Paradigms for Medication Development Purpose
4.4 From Monotherapy to Combination of Medications
5 Summary
References
The Role of Dopamine D3 Receptors in Tobacco Use Disorder: A Synthesis of the Preclinical and Clinical Literature
1 Introduction
2 Tobacco Use Disorder
3 Pharmacotherapy for Smoking Cessation
4 Dopaminergic System and Tobacco Use Disorder
5 Dopamine Receptor D3
6 DRD3 Genetic Polymorphisms and Nicotine Dependence
7 Dopamine Receptor D3 Density
8 Reinforcement
9 Conditioned Stimuli
10 Conditioned Place Preference
11 Reinstatement
12 Drug Discrimination
13 Sensitization
14 Executive Function
15 Withdrawal Signs
16 Summary of Translational Synthesis
References
D3 Receptors and Restless Legs Syndrome
1 Introduction
2 Prevalence of RLS
3 Periodic Limb Movements During Sleep in RLS
4 Pharmacological Treatment Options for RLS: Dopaminergics
5 L-Dopa, the First Dopaminergic Drug to Treat RLS
6 The Caveat of Dopamine D3 Receptor Agonists in the Treatment of RLS
7 Dopamine Receptor Heteromers and D3-D1 Receptor Interactions
8 Beyond Dopamine D3 and D1 Receptors as Individual Entities
9 Is There a Future for D3 Receptor Modulators in RLS?
References
D3 Receptors and PET Imaging
1 Introduction
2 Addiction
2.1 Cocaine
2.2 Methamphetamine
2.3 Alcohol
2.4 Nicotine
2.5 Cannabis
2.6 Food Addiction
2.7 Gambling Disorders
3 Neuropsychiatric Disorders
3.1 Schizophrenia
3.2 Parkinson´s Disease
3.3 Tourette Syndrome
3.4 TBI
4 Other Studies Investigating D3R in Humans
4.1 Aging
4.2 Social Effects
4.3 Retinal Studies
4.4 Next-Generation D3R Tracers
5 Conclusion
References