Substance Use Disorders From Etiology to Treatment

Preface
	References
Contents
Methods for Population Research on Substance Use and Consequences
	1 Introduction
	2 Population Research on Substance Use and Consequences
		2.1 Data Collection Methods
			2.1.1 Surveys
			2.1.2 Ecological Momentary Assessment
			2.1.3 Administrative Data
			2.1.4 Audit Methods
			2.1.5 Unobtrusive Assessment of Substance Use
	3 Measures
		3.1 Measures of Own Use
			3.1.1 Type of Substance
			3.1.2 Mode of Consumption
			3.1.3 Quantity and Frequency of Use
			3.1.4 Setting
			3.1.5 Source
			3.1.6 Problems Associated with Use
		3.2 Harming Others
	4 Causal Factors and Correlates of Substance Use and Consequences
		4.1 Individual Causal Factors and Correlates
			4.1.1 Sociodemographic Factors
			4.1.2 Sexual Orientation and Identity
			4.1.3 Personality and Attitudinal Factors
			4.1.4 Personality and Attitudinal Factors
			4.1.5 Mental Health
		4.2 Environmental Causal Factors and Correlates
			4.2.1 Situational Factors
			4.2.2 Family Factors
			4.2.3 Peer Networks
			4.2.4 Availability of Substances
			4.2.5 Price
			4.2.6 Marketing
			4.2.7 Policy
			4.2.8 Enforcement Practices
			4.2.9 Community Characteristics
	5 Summary and Conclusion
		5.1 Accumulation of Knowledge
		5.2 Translation of Knowledge
		5.3 Limitations
	References
Translational Molecular Approaches in Substance Abuse Research
	1 Introduction
	2 The Neurobiology of Substance Use Disorder
	3 Substance Use Disorder Heritability
	4 Genetic Components of SUD
		4.1 Consideration of SUD Phenotypes in Human Clinical Populations
		4.2 Genome-Wide Associations and Functional Validation Studies Reveal Genetic Susceptibility and Neurobiological Mechanisms of...
		4.3 GWAS Identified a nAChR Subunit Risk Variant Associated with Nicotine Dependence
		4.4 Molecular and Pharmacological Approaches Have Defined Roles for Genetic Polymorphisms in Substance Use Disorder Physiology
		4.5 Animals: Behavioral Models of Substance Use Disorder
		4.6 Use of Animal Models to Explore Genetic Polymorphisms Associated with Substance Use Disorder
		4.7 Transcriptomics and Substance Use Disorder
		4.8 Cell-Type Specificity: Single-Cell and FACS-Based Approaches
	5 Epigenetic Components of SUD
		5.1 Histone Modifications
		5.2 DNA Methylation
		5.3 Chromatin Structure
	6 Conclusions and Future Directions
	References
Small Molecule Neuropeptide S and Melanocortin 4 Receptor Ligands as Potential Treatments for Substance Use Disorders
	1 SUDs Medications Development
	2 Neuropeptide S (NPS)
		2.1 Oxazolo[3,4-a]pyrazin-3-ones
		2.2 Pyranopyrimidine Derivatives
		2.3 Furo[3,4-c]pyridine Derivatives
		2.4 Imidazopyridines
		2.5 Quinolinone Derivatives
		2.6 Tricyclic Imidazole Derivatives
		2.7 Indan-1,3-dione and Indan-1-one Derivatives
		2.8 Pyrroloimidazole Derivatives
	3 Melanocortin 4 (MC4)
		3.1 Spiropiperidines
		3.2 Piperazinebenzylamine
		3.3 Arylpiperazinylpiperazines
		3.4 Imidazoles
		3.5 Pyridazinones
		3.6 2,4-Difluorophenylpyrrolidines
		3.7 2-Oxopiperazines
	References
Emerging Insights into Mu Opioid Pharmacology
	1 Introduction: Mu Opioids and the Opioid Epidemic
	2 MOR Tertiary Structure
	3 Signaling Pathways: Biased and Unbiased Agonists
	4 Allosteric Agonists
	5 MOR Heteromers and Bivalent Ligands
	6 MOR Regulation by Receptor Phosphorylation
	7 Alternative Splicing of the Mu Opioid Receptor Gene, OPRM1
		7.1 Full-Length 7TM C-Terminal Variants and 3′ Splicing
		7.2 Truncated 6TM Variants, Alternative Exon 11 Promoter, and 5′ Splicing
		7.3 Truncated Single TM Variants and Exon Skipping and Insertion
	8 Expression and Function of OPRM1 Splice Variants
		8.1 mRNA and Protein Expression
		8.2 Functions of OPRM1 Full-Length 7TM C-Terminal Variants
			8.2.1 In Vitro Studies Using Cell Models: Radioligand Binding, Signaling, Phosphorylation
			8.2.2 In Vivo Studies Using Animal Models
				Antisense Oligonucleotides
				C-Terminal Truncation Mouse Models
		8.3 Functions of OPRM1 Truncated 6TM Variants
			8.3.1 Loss of Function Studies: Exon 11 KO Mouse Model
			8.3.2 Gain of Function Studies: Lentiviral Rescue of IBNtxA Analgesia
			8.3.3 Classification of Opioids Based on the Oprm1 Variant Targets
			8.3.4 The Role of 6TM Variants in Morphine Actions
			8.3.5 The Functions of OPRM1 Truncated Single TM Splice Variants
	9 Overall Conclusions
	References
Behavioral Pharmacology of Drugs Acting at Mu Opioid Receptors
	1 Introduction
	2 Pharmacodynamics and Pharmacokinetics of Drugs Acting at Opioid Receptors
	3 Pharmacological Efficacy
		3.1 Preclinical Assessment of Efficacy Differences
		3.2 Therapeutic Considerations for Drugs that Vary in Efficacy
	4 Drug-Receptor Interactions
		4.1 Reversible Interactions and Surmountability
		4.2 Allosteric Modulation of Mu Opioid Receptors
		4.3 Biased Agonism
	5 Selectivity for Opioid Receptor Types
	6 Conclusions
	References
The Rise and Fall of Kappa-Opioid Receptors in Drug Abuse Research
	1 Preclinical Evaluation of Candidate Substance Use Disorder Treatments
	2 Rationale for Kappa-Opioid Receptors as Candidate SUD Treatments
	3 KOR Agonist Effects on Preclinical Drug SA
		3.1 Preclinical SA of KOR Agonists and Drug of Abuse Combinations
		3.2 KOR Agonists as Pretreatments to Preclinical Drug of Abuse SA
	4 KOR Antagonist Effects on Preclinical Drug Self-Administration
		4.1 KOR Antagonist Effects on Preclinical Drug Choice SA
		4.2 KOR Antagonist Effects on Human Drug SA Metrics
	5 Conclusions and Future Directions
	References
Clinical Trials for Opioid Use Disorder
	1 Background
	2 Current OUD Pharmacotherapies
	3 Novel Pharmacotherapies Under Study
		3.1 Opioid Receptor Modulators
		3.2 Cannabidiol, THC, and Cannabis
		3.3 Psychedelics
		3.4 Neuropeptides and Neuropeptide Receptor Modulators
		3.5 Serotonin Receptor Modulators
		3.6 Anti-inflammatory and Immunomodulatory Agents
		3.7 Other: Analgesics, Calcium Channel Blockers, and Acetyl-Cholinesterase Inhibitors
	4 Vaccines
	5 New Formulations of Existing Drugs
	6 Trials to Expand Use of Existing Marketed Agents, New Models of Care
	7 Helping to End Addiction Long-Term (HEAL)
	8 Initiatives for Special Populations
	9 Devices, Apps, and Behavioral Interventions
	10 Summary, Conclusions, and New Directions
	References
Modelling Differential Vulnerability to Substance Use Disorder in Rodents: Neurobiological Mechanisms
	1 Introduction
	2 Behavioural Endophenotypes of SUD
		2.1 Relationship Between Impulsivity and SUD-Like Behaviour
		2.2 Relationship Between Sensation-Seeking and SUD-Like Behaviour in Rodents
		2.3 Relationship Between Anxiety and SUD-Like Behaviour in Rodents
		2.4 Relationship Between Incentive Salience Attribution and SUD-Like Behaviour
	3 Neural Substrates of SUD-Relevant Behavioural Endophenotypes
		3.1 Impulsivity
		3.2 Sensation-Seeking
		3.3 Anxiety
		3.4 Incentive Salience Attribution
	4 Implications for Neural Mechanisms of SUD Vulnerability
	5 Conclusions
	References
Activity-Dependent Epigenetic Remodeling in Cocaine Use Disorder
	1 Introduction
	2 Synaptic Mechanisms of Substance Use Disorder
	3 The Interface Between Neural Activity and Epigenetic Modifications in Substance Use Disorder
	4 Epigenetic Regulation of Neural Plasticity
		4.1 Histone Posttranslational Modifications, DNA Methylation, and Nucleosome Remodeling
		4.2 Histone Acetylation
		4.3 Histone Methylation
		4.4 Nucleosome Remodeling
		4.5 DNA Methylation [For More Detailed Review on DNA Methylation in Cocaine Use Disorders, See Vaillancourt et al. (2017)]
		4.6 Histone Marks Do Not Occur in Isolation
	5 The Interplay Between Acute Drug Effects and Activity-Dependent Epigenetic Dysregulation in the Transition to Substance Use ...
	6 Transient Changes as a Scaffold for Long-Term Epigenetic Changes
	7 Causally Linking Epigenetic Modification to Substance Use Disorder
	8 Linking Changes in Epigenome to Changes in Synaptic Function
	9 Defining Causal Links Between Epigenetic Factors and Neural Activity in Substance Use Disorder
	References
Molecular Mechanisms of Amphetamines
	1 Introduction
	2 Amphetamine and Dopamine (DA) Uptake, Efflux, and Storage
		2.1 Amphetamine as a Substrate for Uptake at the DA Transporter (DAT)
		2.2 Role of Na+ and Transporter Conformation
		2.3 DA Synthesis and VMAT2
		2.4 Organic Cation 3 Transporter (OCT3)
	3 Requirements for Amphetamine Stimulation of Outward Transport of DA
		3.1 Intracellular Calcium
		3.2 PKC Activity
		3.3 CaMKII Activity
		3.4 ERK Activity
	4 Effects of Modifiers of Presynaptic Amphetamine Action on Behavior and Therapeutic Possibilities Directed at Amphetamine Abu...
		4.1 DAT Blockers/Substrates
		4.2 VMAT2 Blockers/Substrates
		4.3 PKC Inhibitors
		4.4 CaMKII Inhibitors
		4.5 OCT3 Inhibitors
	5 Concluding Remarks
	References
Clinical Trials for Stimulant Use Disorders: Addressing Heterogeneities That May Undermine Treatment Outcomes
	1 Cocaine Use on the Rise (Again)
	2 The Challenges of Translation
	3 Tonic and Phasic Dopamine Changes with Stimulant Administration
		3.1 Enhancing Tonic Dopamine
			3.1.1 Short-Acting Dopamine Enhancers
			3.1.2 Long-Acting Dopamine Enhancers
			3.1.3 Summary: Enhancing Tonic Dopamine
		3.2 Reducing Phasic Dopamine
			3.2.1 Gamma-Vinyl GABA (GVG)
			3.2.2 Baclofen
			3.2.3 Topiramate
			3.2.4 Summary: Reducing Phasic Dopamine
		3.3 Combination Pharmacotherapies: Addressing Both Tonic and Phasic Dopamine
			3.3.1 Summary: Combination Pharmacotherapies
	4 Interindividual Phenotypic Heterogeneity
		4.1 Sex Differences
		4.2 Pharmacogenetics
		4.3 Cue-Vulnerable Phenotypes
		4.4 Stress-Related Phenotypes
		4.5 Interaction of Cue-Vulnerability and Stress-Related Pathologies (Prior Adversity)
		4.6 Poor Frontal Function Endophenotype
		4.7 Drug Use Severity
	5 Conclusions and Future Directions
	References
Molecular Mechanism and Cannabinoid Pharmacology
	1 A Historical Perspective of, and Introduction to, Cannabinoids
		1.1 Phytocannabinoids
		1.2 Synthetic Cannabinoids
		1.3 Endocannabinoids
	2 Cannabinoid Receptor Discovery and Function
		2.1 CB1 Receptor In Vitro Evidence
			2.1.1 G Proteins and Adenylyl Cyclase
			2.1.2 Radioligand Binding and Cloning of Cannabinoid Receptors in the CNS
		2.2 CB1 Receptor In Vivo Evidence
		2.3 CB1 Receptor Allosteric Modulation
		2.4 CB1 Receptor Functional Selectivity (Biased Agonism)
		2.5 CB2 Receptors
	3 The Endocannabinoids and Their Enzymatic Regulation
		3.1 N-Arachidonylethanolamine (Anandamide)
		3.2 2-Arachidonoylglycerol (2-AG)
		3.3 Other Endocannabinoids, Hemopressins, and Related Lipids
	4 Drug Interactions
		4.1 Opioid-Sparing Effects
		4.2 Cytochrome P450 Enzymes
	5 Conclusions
	References
Pharmacotherapies for Cannabis Use Disorders: Clinical Challenges and Promising Therapeutic Agents
	1 Background
		1.1 Acute Effects of Cannabis
		1.2 Long-Term Effects of Cannabis and Cannabis Use Disorders
		1.3 Neurobiology of Cannabis Use
	2 Pharmacotherapies Tested for CUD
		2.1 Medications of Limited or No Value
			2.1.1 Antidepressants
			2.1.2 Anticonvulsants and Mood Stabilisers
			2.1.3 Other Medications
		2.2 Medications of Uncertain Value
		2.3 Medications Warranting Further Research
			2.3.1 Cannabinoid Agonists
			2.3.2 Other Pharmacological Approaches to Explore
	3 CUD in Special Populations
		3.1 Pharmacotherapy for CUD in People with Concurrent Mental Health Conditions
		3.2 Pregnancy
	4 Future Directions
		4.1 CUD in the Context of Therapeutic Use
		4.2 Future Research
	References
Molecular Mechanisms Associated with Nicotine Pharmacology and Dependence
	1 Introduction
	2 Basic Neurocircuitry of Nicotine Addiction
	3 Role of Nicotinic Receptors in Nicotine Dependence and Brain Function
	4 Modulatory Factors That Influence nAChR Expression and Signaling
	5 Genomics and Genetics of Nicotine Dependence
		5.1 Overview
		5.2 Human and Animal Genetic Studies
		5.3 Transcriptionally Adaptive Changes
	6 Other Constituents in Nicotine and Tobacco Products Mediating Dependence
	7 Therapeutic Approaches for Tobacco and Nicotine Dependence
		7.1 Nicotine Replacement Therapies
		7.2 Varenicline and Bupropion
		7.3 Novel Approaches
	8 Conclusion
	References
Randomized Clinical Trials Investigating Innovative Interventions for Smoking Cessation in the Last Decade
	1 Introduction
	2 Cholinergic System
		2.1 Agonists
		2.2 Antagonists
		2.3 Positive Allosteric Modulators and Acetylcholinesterase Inhibitors
	3 Endocannabinoid System
		3.1 CB1 Receptor Inverse Agonists
		3.2 Cannabidiol
	4 Naltrexone
	5 Lorcaserin
	6 Antidepressants
		6.1 Selective Serotonin Reuptake Inhibitors
		6.2 Monoamine Oxidase Inhibitors
		6.3 Tricyclic Antidepressants
		6.4 Nontraditional Antidepressants
	7 The Noradrenergic System
	8 Anti-epileptic Drugs
		8.1 Gabapentin and Pregabalin
		8.2 Topiramate and Zonisamide
	9 Gamma-Aminobutyric Acid (GABA) Receptors
	10 Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists
	11 Statins
	12 Stimulants and Atomoxetine
		12.1 Attention Deficit Hyperactivity Disorder (ADHD) Medications
		12.2 Atomoxetine
		12.3 Modafinil
	13 N-Acetylcysteine
	14 N-Methyl-d-Aspartate (NMDA) Receptors
	15 Progesterone
	16 Conclusion
	References
Adolescent Vulnerability to Alcohol Use Disorder: Neurophysiological Mechanisms from Preclinical Studies
	1 Background and Overview
	2 Adolescence and Glutamate/GABA Neurotransmitter Systems
	3 Adolescent Ethanol Exposure
		3.1 Adolescent Ethanol Exposure and Glutamate Neurotransmission
		3.2 Adolescent Ethanol Exposure and GABA Neurotransmission
	4 Concluding Remarks
	References
Medication Development for Alcohol Use Disorder: A Focus on Clinical Studies
	1 Introduction
		1.1 Medications That Have Shown Efficacy in Research Clinical Studies for AUD
			1.1.1 ABT-436 (Vasopressin V1b Receptor Antagonist)
			1.1.2 Aripiprazole
			1.1.3 Baclofen
			1.1.4 Gabapentin
			1.1.5 Ondansetron
			1.1.6 Prazosin and Doxazosin
			1.1.7 Topiramate and Zonisamide
			1.1.8 Varenicline
		1.2 Other Promising Medications or Compounds for AUD
	2 Conclusions
	References
Newly Emerging Drugs of Abuse
	1 Introduction
	2 Opioids
		2.1 Epidemiology
		2.2 Chemistry and Chemical Structures
		2.3 Pharmacology and Physiology Overview
		2.4 Clinical Effects
		2.5 Laboratory Detection and Methodology
		2.6 Treatment
	3 Cannabinoids
		3.1 Epidemiology
		3.2 Chemistry and Chemical Structures
		3.3 Pharmacology and Physiology Overview
		3.4 Clinical Effects
		3.5 Laboratory Detection and Methodology
		3.6 Treatment
	4 Stimulants/Hallucinogens
		4.1 Epidemiology
		4.2 Chemistry and Chemical Structures
		4.3 Pharmacology and Physiology Overview
		4.4 Clinical Effects
		4.5 Laboratory Detection and Methodology
		4.6 Treatment
	5 Dissociative Agents
		5.1 Epidemiology
		5.2 Chemistry and Chemical Structures
		5.3 Pharmacology and Physiology Overview
		5.4 Clinical Effects
		5.5 Laboratory Detection and Methodology
		5.6 Treatment
	6 Sedative-Hypnotics
		6.1 Epidemiology
		6.2 Chemistry and Chemical Structures
		6.3 Pharmacology and Physiology Overview
		6.4 Clinical Effects
		6.5 Laboratory Detection and Methodology
		6.6 Treatment
	7 Conclusion
	References