Organic Cation Transporters in the Central Nervous System (Handbook of Experimental Pharmacology, 266)

Preface
Acknowledgments
Contents
General Overview of Organic Cation Transporters in Brain
	1 Introduction
	2 High Affinity Na+/Cl- Dependent Monoamine Neurotransmitter Transporters
		2.1 Locations in the Brain and Transport Properties
		2.2 Physiological Roles
		2.3 Psychoactive Drugs That Interact with Na+/Cl- Dependent Monoamine Neurotransmitter Transporters
	3 Emergence of the Concept That Low Affinity Monoamine Neurotransmitter Transporters Operate in Brain
		3.1 Pioneering Demonstration of Low Affinity Noradrenaline Transport in the Heart
		3.2 Reasons for the Need of Low Affinity Monoamine Neurotransmitter Transporters in Brain
		3.3 First Data Indicating That OCTs Translocate Monoamine Neurotransmitters and Are Expressed in Brain
	4 Organic Cation Transporters Expressed in Brain
		4.1 Basic Functional Properties of OCT1-3 (SLC22A1-3) and PMAT (SLC29A4)
		4.2 OCT1 (SLC22A1) in Brain
		4.3 OCT2 (SLC22A2) in Brain
			4.3.1 Locations in Brain
			4.3.2 Specificity for Transport of Monoamine Neurotransmitters and Interaction with Psychiatric Drugs
			4.3.3 Presumed Biomedical Functions
		4.4 OCT3 (SLC22A3) in Brain
			4.4.1 Locations in Brain
			4.4.2 Specificity for Transport of Monoamine Neurotransmitters and Interaction with Psychiatric Drugs
			4.4.3 Presumed Biomedical Functions
		4.5 PMAT (SLC29A4) in Brain
			4.5.1 Locations in Brain
			4.5.2 Specificity for Transport of Monoamine Neurotransmitters and Interaction with Psychiatric Drugs
			4.5.3 Presumed Biomedical Functions
		4.6 Potential of Inhibitors to Distinguish Between Transport by Different Organic Cation Transporters
	5 Conclusions
	References
Organic Cation Transporter Expression and Function in the CNS
	1 Introduction
	2 Organic Cation Transporters Relevant to the CNS
		2.1 OCT1 (SLC22A1)
		2.2 OCT2 (SLC22A2)
		2.3 OCT3 (SLC22A3)
		2.4 OCTN1 (SLC22A4)
		2.5 OCTN2 (SLC22A5)
		2.6 OCTN3 (SLC22A21)
		2.7 PMAT (SLC29A4)
		2.8 MATE1 (SLC47A1)
		2.9 MATE2-K (SLC47A2)
		2.10 General Note Concerning Transporter Expression Reported in Brain Capillaries
	3 In Vivo Evidence of Transporter Function in the CNS Derived from Molecular or Pharmacological Knockout Studies
		3.1 Oct1 Knockout
		3.2 Oct2 Knockout
		3.3 Oct1/2 Double Knockout
		3.4 Oct3 Knockout
		3.5 Octn1 Knockout
		3.6 Octn2 Knockout
		3.7 Octn3 Knockout
		3.8 Pmat Knockout
		3.9 Mate1 Knockout
		3.10 Mate2-K Knockout
	4 Summary
	References
Genetic and Epigenetic Regulation of Organic Cation Transporters
	1 Impact of Genetic and Epigenetic Regulation on the Function of Organic Cation Transporters: A Short Overview
		1.1 Genetic Variants of OCTs
		1.2 Epigenetic Regulation of OCTs
	2 Implications of OCT Regulation in the CNS
		2.1 Genetic Regulation of OCT2 in the CNS
			2.1.1 Localization of OCT2 in the CNS
			2.1.2 Consequences of Disturbed OCT2 Function in the CNS: What Do We Learn from Animal Studies?
			2.1.3 Genetic Variants of OCT2 and Their Implications on CNS Function
		2.2 Genetic Regulation of OCT3 in the CNS
			2.2.1 Localization of OCT3 in the CNS
			2.2.2 Consequences of Disturbed OCT3 Function in the CNS: What Do We Learn from Animal Studies?
			2.2.3 Genetic Variants of OCT3 and Their Implications on CNS Function
	3 Conclusion
	References
Experimental Methods for Investigating Uptake 2 Processes In Vivo
	1 Introduction
	2 Methods for Investigating Uptake 2 Processes in Vivo
		2.1 Scintillation Microspectrophotometry
		2.2 Microdialysis
		2.3 Chronoamperometry
		2.4 Fast Scan Voltammetry
	3 Conclusion
	References
Substrates and Inhibitors of Organic Cation Transporters (OCTs) and Plasma Membrane Monoamine Transporter (PMAT) and Therapeut...
	1 Introduction
	2 Basic Properties of OCTs and PMAT: Structures and Transport Function
		2.1 Membrane Topology and Structure-Function of OCTs
		2.2 Membrane Topology and Basic Functions of PMAT
		2.3 Model for Transport by OCTs and PMAT
	3 Human OCTS and hPMAT: Distribution and Endogenous Substrates and Inhibitors
		3.1 Tissue Expression of hOCTs and hPMAT
		3.2 Endogenous Substrates and/or Inhibitors of hOCTs and hPMAT
	4 Model Substrates or Inhibitors of hOCTs and hPMAT
	5 Drugs as Substrates or Inhibitors of hOCTs and hPMAT
		5.1 Antiviral Drugs
		5.2 Cytostatic/Antineoplastic Drugs
		5.3 Drugs That Act in the Central Nervous System (CNS)
			5.3.1 Antidepressants (ADs)
			5.3.2 Antipsychotics
			5.3.3 Psychostimulants
			5.3.4 Opioid Analgesics
			5.3.5 Antiepileptics
			5.3.6 Anti-Parkinsonian Drugs
		5.4 Other Drugs Acting at hOCTs and/or hPMAT
	6 Clinical Relevance of hOCTs and hPMAT as Targets for Drug-Drug Interactions (DDIs) and as Drug Transporters
		6.1 The Antidiabetic Metformin as an Example for DDIs at hOCTs
		6.2 Human OCTs and hPMAT as Transporters for Endogenous Substances
		6.3 Human OCTs and hPMAT Involved in Therapeutic or Toxic Effects of Drugs
			6.3.1 Cytostatics/Antineoplastic Drugs
			6.3.2 Antiviral Drugs
			6.3.3 CNS Active Drugs
				Antidepressants
				Antipsychotics
				Psychostimulants
	7 Summary and Conclusion
	References
Organic Cation Transporters in Brain Histamine Clearance: Physiological and Psychiatric Implications
	1 Histamine in the Central Nervous System
	2 Monoamine Neurotransmitter Transporters in the Central Nervous System
		2.1 Organic Cation Transporter 2
		2.2 Organic Cation Transporter 3
		2.3 Plasma Membrane Monoamine Transporter
		2.4 Other SLC22 Family Transporters
	3 Histamine Uptake in the Central Nervous System
	4 Future Perspectives
	References
Organic Cation Transporters in Brain Catecholamine Homeostasis
	1 Introduction
	2 Transport of Catecholamines by Uptake2 Transporters: Cell Culture Studies
	3 Expression and Localization of Uptake2 Transporters in Brain
		3.1 OCT3
		3.2 OCT2
		3.3 PMAT
	4 Roles for Uptake2-Mediated Transport in Brain Catecholamine Homeostasis: In Vivo and Ex Vivo Studies
	5 Subcellular Localization of Uptake2 Transporters
	6 Summary
	References
The Interaction of Organic Cation Transporters 1-3 and PMAT with Psychoactive Substances
	1 Introduction
	2 In Vitro Studies
	3 In Vivo Studies
		3.1 Pharmacokinetics of Drug Disposition
		3.2 Neurotoxicity
		3.3 Stress-Addiction Axis
		3.4 Sensitivity to Psychoactive Substances
		3.5 Polymorphisms
	4 Conclusions
	References
Organic Cation Transporters in Psychiatric Disorders
	1 Introduction
		1.1 Role of Serotonin in Depression
		1.2 Uptake-2 Transporters
		1.3 Organic Cation Transporter 1 (SLC22A1)
		1.4 Organic Cation Transporter 2 (SLC22A2)
		1.5 Organic Cation Transporter 3 (SLC22A3)
	2 Plasma Membrane Monoamine Transporter (SLC29A4)
	3 Conclusions and Future Perspective
	References
Organic Cation Transporters and Nongenomic Glucocorticoid Action
	1 Uptake2: Corticosteroid-Sensitive Monoamine Transport
	2 Corticosteroid Sensitivity of Uptake2 Transporters
	3 Sensitivity of Uptake2 Transporters to Other Steroids
	4 Expression of OCT2 and OCT3 in the Central Nervous System
	5 Corticosteroid Regulation of Monoaminergic Neurotransmission and Behavior
		5.1 Corticosteroid Regulation of Dopamine Clearance and Cocaine-Seeking Behavior
		5.2 Corticosterone-Sensitive Serotonin Clearance
	6 Summary
	References
Brain Plasma Membrane Monoamine Transporter in Health and Disease
	1 Introduction
	2 Molecular and Functional Characteristics of PMAT
		2.1 Molecular Features
		2.2 Substrate Specificity
		2.3 PMAT Inhibitors
		2.4 Mechanism of Transport
	3 Expression and Distribution in the CNS
		3.1 Regional Expression in Rodent and Human Brains
		3.2 Cell Type-Specific Expression in the Brain
	4 Mouse Model for PMAT
	5 Physiological Roles in Monoamine Neurotransmission
		5.1 Uptake1 and Uptake2
		5.2 PMAT as a Brain Uptake2 Transporter
		5.3 Comparison Between PMAT and OCT3
		5.4 PMAT in Brain 5-HT Clearance
		5.5 PMAT as a Clearance Mechanism at the Blood-CSF Barrier
	6 Potential Involvement in Brain Pathophysiological Processes
		6.1 Autism
		6.2 Depression
		6.3 Parkinson´s Disease
	7 Summary
	References
Regulation of Neurogenesis by Organic Cation Transporters: Potential Therapeutic Implications
	1 Introduction: Neurogenesis, Neural Stem Cells, and the Neurogenic Niche
	2 Organic Cations Transporting Solute Carriers Expressed in NSCs
		2.1 OCTN1/SLC22A4 and Its Substrate Ergothioneine (ERGO)
		2.2 OCTN2/SLC22A5 and Its Substrates Carnitine and Acetyl-L-Carnitine
		2.3 SERT/SLC6A4 and Serotonin
	3 OCTs Expressed in the Neurogenic Niche
		3.1 OCT2/SLC22A2 in the Hippocampus
		3.2 OCT3/SLC22A3 in the Hippocampus
		3.3 OCTN1/SLC22A4 in the Hippocampus
	4 Possible Regulation of Neurogenesis by Clinically Used OCT Substrate Drugs
		4.1 Metformin
		4.2 Ketamine
		4.3 Memantine
		4.4 Gabapentin
	5 Future Perspectives
	References
Organic Cation Transporter (OCT/OCTN) Expression at Brain Barrier Sites: Focus on CNS Drug Delivery
	1 Introduction
	2 BBB Localization and Expression of OCTs and OCTNs
	3 BCSFB Localization and Expression of OCTs and OCTNs
	4 Localization of OCTs and OCTNs in Brain Parenchyma
	5 Regulation of OCTs and OCTNs at Brain Barrier Sites
		5.1 CNS Delivery by OCTs and/or OCTNs of Centrally Acting Drugs for Treatment of Neurological Diseases
		5.2 Ischemic Stroke
		5.3 Parkinson´s Disease
		5.4 Schizophrenia
	6 Summary and Conclusion
	References