Addictive Substances and Neurological Disease: Alcohol, Tobacco, Caffeine, and Drugs of Abuse in Everyday Lifestyles

By Ronald Ross Watson

Addictive Substances and Neurological Disease: Alcohol, Tobacco, Caffeine, and Drugs of Abuse in Everyday Lifestyles is a complete guide to the manifold effects of addictive substances on the brain, providing readers with the latest developing research on how these substances are implicated in neurological development and dysfunction.

Cannabis, cocaine, and other illicit drugs can have substantial negative effects on the structure and functioning of the brain. However, other common habituating and addictive substances often used as part of an individual’s lifestyle, i.e., alcohol, tobacco, caffeine, painkillers can also compromise brain health and effect or accentuate neurological disease.

This book provides broad coverage of the effects of addictive substances on the brain, beginning with an overview of how the substances lead to dysfunction before examining each substance in depth. It discusses the pathology of addiction, the structural damage resulting from abuse of various substances, and covers the neurobiological, neurodegenerative, behavioral, and cognitive implications of use across the lifespan, from prenatal exposure, to adolescence and old age.

This book aids researchers seeking an understanding of the neurological changes that these substances induce, and is also extremely useful for those seeking potential treatments and therapies for individuals suffering from chronic abuse of these substances.

• Integrates current research on the actions of addictive substances in neurological disease
• Includes functional foods, such as caffeine beverages, that have habituating effects on the brain
• Provides a synopsis of key ideas associated with the consequences of addictive and habituating lifestyle substances

• Language: English
• Publisher: Academic Press
• Release date: Feb 18, 2017
• ISBN: 9780128092965

Book preview

Addictive Substances and Neurological Disease

Alcohol, Tobacco, Caffeine, and Drugs of Abuse in Everyday Lifestyles

Editors

Ronald Ross Watson

University of Arizona, Arizona Health Sciences Center, Tucson, AZ, USA

Sherma Zibadi

Department of Pathology, University of South Florida Medical School, Tampa, FL, USA

Table of Contents

Cover image

Title page

Copyright

List of Contributors

Preface

Acknowledgments

Part I. Alcohol and Neurological Dysfunction

Chapter 1. Acute Ethanol-Induced Changes in Microstructural and Metabolite Concentrations on the Brain: Noninvasive Functional Brain Imaging

Introduction

Conclusion

Chapter 2. Prenatal Alcohol Exposure and Neuroglial Changes in Neurochemistry and Behavior in Animal Models

Ethanol Exposure and Brain Development

Ethanol, Glia, and Neurodevelopment

Cognitive and Behavioral Effects of Pre- and Postnatal Ethanol Exposure

Chapter 3. Alcohol on Histaminergic Neurons of Brain

Introduction

The Effects of Alcohol on Histamine Levels in the Brain

Brain Histaminergic System in Human Alcoholics

The Role of H3 Receptors in Modulation of Alcohol Stimulation and Reward

Histological Changes in Histaminergic Neurons Following Alcohol Administration

Histochemical Changes in Histaminergic Neurons Following Alcohol Administration

Alcohol Effects Into a Histaminergic Neurons Ultrastructure

Chapter 4. Antenatal Alcohol and Histological Brain Disturbances

Introduction

Neurohistology

Cellular and Molecular Disorders

Possible Mechanisms for the Development of Behavioral and Mental Disorders After Prenatal Alcohol Exposure

Chapter 5. Alcohol Intoxication and Traumatic Spinal Cord Injury: Basic and Clinical Science

Introduction

Pathophysiology of Traumatic Spinal Cord Injury

Vascular Injury

Membrane Dysfunction and Edema Formation

Inflammation and Immune-Mediated Response to Spinal Cord Injury

Free Radical Formation and Lipid Peroxidation

Excitatory Neurotransmitters

Alcohol Intoxication and the Effects on Preclinical Spinal Cord Injury

Alcohol and Functional Outcomes

Alcohol Intoxication and Injury Severity

Alcohol Use and Spinal Cord Injury Patients

Conclusion

Chapter 6. Visual and Auditory Changes After Acute Alcohol Ingestion

Introduction

Characterization of Acute Use of Alcohol

Alcohol and Visual Perception

Alcohol and Auditory Perception

Research Carried Out by the Laboratory of Research in Perception, Neuroscience, and Behavior—LPNeC

Alcohol in Neural Systems of Vision and Hearing

Chapter 7. Zebrafish Models of Alcohol Addiction

Alcohol Addiction in Humans

Animal Models of Alcohol Addiction

Zebrafish as an Animal Model for Behavioral Neuroscience

Zebrafish as an Animal Model for Alcohol Addiction

Alcohol-Induced Locomotor Activity

Alcohol-Induced Anxiolysis

Alcohol-Induced Tolerance

Alcohol-Induced Sensitization

Alcohol-Induced Withdrawal

Alcohol-Induced Conditioned Place Preference

Voluntary Alcohol Consumption

Limitations of the Zebrafish Model

Chapter 8. Effect of Alcohol on the Regulation of α-Synuclein in the Human Brain

Overview

α-Synuclein Function

Conclusion

Chapter 9. Consumption of Ethanol and Tissue Changes in the Central Nervous System

Introduction

Neuronal and Glial Changes

Modulations in Cell Proliferation and Neurogenesis

Most Significant Regional Alterations

Chapter 10. Ethanol Consumption and Cerebellar Disorders

Introduction

Cerebellum: An Anatomo-physiological Review

EtOH Effects on the Cerebellum Neurophysiology

Functional and Cellular Changes From Ingesting EtOH

Clinical Changes Resulting From Ingestion of EtOH

Chapter 11. Gene Expression in CNS Regions of Genetic Rat Models of Alcohol Abuse

Introduction

Selectively Bred High and Low Ethanol-Consuming Lines of Rats

Innate Differences in Gene Expression in the VTA, Acb-Shell, and CeA Between HEC and LEC Rats

Multiple Interacting Factors Can Impact the Effects of Alcohol Drinking on Gene Expression in the CNS

The P Rat as an Animal Model for Studying Alcohol Drinking–Induced Changes in Gene Expression

Gene Expression Changes in the Acb Following 24-h Free-Choice Alcohol Drinking: Effects of Withdrawal

Gene Expression Changes in the Acb During Operant Scheduled Access Alcohol Drinking

Changes in Gene Expression in the Acb-Shell and CeA Following Daily Multiple Alcohol Binge Drinking Episodes

Changes in Gene Expression in the VTA Following Daily Multiple Excessive Alcohol Binge–Drinking Episodes

Conclusions

Chapter 12. Role of TLR4 in the Ethanol-Induced Modulation of the Autophagy Pathway in the Brain

Autophagy as a Physiological Self-degradative Process

Ethanol Effects on the Autophagy Pathway

The TLR4 Immune Response

Conclusions and Future Directions

Chapter 13. Ghrelinergic Signaling in Ethanol Reward

Introduction: Ghrelin Physiology

Energy Metabolism and Homeostasis

Limbic System Signaling

Mesolimbic Reward Pathway

Ethanol and Drug Reward

Conclusion

Chapter 14. Alcoholic Neurological Syndromes

Introduction

Fetal Alcohol Syndrome

Pharmacokinetic Mechanisms of Alcohol Teratogeny

Teratogenic Effects of Alcohol on the CNS

Clinical Diagnosis of Fetal Alcohol Spectrum Disorders

Central Pontine and Extrapontine Myelinolysis

Marchiafava–Bignami Disease

Wernicke–Korsakoff Syndrome

Final Comments

Chapter 15. Frontal Lobe Dysfunction After Developmental Alcohol Exposure: Implications From Animal Models

Introduction

FASDs in Humans

Animal Models of FASDs

Conclusion

Chapter 16. Ethanol's Action Mechanisms in the Brain: From Lipid General Alterations to Specific Protein Receptor Binding

Introduction

Ethanol Actions on Lipid Membrane

Protein Targets Related to Ethanol Effects

Conclusions

Chapter 17. Antioxidant Vitamins and Brain Dysfunction in Alcoholics

Introduction

Vitamin E Deficiency

Vitamin A Deficiency

Vitamin D Deficiency

Vitamin B12, B6, and Folate Alterations: Hyperhomocysteinemia

Thiamine Deficiency and Wernicke Encephalopathy

Vitamin C Deficiency

Conclusions and Future Prospects

Chapter 18. Serotonin Deficiency and Alcohol Use Disorders

Introduction

Alcohol Typologies

5-HT Depletion Studies

5-HT Dysfunction and Alcohol Consumption

5-HT Deficiency, Impulsivity, and Aggression

5-HT Deficiency and AUD Treatment Responses

Concluding Remarks

Glossary

Part II. Addictive Substances and Behavioral Health

Chapter 19. Functional Reorganization of Reward- and Habit-Related Brain Networks in Addiction

Introduction

Functional Reorganization Processes in Brain Circuits of Reward and Motivation

Functional Reorganization Processes in Brain Circuits of Habits and Automaticity

Conclusion

Chapter 20. Ethanol: Neurotoxicity and Brain Disorders

Introduction

Alcohol Chemistry and Kinetics

Mechanisms of Neurotoxicity

CNS Structural Changes and Behavioral Effects

Perspectives and Final Comments

Chapter 21. Functionally Relevant Brain Alterations in Polysubstance Users: Differences to Monosubstance Users, Study Challenges, and Implications for Treatment

Introduction

Prevalence of PSU

Overview of Cognition in Monosubstance Users

Overview of Neuroimaging in Monosubstance Users

Review of Cognition in Polysubstance Users

Review of Neuroimaging in Polysubstance Users

Review Summary and Outlook

Chapter 22. Deep Brain Stimulation: A Possible Therapeutic Technique for Treating Refractory Alcohol and Drug Addiction Behaviors

Introduction

Effects of Deep Brain Stimulation on Alcohol Addiction Behaviors

Effects of Deep Brain Stimulation on Psychostimulants Addiction Behaviors

Effects of Deep Brain Stimulation on Nicotine Addiction Behaviors

Effects of Deep Brain Stimulation on Heroin Addiction Behaviors

Conclusion

Part III. Tobacco Smoking in Neuromodulation

Chapter 23. Understanding the Roles of Genetic and Environmental Influences on the Neurobiology of Nicotine Use

Introduction

The Brain Disease Model of Nicotine Dependence

Elucidating the Neurobiology of Nicotine Dependence Using Structural Magnetic Resonance Imaging

The Genetic Epidemiology of Smoking and Brain Structure

Twin and Family Studies

Understanding the Neurobiological Pathways Involved in Nicotine Dependence

Gene-Based Genetic Epidemiological Study Designs

Candidate Gene Association Studies

Genome-Wide Association Studies

The Impact of Genome-Wide Significant Variants for Smoking on Brain Structure

Limitations of Genetic Association Studies

Epigenetic Studies

DNA Methylation and Smoking Behavior

Epigenetic Studies of Brain Morphology

Future Directions

Chapter 24. Tobacco Smoke and Nicotine: Neurotoxicity in Brain Development

Introduction

Development of the Central Nervous System

Effect of Nicotine on Development of the Central Nervous System

Tobacco Smoking Affects the Development of the Central Nervous System

Chapter 25. Paradise Lost: A New Paradigm for Explaining the Interaction Between Neural and Psychological Changes in Nicotine Addiction Patients

Introduction

Neural Events During the Development of Nicotine Addiction

Four Characteristics of Cigarette Smoking That Cause Addiction

Drug or Trait?

Implications for Intervention

Conclusions

Chapter 26. Interactions of Alcohol and Nicotine: CNS Sites and Contributions to Their Co-abuse

Introduction

Animal Models of Co-abuse of Ethanol and Nicotine

Impact of Nicotine on Alcohol Drinking, Seeking, and Relapse

Common Receptors for the Interactions of Alcohol and Nicotine

CNS Sites for the Interactions of Alcohol and Nicotine

Interactions Within the VTA

Interactions Within the Nucleus Accumbens

Interactions Within the Medial Prefrontal Cortex

Genetic Associations Between Nicotine and Alcohol Dependence

Conclusions

Chapter 27. Role of Basal Forebrain in Nicotine Alcohol Co-abuse

Introduction

Neuronal Mediators of Sleep–Wakefulness

Neuronal Mediators of Alcohol-Induced Sleepiness

Nicotine Acts via BF to Suppress Negative Effects of Alcohol

Neuroanatomical Substrates Mediating the Rewarding Effects of Alcohol

Nicotine Acts via BF to Enhance the Rewarding Effects of Alcohol

Summary

Chapter 28. Chronic and Acute Nicotine Exposure Versus Placebo in Smokers and Nonsmokers: A Systematic Review of Resting-State fMRI Studies

Background

Methods

Results

Discussion

Part IV. Drugs of Abuse and Brain Structure and Function

Chapter 29. Novel Psychoactive Substances: A New Behavioral and Mental Health Threat

Introduction

Synthetic Cannabinoids

Synthetic Cathinones

Phenethylamines

Piperazines

Ketamine and Phencyclidine-Type Substances

Tryptamines

Other Substances

Conclusions

Chapter 30. Cholesterol and Caffeine Modulate Alcohol Actions on Cerebral Arteries and Brain

Introduction

Modulation of Alcohol Action by Caffeine

Cholesterol Modulation of Alcohol Effect

Concluding Remarks

Chapter 31. Sleep, Caffeine, and Physical Activity in Older Adults

Introduction

Two Factors Related to Physical Activity: Sleep and Caffeine

Physiological Contributors to Physical Activity Level

Benefits of Physical Activity on Obstructive Sleep Apnea

Benefits of Physical Activity on Sleep in Sedentary Older Persons

Effects of Sleep on Physical Activity in OSA Patients

Effects of Sleep on Physical Activity in Healthy Older Persons

Effects of Caffeine on Sleep, Metabolism, and Physical Activity

Chapter 32. Ketamine: Neurotoxicity and Neurobehavioral Disorders

Introduction

Chemistry and Kinetics

Mechanisms of Neurotoxicity and Neurobehavioral Effects

Behavioral Effects

Prospects and Final Comments

Chapter 33. Left/Right Hemispheric Unbalance Model in Addiction

Bias of Reward Mechanisms in Addiction

Neurophysiological Correlates in Addiction

An Integrative Cortical Unbalance Model

Conclusions and Future Perspectives

Index

Copyright

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List of Contributors

S. Abtahi,     Reed College, Portland, OR, United States

M. Balconi,     Catholic University of the Sacred Heart, Milan, Italy

V. Batra,     Louisiana State University Health Sciences Center, Shreveport, LA, United States

H.M. Baumgartner,     Reed College, Portland, OR, United States

L.O. Bittencourt,     Federal University of Pará, Belém, Brazil

E.I. Bon,     Grodno State Medical University, Grodno, Belarus

G. Brolese,     Federal University of Rio Grande do Sul, Porto Alegre, Brazil

S.J. Brooks,     University of Cape Town, Cape Town, South Africa

A.N. Bukiya,     The University of Tennessee Health Science Center, Memphis, TN, United States

R. Camarini,     University of São Paulo, São Paulo, Brazil

S.C. Cartágenes,     Federal University of Pará, Belém, Brazil

M.K. Cavalcanti Galdino,     Federal University of Paraiba, João Pessoa, Brazil

J. Clifford,     Virginia Commonwealth University, Richmond, VA, United States

C.L. Crutcher II ,     Louisiana State University Health Science Center, New Orleans, LA, United States

P.J. Currie,     Reed College, Portland, OR, United States

E. Fontes de Andrade Jr. ,     Federal University of Pará, Belém, Brazil

J.A. da Silva,     Federal University of Pelotas, Pelotas, Brazil

A.C.A. de Oliveira,     Federal University of Pará, Belém, Brazil

K. Dodson,     Villanova University, Villanova, PA, United States

A.M. Dopico,     The University of Tennessee Health Science Center, Memphis, TN, United States

N.A. dos Santos,     Federal University of Paraiba, João Pessoa, Brazil

L. Fattore,     Institute of Neuroscience-Cagliari, National Research Council, Cagliari, Italy

L.M.P. Fernandes,     Federal University of Pará, Belém, Brazil

R.M. Fernandes,     Federal University of Pará, Belém, Brazil

R. Finocchiaro,     Catholic University of the Sacred Heart, Milan, Italy

E.E. Garling,     Reed College, Portland, OR, United States

R. Gerlai

University of Toronto, Toronto, ON, Canada

University of Toronto Mississauga, Mississauga, ON, Canada

C.-A. Gonçalves,     Federal University of Rio Grande do Sul, Porto Alegre, Brazil

E. González-Reimers,     Universidad de La Laguna, Tenerife, Canary Islands, Spain

C. Guerri,     Príncipe Felipe Research Center, Valencia, Spain

Z.H. Gursky,     University of Delaware, Newark, DE, United States

S.R. Hauser,     Indiana University School of Medicine, Indianapolis, IN, United States

J. Ipser,     University of Cape Town, Cape Town, South Africa

T. Isomura,     Reset Behavior Research Group, Nagoya, Japan

P. Janeczek,     Griffith University, Gold Coast Campus, QLD, Australia

J. Kaiser,     Goethe University, Frankfurt am Main, Germany

M. Kano,     Shin-Nakagawa Hospital, Yokohama, Japan

A.Y. Klintsova,     University of Delaware, Newark, DE, United States

G. Langi,     Virginia Commonwealth University, Richmond, VA, United States

L.K.R. Leão,     Federal University of Pará, Belém, Brazil

J.M. Lewohl,     Griffith University, Gold Coast Campus, QLD, Australia

R.R. Lima,     Federal University of Pará, Belém, Brazil

L.H. Lobo Torres,     Federal University of Alfenas, Alfenas, Brazil

F. Lopes,     Federal University of Rio Grande do Sul, Porto Alegre, Brazil

P. Lunardi,     Federal University of Rio Grande do Sul, Porto Alegre, Brazil

C.S.F. Maia,     Federal University of Pará, Belém, Brazil

T. Marcourakis,     University of São Paulo, São Paulo, Brazil

M.T. Marin,     São Paulo State University (UNESP), Araraquara, Brazil

M.C. Martín-González,     Universidad de La Laguna, Tenerife, Canary Islands, Spain

W.J. McBride,     Indiana University School of Medicine, Indianapolis, IN, United States

A.S. Melo,     Federal University of Pará, Belém, Brazil

D.J. Meyerhoff,     University of California San Francisco, San Francisco, CA, United States

M.C. Monteiro,     Federal University of Pará, Belém, Brazil

G. Morais-Silva,     São Paulo State University (UNESP), Araraquara, Brazil

T. Murai,     Kyoto University, Kyoto, Japan

M.J. Naumer,     Goethe University, Frankfurt am Main, Germany

M. Pascual,     Príncipe Felipe Research Center, Valencia, Spain

R. Pastor,     Universitat Jaume I, Castellón, Spain

K.M. Phedina,     Grodno State Medical University, Grodno, Belarus

B.G. Pinheiro,     Federal University of Pará, Belém, Brazil

A. Pla,     Príncipe Felipe Research Center, Valencia, Spain

R.D. Prediger,     Federal University of Santa Catarina, Florianópolis, Brazil

E. Prom-Wormley,     Virginia Commonwealth University, Richmond, VA, United States

B. Puty,     Federal University of Pará, Belém, Brazil

G. Quintero-Platt,     Universidad de La Laguna, Tenerife, Canary Islands, Spain

J. Real,     Virginia Commonwealth University, Richmond, VA, United States

Z.A. Rodd,     Indiana University School of Medicine, Indianapolis, IN, United States

L. Romero-Acevedo,     Universidad de La Laguna, Tenerife, Canary Islands, Spain

B.D. Sachs,     Villanova University, Villanova, PA, United States

P. Sahota,     HSTMV Hospital, University of Missouri, Columbia, MO, United States

F. Santolaria-Fernández,     Universidad de La Laguna, Tenerife, Canary Islands, Spain

D.P. Santos,     Federal University of Pará, Belém, Brazil

M.A. Schrager,     Stetson University, DeLand, FL, United States

R. Sharma,     HSTMV Hospital, University of Missouri, Columbia, MO, United States

D.J. Stein

University of Cape Town, Cape Town, South Africa

MRC Unit on Anxiety & Stress Disorders, Cape Town, South Africa

R.C. Tamborelli Garcia,     Federal University of São Paulo (UNIFESP), Diadema, Brazil

F.B. Teixeira,     Federal University of Pará, Belém, Brazil

G.C. Tender,     Louisiana State University Health Science Center, New Orleans, LA, United States

M.M. Thakkar,     HSTMV Hospital, University of Missouri, Columbia, MO, United States

S. Tran,     University of Toronto, Toronto, ON, Canada

J. Veith,     Louisiana State University Health Science Center, New Orleans, LA, United States

K.L. Vieira,     Federal University of Pará, Belém, Brazil

J.A. Wilden,     Willis-Knighton Health Systems, Shreveport, LA, United States

Y. Yalachkov

University Hospital Frankfurt, Frankfurt am Main, Germany

Goethe University, Frankfurt am Main, Germany

L.J. Zallar,     Reed College, Portland, OR, United States

M.T. Zanda,     University of Cagliari, Cagliari, Italy

W.B. Zheng,     The Second Affiliated Hospital, Medical College of Shantou University, Shantou, China

S.M. Zimatkin,     Grodno State Medical University, Grodno, Belarus

Preface

Bioactive foods such as alcohol, tobacco, and caffeine modulate nerves producing neurological diseases and their complications. The effects of such foods produce diseases with neurological function and structure changes that are reviewed by researchers writing concise, definitive, and focused chapters. Reflecting the widespread use and abuse of alcohol, a significant portion of the book relates to ethanol and related neurological actions.

Alcohol and Neurological Dysfunction Including Nutritional Therapy

This section primarily focuses on the role of alcohol (ethanol) in the diet and brain function and damage. The mechanisms and symptoms of the wide variety of brain and other neurological systems as caused, accentuated, or modified by addictive foods and alcoholic beverages are discussed. Zheng reviews structural and metabolite changes using noninvasive brain imaging. Brolese and his group describe alcohol's effects on neuroglial changes in neurochemistry and the resulting changes in activity and actions. Zimatkin et al. describe dietary alcohol and histaminergic neurons. Crutcher et al. review excess and debilitating alcohol consumption, as well as the basic and clinical events of intoxication in spinal cord.

Alcohol impacts cellular processes, ranging from involvement in preventing DNA damage to influence in intracellular signaling. Neurological damage due to alcohol affects the functions of the eye and ear due to acute consumption. Cavalcanti Galdino's group reviewed the effects of neurological changes involved. Tran and Gerlai describe the effects of alcohol addiction by developing a novel model, zebrafish. Pinheiro et al. describe a variety of neurological syndromes induced by alcohol. Its actions on brain and neurological disorders causing biochemical, structural, and electrical abnormalities with adverse symptoms are described. Janeczek and Lewohl review specific modulators as changed by alcohol in the human brain, specifically alpha-synuclein. Potential therapy using deep brain stimulation is described for human brains suffering from alcohol-addictive behaviors. This is followed by Bittencourt et al. describing alcohol consumption and related changes in neurological tissues. As the chapter by de Oliveira et al. shows, alcohol abuse is significantly involved in various cerebellar disorders. McBride discusses the role of gene expression and inhibition in neurons of rats in alcohol models. TLR4 actions in alcohol modulation of autophagy pathway are critical to brain functions. Marin and Morais-Silva describe mechanism from lipid changes to specific protein receptor binding. Sachs and Dodson review the effects of serotonin deficiency and alcoholism and alcohol intake. Finally, Gonzalez-Reimers and collaborators review effects of antioxidant vitamin on brain dysfunction in alcohol abusers.

Tobacco and Nicotine in Neuromodulation and Behavioral Health

Bioactive drugs of abuse as nonnutrient dietary materials play key roles in accentuating neurological diseases, and possible toxicities and/or lack of function. Yalachkov and Kaiser extend their interest to the reward and habit functions of the brain for a variety of additive materials as an example of how they can function. Alcohol's neurotoxicity directly induces behavior disorders as reviewed by Fernandes et al. Deep brain stimulation is described as a therapeutic technique for treating drug addiction behaviors by Hauser et al. Brooks et al. review the various actions of nicotine on brain functions focusing on fMRI studies with examples. Torres and Garcia evaluate the materials after tobacco combustion in neurotoxicity of the developing brain. Isomura, Murai, and Kano use their experience and the literature to develop new explanations for neuronal functions and psychological changes in nicotine addiction subjects. Frequently heavy smokers also consume lots of alcohol, as if there were a relationship and regulation between the two drugs. McBride reviews the CNS sites and their role in both alcohol and nicotine abuse.

Sharma et al. also discuss alcohol–nicotine co-abuse focusing on the basal forebrain.

Drugs of Abuse and Mechanisms and Models of Addiction Relevant to Drugs of Abuse

Several less traditional but frequently used drugs modify nerves and their functions with less damage than alcohol and nicotine. For example, about 85% of adults use caffeine. Bukiya and Dopico look at caffeine's role as a modulator of the brain. Besides, the additional role of caffeine in modulating alcohol's neuromodulation is focused upon. The Cartagenes et al. chapter on ketamine adds neurotoxicity and causes neurobehavioral disorders.

Zanda and Fattore review additional, novel psychoactive substances beyond nicotine as future mental health modulators contributing to behavioral changes. Finocchiaro and Balconi evaluate data showing that hemispheric imbalance affects addiction and may explain addiction in some patients.

Acknowledgments

The work of Dr. Watson's editorial assistant, Bethany L. Stevens, in communicating with authors and working on the manuscripts was critical to the successful completion of the book. The help of Kristi L. Anderson is also very much appreciated. Support for Ms. Stevens' and Dr. Watson's work was graciously provided by Natural Health Research Institute, www.naturalhealthresearch.org—an independent, nonprofit organization that promotes science-based research on natural health and wellness. The institute is committed to informing about scientific evidence on the usefulness and cost-effectiveness of diet, supplements, and a healthy lifestyle to improve health and wellness and to reduce disease. The work of Mari Stoddard, the librarian of Arizona Health Science Library, was vital and very helpful in identifying key researchers who contributed to this book.

Part I

Alcohol and Neurological Dysfunction

Outline

Chapter 1. Acute Ethanol-Induced Changes in Microstructural and Metabolite Concentrations on the Brain: Noninvasive Functional Brain Imaging

Chapter 2. Prenatal Alcohol Exposure and Neuroglial Changes in Neurochemistry and Behavior in Animal Models

Chapter 3. Alcohol on Histaminergic Neurons of Brain

Chapter 4. Antenatal Alcohol and Histological Brain Disturbances

Chapter 5. Alcohol Intoxication and Traumatic Spinal Cord Injury: Basic and Clinical Science

Chapter 6. Visual and Auditory Changes After Acute Alcohol Ingestion

Chapter 7. Zebrafish Models of Alcohol Addiction

Chapter 8. Effect of Alcohol on the Regulation of α-Synuclein in the Human Brain

Chapter 9. Consumption of Ethanol and Tissue Changes in the Central Nervous System

Chapter 10. Ethanol Consumption and Cerebellar Disorders

Chapter 11. Gene Expression in CNS Regions of Genetic Rat Models of Alcohol Abuse

Chapter 12. Role of TLR4 in the Ethanol-Induced Modulation of the Autophagy Pathway in the Brain

Chapter 13. Ghrelinergic Signaling in Ethanol Reward

Chapter 14. Alcoholic Neurological Syndromes

Chapter 15. Frontal Lobe Dysfunction After Developmental Alcohol Exposure: Implications From Animal Models

Chapter 16. Ethanol's Action Mechanisms in the Brain: From Lipid General Alterations to Specific Protein Receptor Binding

Chapter 17. Antioxidant Vitamins and Brain Dysfunction in Alcoholics

Chapter 18. Serotonin Deficiency and Alcohol Use Disorders

Chapter 1

Acute Ethanol-Induced Changes in Microstructural and Metabolite Concentrations on the Brain

Noninvasive Functional Brain Imaging

W.B. Zheng     The Second Affiliated Hospital, Medical College of Shantou University, Shantou, China

Abstract

In this review, we summarize recent studies highlighting acute brain responses to alcohol with the use of noninvasive functional brain imaging, how those images might explain behavioral effects of alcohol intoxication and, finally, how alcohol intoxication affects traumatic brain injury.

Keywords

Apparent diffusion coefficient (ADC); Diffusion kurtosis imaging (DKI); Diffusion tensor imaging (DTI); Ethyl alcohol (ETOH); Fractional anisotropy (FA); Functional brain Imaging; Magnetic resonance spectroscopy (MRS); Mean kurtosis (MK); Resting-state fMRI (rf-MRI)

Introduction

Alcoholism is a major health issue that afflicts people all over the world. In addition, researchers have raised concerns about health and the social consequences of excessive drinking (Das, Balakrishnan, & Vasudevan, 2006). The consumption of alcohol and the subsequent production of its oxidative metabolites have many direct and indirect effects both on the developing and the developed nervous system, and have acute and chronic complications (Alderazi & Brett, 2007). Alcohol impairs cognitive function and is associated with a variety of behavioral changes resulting in deficits in perceptual and emotional function. Alcohol consumption has immediate effects on multiple cognitive–motor processing domains and leads to damage of multiple attentional abilities (Mongrain & Standing, 1989). Given the high prevalence of alcohol abuse, and the current limited and inefficient treatment options, the need for a better understanding of the effects of alcohol is clear (Nielsen & Nielsen, 2015).

Alcohol and Neurological Dysfunction

Historically, it is well documented that acute alcohol intoxication could result in changes in regional brain function, as assessed by changes in glucose metabolism or cerebral blood flow (Volkow et al., 1988, 1990), cognitive performance (Lau, Pihl, & Peterson, 1995; Lindman, Sjoholm, & Lang, 2000; Reynolds, Richards, & de Wit, 2006), motor function (Lemon, 1993), and behavior (Kong, Zheng, Lian, & Zhang, 2012; Zheng, Kong, Chen, Zhang, & Zheng, 2015; Mongrain & Standing, 1989).

Laboratory studies, which typically examine blood alcohol concentrations (BACs) in the range of 0.03–0.08%, indicate that, at these doses, the influence of alcohol on memory depends on the cognitive functions required by the particular experimental task (e.g., Bisby, Leitz, Morgan, & Curran, 2010; Söderlund, Parker, Schwartz, & Tulving, 2005).

Acute alcohol intake has pronounced effects on brain function in a general way. Until recently, the effect of alcohol on neural mechanisms had not been fully elucidated. These effects include neurotoxicity of the ethanol molecule itself, and the consequences of nutritional deficiencies or liver dysfunction, each of which can lead to the possibility of alcohol-induced neuro-inflammation. A number of measures have been used to investigate these issues. For example, George used the P300 event-related potentials (ERPs) component to assess the relationship of alcoholism with frontal lobe damage, indicating that the frontal lesion subject group of the study had significant P300 amplitude reduction. There was a similar trend for the alcohol-dependent group, but not for the subcortical group when compared to the control subjects (George, Potts, Kothman, Martin, & Mukundan, 2004).

The misuse of alcohol can affect the adult central and peripheral nervous systems, and direct effects are the result of the toxic and intoxicating effects of alcohol. It is well accepted that alcohol intoxication results in changes in physical and mental impairments including thought, judgment, coordination, concentration, and reasoning. Moreover, alcohol can lead to confusion, ataxia, and loss of social inhibition, and in some circumstances, aggression, putting a person at risk of traumatic injury.

Neuroimaging in Acute Ethanol Consumption

A number of measures have been used to examine the effects of acute ethanol consumption on the brain. Previously, magnetic resonance (MR) imaging has been applied to the study of human chronic alcoholism. Early observations utilizing structural MR imaging studies reported that white matter (WM) subjacent to the cortex and the pons suffers structural volume in those with uncomplicated alcoholism. Specific brain regions affected by chronic alcohol exposure as determined on structural MR imaging include the cortical gray matter (GM) and WM, the thalamus (Bellis et al., 2005), and particularly the prefrontal areas in older alcoholic individuals (Cardenas, Studholme, & Gazdzinski, 2007).

Traditionally, neuroimaging has provided noninvasive anatomic views of the brain, but the applications of neuroimaging have now expanded to include the measurement of neurochemical concentrations and specific proteins, such as subtypes of neurotransmitter receptors or transporters, rates of metabolic pathways and blood flow, and the detection of functional or pharmacological changes in the brain and evaluations of connections among brain regions (Niciu & Mason, 2014). In vivo modern neuroimaging modalities, including diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS), and functional magnetic resonance imaging (fMRI), provide important information regarding coexistent structural and functional brain damage, are powerful approaches to the study of brain function, and may provide novel opportunities for investigating the impact of alcohol on the nervous system. The effects of chronic alcohol exposure on the brain and its neurochemistry can be assessed through MRS (Kroenke et al., 2013). In addition, as the microstructural scale can also be assessed through DTI, neuroimaging has dramatically improved researchers' ability to understand the neuropathology of alcoholism (Nagel & Kroen, 2008). Neuroimaging data delineating alcohol effects on brain function are, however, scant. Therefore, the use of these techniques will no doubt provide important information in the near future regarding the mechanisms related to alcohol-induced brain function impairments. This chapter reviews what we have done, to date, regarding the specific imaging features of acute alcohol-induced brain dysfunction, including microstructural changes on the brain and metabolic product concentrations using these noninvasive functional brain imaging techniques.

DTI- and DKI-Detected Acute Ethanol-Induced Changes on Microstructures in the Brain

DTI has identified reduced diffusion anisotropy within the frontal WM of chronic alcoholics (Harris et al., 2008) in the genu of the corpus callosum, the centrum semiovale (Rosenbloom, Sullivan, & Pfefferbaum, 2003), and the frontal and superior sites, such as frontal forceps, internal and external capsules, and the fornix (Pfefferbaum, Rosenbloom, Rohlfing, & Sullivan, 2009), which is interpreted as a manifestation of alcohol-related WM damage. DTI has also revealed evidence for microstructural disruption of WM in alcoholic men and women, even in regions appearing normal on conventional volume imaging (Yeh, Simpson, Durazzo, Gazdzinski, & Meyerhoff, 2009). These findings are consistent with the impaired attention and emotion processing seen with WM fiber disruption (Schulte, Müller-Oehring, Sullivan, & Pfefferbaum, 2012). Individuals with alcohol use disorders underwent DTI, revealing reduced axial diffusivity in the bilateral frontal and temporal WM and lower fractional anisotropy (FA) in bilateral parietal regions, and exhibited abnormalities in subcortical areas associated with sensory processing and memory (Monnig, Tonigan, Yeo, Thoma, & McCrady, 2013). In summary, DTI measures enable examination of the effect of chronic excessive alcohol consumption on the microstructural integrity of major fiber bundles in vivo.

Ethanol is also known to increase the fluidity of cell membranes, thereby causing a change in ion permeability and cell membrane function. It was shown that acute exposure to alcohol induced cellular edema in neonatal rat primary astrocyte cultures and was also associated with a dose-dependent increase in astrocyte volume (Aschner, Mutkus, & Allen, 2001), but the acute effect ethanol exerts on the human brain has not yet been addressed by longitudinal DTI experiments. In the only DTI study of acute alcoholism in humans, researchers demonstrated that ADC values of the frontal lobe, thalamus, and middle cerebellar peduncle were significantly reduced, reaching a minimum value in 1 or 2  h. In contrast, BrAC (BAC) was significantly increased to reach a peak at 0.5  h in both doses and decreased gradually. In addition, FA values (indicating an increase in diffusion along a specific axis or trajectory) of the frontal lobe were significantly increased. Researchers concluded that DTI can detect alcohol-induced cytotoxic brain edemas that are not detectable by conventional magnetic resonance imaging (MRI), and that the frontal lobe, thalamus, and middle cerebellar peduncle are among regions most sensitive to the effects of acute alcohol consumption (Kong et al., 2012).

DTI measurements are based on the assumption of a Gaussian displacement probability distribution of water molecules due to water self-diffusion, such as water in isotropic liquid media (Hui, Cheung, Chan, & Wu, 2010). However, the diffusion of water molecules in most biological tissues, especially brain tissues, is restricted by barriers, such as cellular membranes, which cause diffusion to deviate substantially from a Gaussian form (Filli et al., 2014), making DTI a limited indicator of complexity. Therefore, new imaging methods based on non-Gaussian diffusion models, such as diffusion kurtosis imaging (DKI), may assess microstructural complexity more accurately than DTI, especially in GM (Hori et al., 2012; Jensen & Helpern, 2010; Jensen, Helpern, Ramani, Lu, & Kaczynski, 2005). Moreover, DKI datasets generally include DTI datasets as part of the total measurements (Stokum et al., 2015).

A new 7.0  T MRI study uses DKI to test the microstructural changes in the brains of rats after acute alcohol intoxication. In this study, compared with DTI, DKI can provide a more comprehensive evaluation of EtOH-related brain changes at varying time points, and not only in anisotropic WM, but also in GM. DKI possesses sufficient sensitivity for tracking pathophysiological changes at various stages associated with acute alcohol intoxication and may provide additional information that may be missed by conventional DTI parameters. In addition, the thalamus may be especially vulnerable to effects of acute alcohol intoxication (Chen, Zeng, Kong, & Zheng, 2016).

MRS-Detected Acute Ethanol-Induced Changes on Metabolites in the Brain

Particularly, acute alcohol consumption has marked effects on brain metabolism, by decreasing glucose metabolism throughout the human brain while also causing functional and morphological changes in cells. Alcohol affects multiple neurotransmitter systems in brain and brain functions that depend on a delicate balance between excitation and inhibitory neurotransmission (Mukherjee, Das, Vaidyanathan, & Vasudevan, 2008). Substantial evidence now indicates that alcohol selectively alters the activity of specific complexes of proteins embedded in the membranes of cells that bind neurotransmitters such as gamma-aminobutyric acid (GABA), glutamate, serotonin, acetylcholine, and glycine (White, 2003).

In vivo ¹H MRS provides unique information about brain function metabolism. The concentrations of N-acetyl aspartate (NAA), total creatine phosphate phosphocreatine (CrPCr), choline-containing compounds (Cho), myo-inositol (myo-Ins), glutamate (Glu), glutamine (Gln), and glucose (Glc) can be determined using a steady-state ¹H MR spectra. It has been repeatedly demonstrated that MRS is the most direct MR-based technique for studying alcohol in the brain. This approach has been used to characterize alcohol pharmacodynamics in animals (Adalsteinsson, Sullivan, Mayer, & Pfefferbaum, 2006; Lee et al., 2012), humans (Biller, Bartsch, Homola, Solymosi, & Bendszus, 2009), and nonhuman primates (Kroenke et al., 2013).

Previous MRS studies have shown the chronic effects of EtOH on regional brain structure and brain metabolism (Ende et al., 2005; Meyerhoff et al., 2004). The results of Braunová may indicate that myo-Ins loss, reflecting a disorder in astrocytes, might be one of the first changes associated with alcoholism, which could be detected in the brain using in vivo ¹H MRS (Braunová et al., 2000). Some MRS studies have shown that individuals who have chronically consumed alcohol demonstrate persistent N-acetyl aspartate decreases in the frontal lobe, the thalamus, and the cerebellum, while others have found improvement in the levels of N-acetyl aspartate and choline. Moreover, alcohol interferes with the conversion of thiamine to its metabolically active form, thereby interrupting the production of glucose-derived neurotransmitters. These metabolic deficits can contribute to neuronal and WM damage (Zahr, Kaufman, & Harper, 2011). Most investigators report reduced levels of NAA and Cho in alcoholics compared with those levels in healthy subjects and alcoholics before and after abstinence, respectively. A study examining ¹H MRS and high resolution magic angle spinning nuclear magnetic resonance (HR-MAS NMR) spectroscopy in a rat model for long-term alcohol exposure using the liquid diet technique, to assess neurochemical changes in the frontal cortex region, suggested that the reduced myo-Ins concentrations and increased Cho concentrations might be utilized as key markers in chronic alcohol intoxication, providing useful neurochemical information about human chronic alcoholism-related brain damage (Lee et al., 2013). Biller longitudinally characterized cerebral metabolism changes in 15 healthy individuals by¹H-MRS subsequent to the ingestion of a standard beverage, and discovered that supratentorial creatine, choline, inositol, and aspartate levels decreased after ethanol administration, whereas glucose levels increased (Biller et al., 2009).

Subsequent research provided additional evidence suggesting a link between ethanol and GABA receptors (Follesa et al., 2015; Silveri, 2014). Follesa measured hippocampal gamma-aminobutyric acid type A (GABAAR) expression at different time points during and after voluntary EtOH consumption following forced EtOH vapor exposure in mice by comparing molecular data with concomitant EtOH concentrations (BECs). The findings indicate that hippocampal GABAAR delta subunit expression changes transiently over the course of a chronic intermittent ethanol (CIE) exposure model associated with voluntary intake, in response to ethanol-mediated disturbance of GABAergic neurotransmission (Follesa et al., 2015). Flory extended ethanol MRS techniques to nonhuman primate subjects, and demonstrated that brain ¹H MRS following intravenous infusion of ethanol can be used to perform quantitative measurements of ethanol MRS signal intensity in GM and WM within 12 monkeys (Flory, O'Malley, Grant, Park, & Kroenke, 2010). Furthermore, Kroenke used in vivo MRS to measure the GM and WM ethanol methyl ¹H MRS intensity in 18 adult male primates throughout the course of a chronic drinking experiment, and found that chronic exposure to ethanol is associated with brain changes that result in differential increases in ethanol MRS intensity in GM and WM (Kroenke et al., 2013).

Increased Tau levels have been reported in the frontal cortex and nucleus accumbens under acute and chronic ethanol administration in animals (Lee et al., 2012). Acute exposure of ethanol perturbs the level of neurometabolites and decreases the excitatory and inhibitory activity differentially across the regions of the brain (Tiwari, Veeraiah, Subramaniam, & Patel, 2014). ¹H MRS has been used to study acute ethanol effects before and during a 1-h intravenous alcohol administration in humans. This study found that ethanol acutely reduced cortical GABA and NAA levels. Reductions in GABA levels are consistent with the facilitation of GABA receptor function by ethanol. The gradual decline in NAA levels suggests the inhibition of neural or metabolic activity in the brain. The time course of ethanol in the brain is similar to its time course in the breath, but was faster than that seen in the venous blood (Gomez et al., 2012). In rat brains, MRS findings of acute metabolite changes after intravenous, intragastric, and intraperitoneal ethanol application revealed stable as well as reduced Cho and stable Cr concentrations (Adalsteinsson et al., 2006).

Diffusion Weighted Imaging- and MRS-Detected Acute Ethanol-Induced Changes in the Brain

Liu et al. designed a study to evaluate brain edema and the metabolism of the rat brain tissue acutely exposed to ethanol, and to assess the capability of these techniques in revealing brain metabolic changes. They examined the rat brain tissue in vivo, by means of diffusion weighted imaging (DWI) together with ¹H MRS techniques at a 7.0  T MR, and found that apparent diffusion coefficient (ADC) values in the frontal lobe are lower than other regions at 3  h post exposure. EtOH levels also significantly affected choline, taurine, and glutamate concentrations in the frontal lobes, and EtOH/tCr (tCr: creatine and phosphocreatine) correlates well with these metabolite levels.

The reduction of ADC values in different brain areas reflects the process of cytotoxic edema in vivo. The characterization of metabolic frontal lobe changes and the correlation between metabolic concentrations provide a better understanding of the biological mechanisms in neurotoxic effects of EtOH on the brain. These data provide further evidence that the frontal lobe is more vulnerable to the effects of acute alcohol consumption. Moreover, the correlation between metabolite concentrations and ADC help to understand the development of the ethanol-induced brain cytotoxic edema (Liu et al., 2014).

Resting-State fMRI Study of Alcohol Effects

Another advantage of in vivo MR tools is the ability to conduct behavioral experiments during imaging to determine brain structure–function relationships. Resting-state fMRI (rf-MRI) techniques were applied to demonstrate abnormalities in various neuropsychiatric disorders (Garrity et al., 2007; Zhang et al.,2010). The BOLD signal has been confirmed to indirectly reflect neural activity. The default mode network (DMN) has first been observed as a task-negative network, showing increased metabolic demand during the baseline activity and has therefore been hypothesized to reflect intrinsic default brain processes (Raichle & Snyder, 2007).

It may be helpful to further understand about the abnormalities of brain activity in participants in a resting state while under the acute effect of alcohol, as the absence of demanding cognitive activities and instructions might mitigate subjects' differences in motivation or cognitive abilities when comparing brain activity across groups. Numerous studies indicate that acute alcohol intoxication attenuates activity in fronto-parietal areas during high-conflict and error trials, most prominently in the anterior cingulate cortex (ACC), suggesting that cognitive control functions are vulnerable to acute alcohol intoxication (Anderson et al., 2011; Kovacevic et al., 2012; Marinkovic, Rickenbacher, Azma, & Artsy, 2012). Alcohol intoxication may impair top–down regulative functions by attenuating the anterior cingulate cortex (ACC) activity, resulting in behavioral disinhibition and decreased self-control (Marinkovic, Rickenbacher, Azma, Artsy, & Lee, 2013). However, all of these studies examined the brain activation during the fMRI tasks. In contrast, an rf-MRI study investigated the acute effects of alcohol on the human brain by detecting the functional connectivity of DMN, and using ALFF and ReHo it showed that an rf-MRI could detect selectively vulnerable brain regions including the superior frontal gyrus, cerebellum, hippocampal gyrus, basal ganglia, and internal capsule which were affected by alcohol. These different brain regions, which are related to memory, motor control, cognitive ability, and spatial functions might provide a neural basis for alcohol's effects on behavioral performance (Zheng et al., 2015).

Alcohol Intoxication and Traumatic Brain Injury

Decades of research have established that alcohol use results in the deterioration of judgment, alertness, attention, and a loss of fine motor coordination, as well as a slowing in reaction times and a diminishing of sensory perceptions (Ferguson, 2012). There is no question that alcohol impairs the ability to drive safely. Driving while under the influence of alcohol is a major public health issue whose neural basis is not well understood. Alcohol intoxication is a significant risk factor for TBI, and TBI should be appreciated as a heterogeneous, dynamic pathophysiological process that occurs at the moment of impact and continues over time with sequelae potentially seen many years after the initial event (Currie et al., 2016).

Today the treatment of traumatic brain edema remains a therapeutic challenge, and diagnosis is still largely symptomatic in nature. All treatment modalities presently used are focused on decreasing intracranial pressure. For example, steroids are postulated to seal the endothelial lining, thus, lessening vasogenic brain edema formation. The prevalence of cytotoxic edema formation, however, might explain the limited efficacy of steroids to treat traumatic brain edema (Unterberg, Stover, Kress, & Kiening, 2004). Clinical trials targeting cytotoxic and vasogenic mechanisms of edema formation may benefit from using DWI and FLAIR MRI as a means to differentiate the predominant edema type after TBI (Hudak et al., 2014). Ethanol is known to increase the fluidity of cell membranes, thus causing a change in ion permeability and cell membrane function. Acute EtOH intoxication has been shown to increase the permeability of the blood–brain barrier (BBB) in the injured area following cerebral stab wounds, but the extent of the BBB disruption and brain edema that follows TBI is obviously intensified under conditions of acute EtOH intoxication (Yamakamiet et al., 1995). Brain edema is a critical event in the pathophysiology of TBI, and ethanol adversely affects morbidity and mortality after TBI by accelerating brain edema (Katada et al., 2009). Increased brain edema has been described in TBI rats receiving higher doses of alcohol compared to TBI rats exposed without alcohol (Opreanu, Kuhn, & Basson, 2010).

To characterize the effect of acute EtOH intoxication on the brain following TBI, Kong et al. used DTI and evaluated aquaporin-4 (AQP4) expression changes in rat brain stems following acute alcohol intoxication with diffuse axonal injury (DAI). The results showed changes in ADC and FA values in DAI with acute alcoholism indicating that ethanol can aggravate brain edema and the severity of axonal injury. The correlations between ADC values and the brainstem AQP4 expression at different time points suggest that AQP4 expression follows an adaptative profile to the severity of brain edema (Kong, Lian, Zheng, Liu, & Zhang, 2013).

Conclusion

Taken together, the in vivo modern neuroimaging studies reviewed here reflect several themes on the effects of alcohol that have been investigated. Noninvasive functional brain imaging such as DWI, DTI, DKI, MRS, and rf-MRI can detect abnormalities that may be due to alcohol intoxication, while conventional MRI scans are unable to detect such abnormalities and thus make the scan results look normal. The selectively vulnerable brain regions including the frontal lobe, cerebellum, and thalamus were affected by alcohol. This series of studies suggests that acute ethanol intake can cause cytotoxic brain edema and exacerbate brain edema after acute alcoholism, and lead to detectable brain metabolic abnormalities. The effect of acute ethanol administration on the severity of axonal injury was also detected by these functional brain imaging.

Acknowledgments

This work was supported by Natural Science Foundation of Guangdong Province, China (grant No. S2012010008974, 2014A030313481), and was sponsored by Characteristic Innovation Project of Ordinary University of Guangdong Province, China (No. 922-38040223, No. 923-38040404).

References

Adalsteinsson E, Sullivan E.V, Mayer D, Pfefferbaum A. In vivo quantification of ethanol kinetics in rat brain. Neuropsychopharmacology. 2006;31:2683–2691.

Alderazi Y, Brett F. Alcohol and the nervous system. Current Diagnostic Pathology. 2007;13:203–209.

Anderson B.M, Stevens M.C, Meda S.A, Jordan K, Calhoun V.D, Pearlson G.D. Functional imaging of cognitive control during acute alcohol intoxication. Alcoholism: Clinical and Experimental Research. 2011;35:156–165.

Aschner M, Mutkus L, Allen J.W. Aspartate and glutamate transport in acutely and chronically ethanol exposed neonatal rat primary astrocyte cultures. NeuroToxicology. 2001;22:601–605.

Bellis D, Narasimhan A, Thatcher D.L, Keshavan M.S, Soloff P, Clark D.B. Prefrontal cortex, thalamus, and cerebellar volumes in adolescents and young adults with adolescent-onset alcohol use disorders and comorbid mental disorders. Alcoholism: Clinical and Experimental Research. 2005;29:1590–1600. .

Biller A, Bartsch A.J, Homola G, Solymosi L, Bendszus M. The effect of ethanol on human brain metabolites longitudinally characterized by proton MR spectroscopy. Journal of Cerebral Blood Flow & Metabolism. 2009;29(5):891–902.

Bisby J.A, Leitz J.R, Morgan C.J.A, Curran H.V. Decreases in recollective experience following acute alcohol: A dose–response study. Psychopharmacology. 2010;208:67–74. doi: 10.1007/s00213-009-1709-y.

Braunová Z, Kasparová S, Mlynárik V, Mierisová S, Liptaj T, Tkác I, Gvozdjáková A. Metabolic changes in rat brain after prolonged ethanol consumption measured by 1H and 31P MRS experiments. Cellular and Molecular Neurobiology. 2000;20(6):703–715.

Cardenas V.A, Studholme C, Gazdzinski S. Deformation-based morphometry of brain changes in alcohol dependence and abstinence. NeuroImage. 2007;34:879–887.

Chen X.R, Zeng J.Y, Kong L.M, Zheng W.B. Diffusion kurtosis imaging detects acute microstructural changes in white and gray matter after alcohol intoxication in rat. In: IEEE international conference on biological sciences and technology. February 2016.

Currie S, Saleem N, Straiton J.A, Macmullen-Price J, Warren D.J, Craven I.J. Imaging assessment of traumatic brain injury. Postgraduate Medical Journal. 2016;92(1083):41–50.

Das S.K, Balakrishnan V, Vasudevan D.M. Alcohol: Its health and social impact in India. The National Medical Journal of India. 2006;19(2):94–99.

Ende G, Welzel H, Walter S, Weber-Fahr W, Diehl A, Hermann D, … Mann K. Monitoring the effects of chronic alcohol consumption and abstinence on brain metabolism: A longitudinal proton magnetic resonance spectroscopy study. Biological Psychiatry. 2005;58(12):974–980.

Ferguson S.A. Alcohol-impaired driving in the United States: Contributors to the problem and effective countermeasures. Traffic Injury Prevention. 2012;13(5):427–441.

Filli L, Wurnig M, Nanz D, Luechinger R, Kenkel D, Boss A. Whole-body diffusion kurtosis imaging: Initial experience on non-Gaussian diffusion in various organs. Investigative Radiology. 2014;49(12):773–778.

Flory G.S, O'Malley J, Grant K.A, Park B, Kroenke C.D. Quantification of ethanol methyl (1)H magnetic resonance signal intensity following intravenous ethanol administration in primate brain. Methods. 2010;50(3):189–198.

Follesa P, Floris G, Asuni G.P, Ibba A, Tocco M.G, Zicca L, … Gorini G. Chronic intermittent ethanol regulates hippocampal GABA(A) receptor delta subunit gene expression. Frontiers in Cellular Neuroscience. 2015;9:445.

Garrity A.G, Pearlson G.D, McKiernan K, Lloyd D, Kiehl K.A, Calhoun V.D. Aberrant default mode functional connectivity in schizophrenia. The American Journal of Psychiatry. 2007;164(3):450–457.

George M.R, Potts G, Kothman D, Martin L, Mukundan C.R. Frontal deficits in alcoholism: An ERP study. Brain and Cognition. 2004;54(3):245–247.

Gomez R, Behar K.L, Watzl J, Weinzimer S.A, Gulanski B, Sanacora G, … Mason G.F. Intravenous ethanol infusion decreases human cortical γ-aminobutyric acid and N-acetylaspartate as measured with proton magnetic resonance spectroscopy at 4 tesla. Biological Psychiatry. 2012;71(3):239–242.

Harris G.J, Jaffin S.K, Hodge S.M, Kennedy D, Caviness V.S, Marinkovic K, … Oscar-Berman M. Frontal white matter and cingulum diffusion tensor imaging deficits in alcoholism. Alcoholism: Clinical and Experimental Research. 2008;32(6):1001–1013.

Hori M, Fukunaga I, Masutani Y, Taoka T, Kamagata K, Suzuki Y, Aoki S. Visualizing non-Gaussian diffusion: Clinical application of q-space imaging and diffusional kurtosis imaging of the brain and spine. Magnetic Resonance in Medical Sciences. 2012;11(4):221–233.

Hudak A.M, Peng L, Marquez de la Plata C, Thottakara J, Moore C, Harper C, … Diaz-Arrastia R. Cytotoxic and vasogenic cerebral oedema in traumatic brain injury: Assessment with FLAIR and DWI imaging. Brain Injury. 2014;28(12):1602–1609.

Hui E.S, Cheung M.M, Chan K.C, Wu E.X. B-value dependence of DTI quantitation and sensitivity in detecting neural tissue changes. NeuroImage. 2010;49(3):2366–2374.

Jensen J.H, Helpern J.A. MRI quantification of non-Gaussian water diffusion by kurtosis analysis. NMR in Biomedicine. 2010;23(7):698–710.

Jensen J.H, Helpern J.A, Ramani A, Lu H, Kaczynski K. Diffusional kurtosis imaging: The quantification of non-Gaussian water diffusion by means of magnetic resonance imaging. Magnetic Resonance in Medicine. 2005;53(6):1432–1440.

Katada R, Nishitani Y, Honmou O, Okazaki S, Houkin K, Matsumoto H. Prior ethanol injection promotes brain edema after traumatic brain injury. Journal of Neurotrauma. 2009;26(11):2015–2025.

Kong L.M, Lian G.P, Zheng W.B, Liu H.M, Zhang H.D. Effect of alcohol on diffuse axonal injury in rat brainstem: Diffusion tensor imaging and aquaporin-4 expression study. Biomed Research International. 2013;2013:798261.

Kong L.M, Zheng W.B, Lian G.P, Zhang H.D. Acute effects of alcohol on the human brain: Diffusion tensor imaging study. American Journal of Neuroradiology. 2012;33(5):928–934.

Kovacevic S, Azma S, Irimia A, Sherfey J, Halgren E, Marinkovic K. Theta oscillations are sensitive to both early and late conflict processing stages: Effects of alcohol intoxication. PLoS One. 2012;7:e43957.

Kroenke C.D, Flory G.S, Park B, Shaw J, Rau A.R, Grant K.A. Chronic ethanol (EtOH) consumption differentially alters gray and white matter EtOH methyl 1H magnetic resonance intensity in the primate brain. Alcoholism: Clinical and Experimental Research. 2013;37(8):1325–1332.

Lau M.A, Pihl R.O, Peterson J.B. Provocation, acute alcohol intoxication, cognitive performance, and aggression. Journal of Abnormal Psychology. 1995;104:150–155.

Lee D.W, Kim S.Y, Lee T, Nam Y.K, Ju A, Woo D.C, … Choe B.Y. Ex vivo detection for chronic ethanol consumption-induced neurochemical changes in rats. Brain Research. 2012;1429:134–144.

Lee D.W, Kim S.Y, Kim J.H, Lee T, Yoo C, Nam Y.K, … Choe B.Y. Quantitative assessment of neurochemical changes in a rat model of long-term alcohol consumption as detected by in vivo and ex vivo proton nuclear magnetic resonance spectroscopy. Neurochemistry International. 2013;62(4):502–509.

Lemon J. Alcoholic hangover and performance: a review. Drug and Alcohol Review. 1993;12:299–314.

Lindman R.E, Sjoholm B.A, Lang A.R. Expectations of alcohol-induced positive affect: A cross-cultural comparison. Journal of Studies on Alcohol. 2000;61:681–687.

Liu H.M, Zheng W.B, Yan G, Liu B.G, Kong L.M, Ding Y, … Zhang G. Acute ethanol-induced changes in edema and metabolite concentrations in rat brain. Biomed Research International. 2014;2014:351903.

Marinkovic K, Rickenbacher E, Azma S, Artsy E. Acute alcohol intoxication impairs top–down regulation of stroop incongruity as revealed by blood oxygen level-dependent functional magnetic resonance imaging. Human Brain Mapping. 2012;33:319–333.

Marinkovic K, Rickenbacher E, Azma S, Artsy E, Lee A.K. Effects of acute alcohol intoxication on saccadic conflict and error processing. Psychopharmacology. 2013;230(3):487–497. .

Meyerhoff D.J, Blumenfeld R, Truran D, Lindgren J, Flenniken D, Cardenas V, … Weiner M.W. Effects of heavy drinking, binge drinking, and family history of alcoholism on regional brain metabolites. Alcoholism: Clinical and Experimental Research. 2004;28(4):650–661.

Mongrain S, Standing L. Impairment of cognition, risk taking, and self-perception by alcohol. Perceptual and Motor Skills. 1989;69(1):199–210.

Monnig M.A, Tonigan J.S, Yeo R.A, Thoma R.J, McCrady B.S. White matter volume in alcohol use disorders: a meta-analysis. Addiction Biology. 2013;18(3):581–592.

Mukherjee S, Das S.K, Vaidyanathan K, Vasudevan D.M. Consequences of alcohol consumption on neurotransmitters—an overview. Current Neurovascular Research. 2008;5(4):266–272.

Nagel B.J, Kroen C.D. The use of magnetic resonance spectroscopy and magnetic resonance imaging in alcohol research. Alcohol Research & Health. 2008;31(3):243–246.

Niciu M.J, Mason G.F. Neuroimaging in alcohol and drug dependence. Current Behavioral Neuroscience Reports. 2014;1(1):45–54.

Nielsen A.S, Nielsen B. Implementation of a clinical pathway may improve alcohol treatment outcome. Addiction Science & Clinical Practice. 2015;10:7.

Opreanu R.C, Kuhn D, Basson M.D. Influence of alcohol on mortality in traumatic brain injury. Journal of the American College of Surgeons. 2010;210(6):997–1007.

Pfefferbaum A, Rosenbloom M, Rohlfing T, Sullivan E.V. Degradation of association and projection white matter systems in alcoholism detected with quantitative fiber tracking. Biological Psychiatry. 2009;65(8):680–690.

Raichle M.E, Snyder A.Z. A default mode of brain function: A brief history of an evolving idea. NeuroImage. 2007;37(4):1083–1090.

Reynolds B, Richards J.B, de Wit H. Acute-alcohol effects on the Experiential Discounting Task (EDT) and a question-based measure of delay discounting. Pharmacology Biochemistry and Behavior. 2006;83:194–202.

Rosenbloom M, Sullivan E.V, Pfefferbaum A. Using magnetic resonance imaging and diffusion tensor imaging to assess brain damage in alcoholics. Alcohol Research & Health. 2003;272:146–152.

Schulte T, Müller-Oehring E, Sullivan E, Pfefferbaum A. White matter fiber compromise contributes differentially to attention and emotion processing impairment in alcoholism, HIV-infection, and their comorbidity. Neuropsychologia. 2012;50(12):2812–2822.

Silveri M.M. GABAergic contributions to alcohol responsivity during adolescence: Insights from preclinical and clinical studies. Pharmacology & Therapeutics. 2014;143(2):197–216.

Söderlund H, Parker E.S, Schwartz B.L, Tulving E. Memory encoding and retrieval on the ascending and descending limbs of the blood alcohol concentration curve. Psychopharmacology. 2005;182:305–317. doi: 10.1007/s00213-005-0096-2.

Stokum J.A, Sours C, Zhuo J, Kane R, Shanmuganathan K, Gullapalli R.P. A longitudinal evaluation of diffusion kurtosis imaging in patients with mild traumatic brain injury. Brain Injury. 2015;29(1):47–57.

Tiwari V, Veeraiah P, Subramaniam V, Patel A.B. Differential effects of ethanol on regional glutamatergic and GABAergic neurotransmitter pathways in mouse brain. Journal of Neurochemistry. 2014;128(5):628–640.

Unterberg A.W, Stover J, Kress B, Kiening K.L. Edema and brain trauma. Neuroscience. 2004;129(4):1021–1029.

Volkow N.D, Hitzemann R, Wolf A.P, Logan J, Fowler J.S, Christman D, … Hirschowitz J. Acute effects of ethanol on regional brain glucose metabolism and transport. Psychiatry Research. 1990;35:39–48.

Volkow N.D, Mullani N, Gould L, Adler S.S, Guynn R.W, Overall J.E, Dewey S. Effects of acute alcohol intoxication on cerebral blood flow measured with PET. Psychiatry Research. 1988;24:201–209.

White A.M. What happened? Alcohol, memory blackouts, and the brain. Alcohol Research & Health. 2003;27(2):186–196.

Yamakami I, Vink R, Faden A.I, Gennarelli T.A, Lenkinski R, McIntosh T.K. Effects of acute ethanol intoxication on experimental brain injury in the rat: Neurobehavioral and phosphorus-31 nuclear magnetic resonance spectroscopy studies. Journal of Neurosurgery. 1995;82:813–821.

Yeh P.H, Simpson K, Durazzo T.C, Gazdzinski S, Meyerhoff D.J. Tract-based spatial statistics (TBSS) of diffusion tensor imaging data in alcohol dependence: Abnormalities of the motivational neurocircuitry. Psychiatry Research. 2009;173(1):22–30.

Zahr N.M, Kaufman K.L, Harper C.G. Clinical and pathological features of alcohol-related brain damage. Nature Reviews Neurology. 2011;7(5):284–294.

Zhang Z, Lu G, Zhong Y, Tan Q, Liao W, Wang Z, … Liu Y. Altered spontaneous neuronal activity of the default-mode network in mesial temporal lobe epilepsy. Brain Research. 2010;1323:152–160.

Zheng H.Y, Kong L.M, Chen L.M, Zhang H.D, Zheng W.B. Acute effects of alcohol on the human brain: A resting-state fMRI study. Biomed Research International. 2015;2015:947529.

Chapter 2

Prenatal Alcohol Exposure and Neuroglial Changes in Neurochemistry and Behavior in Animal Models

G. Brolese, P. Lunardi, F. Lopes, and C.-A. Gonçalves     Federal University of Rio Grande do Sul, Porto Alegre, Brazil

Abstract

Ethylic alcohol consumption is widely accepted and practiced in our society, including by women during gestation. It is quite clear that prenatal ethanol exposure (PEE) at high doses has long-lasting detrimental effects on brain development. However, less reported, behavioral alterations are also associated with moderate PEE in humans and in animal models, and such alterations are mainly related to neuronal changes. As of 2016, based on the tripartite concept, the role of astrocytes in these behavioral alterations cannot be ignored. It is important to investigate the astroglial alterations due to PEE to understand long-lasting brain and behavioral modifications, as well as brain susceptibility to further injuries. This chapter discusses the effects of PEE on glial parameters and behavioral changes using different animal models.

Keywords

Animal models; Astrocytes; Ethanol; GFAP; Glutamate uptake; Prenatal; S100B and behavior

Ethanol Exposure and Brain Development

Drugs such as alcohol have the ability to change our state of consciousness, which explains our behavioral change after few drinks. In general, we can feel anything from euphoric, talkative, and sociable to dizzy, sick, sad, and sleepy. Alcohol pharmacology and its effects on the brain are still relatively poorly characterized, and the mechanism of its action is considered unspecific, because ethanol can have long-lasting effects on different kinds of neurons and glial cells. However, it is already well accepted in the literature that ethanol can act not only in exacerbating the inhibitory GABAergic synapses, but also in reducing the excitatory glutamatergic synapses. This effect could explain why ethanol is considered a depressor of the central nervous system, CNS, increasing excitation and decreasing inhibition, and why symptoms such as alcohol intoxication, amnesia, and ataxia appear. Alcohol reward effects are mediated especially by the mesolimbic dopaminergic reward system. These effects are mediated not only by the gamma-aminobutyric acid (GABA) and glutamate systems, but also by direct and indirect pathways by opioid and cannabinoid synapses.

Prenatal ethanol exposure (PEE) has been linked to widespread impairments in brain structure and function. Many countries do not have a clear recommendation regarding alcohol abstinence during gestation. Prenatal alcohol consumption has been shown to be associated with a higher incidence of juvenile behavioral and cognitive problems, including deficits in cognitive behavior. Following PEE, general CNS disorganization is observed, with errors in neuronal migration, glial differentiation, and microcephaly, as well as abnormalities of the brain stem, cerebellum, basal ganglia, hippocampus, corpus callosum, pituitary gland, and optic nerve (Jones & Smith, 1973). In fact, the developing hippocampus is one of the areas of the brain that is most vulnerable to effects of ethanol. However, the range of alcohol-related disorders depends on differences in the duration, timing, and pattern of ethanol exposure.

The most severe effect of ethanol exposure during pregnancy is fetal alcohol syndrome (FAS), and the more consistent characteristics of FAS are (1) facial abnormalities with short palpebral fissures, thin vermilion border of the upper lip, and epicanthal folds; (2) mental retardation varying in degree from mild to severe; (3) small weight and height at birth that persist in the postnatal period; and (4) abnormalities in the cardiovascular and skeletal systems (Wilhelm & Guizzetti, 2016). It is clear that binge drinking during PEE can produce significant and severe brain damage and cognitive behavioral dysfunction. Damage becomes apparent in juveniles, including a reduction in general intellectual functioning and academic skills, as well as deficits in learning, spatial memory and reasoning, reaction time, balance, and other cognitive and motor skills. These deficits are pervasive and can persist throughout the person's life.

Additionally, the negative consequences of PEE are not limited to high levels of alcohol; moderate (or social) prenatal ethanol consumption has been shown to be associated with a higher incidence of behavioral and cognitive problems in childhood and/or adolescence, including alterations in the neurophysiology of the CNS and in the glutamate system, oxidative stress, and glial proteins (Brolese et al., 2014, 2015). Although there are no agreed guidelines in the literature defining the exact amounts for low, moderate, or high ethanol doses, in animal models, commonly used low to moderate doses result in a blood ethanol concentration (BAC) of between 80 and 150  mg/dL; binge drinking and/or FAS usually reach BAC  >  200 mg/dL (Patten, Fontaine, & Christie, 2014).

Ethanol exposure during brain development, even in moderate doses, induces a variety of disruptions in normal neuronal development patterns. Abnormalities in glial development have been also suspected to contribute to the adverse effects of ethanol on the developing brain. Significant differentiation of the CNS occurs during gestational days (GDs) 11–21 in rats and is highlighted by a burst of neurogenesis and population of the cerebral cortex and hippocampus by migrating neurons (Guerri, 1998). The newborn cells differentiate into neurons and glia and start to mature, forming axonal and dendritic processes. Ethanol exposure during this time causes decreased neurogenesis and disrupted radial glia, as well as reduced migration and survival of neurons. Additionally, a key maturation called the brain growth spurt, which occurs during the third trimester of gestation in humans, takes place postnatally in rats; during this period a substantial increase in brain size, dendritic arborization, and synaptogenesis, which corresponds to proliferation of astrocytes, oligodendrocyte precursors, and initiation of myelination, occurs from late gestation up to postnatal day (PND) 9 in rats. This time corresponds to a period of major development of glial and myelin structures and suggests a potential effect of ethanol on glial cells (see review by Wilhelm & Guizzetti, 2016).

During these particular periods, changes including morphological and functional alterations affect the balance of synaptic plasticity and alter the protective and supportive functions of glial cells. Alcohol exposure at different stages of development can harm different populations of neurons, glial cells, and neurotransmitter systems. During early stages of cell differentiation, ethanol can alter synapse formation, some types of neurons and glial cells. In other words, cells die when alcohol exposure either prevents them from migrating properly or induces a delayed cell death that occurs after migration, even though exposure occurred before migration started. Moreover, multiple mechanisms may operate simultaneously to produce abnormal cell development or cell death. To better understand the mechanisms and ethanol actions during brain development, different kinds of animal models have been used.

Animal Models of Prenatal Ethanol Exposure

The effects of alcohol are detrimental throughout the developing nervous system, and therefore heavy alcohol exposure can be harmful to the fetus at any stage of gestation; moderate doses that cause lower BACs can also have long-lasting effects. For a greater understanding of alcohol effects on brain development and behavioral effects of PEE, several animal models have been developed. At the structural level, rodent models of fetal alcohol spectrum disorder (FASD) exhibit similar brain alterations as those seen in humans. There are several animal models that can be used to study the structural and functional deficits caused by PEE. Regarding the variability of experimental protocols using rodents to study the effects of alcohol during the prenatal period, there are three major methods of ethanol administration commonly used: ingestion (through liquid diet, water, or near beer, or intubation), injection, or inhalation (see Fig. 2.1).

Ingestion

Dietary. The liquid diet model developed by Lieber and DeCarli is one of the most commonly utilized routes of delivery in rodent models of ethanol exposure during pregnancy and was one of the first models to be developed. In this model the food provided to pregnant dams in their cages is a liquid diet in which a percentage of the calories (usually ∼35%, which equals 6.61%  v/v) is derived from ethanol. The diet has all the nutrients specifically required for pregnancy and is offered throughout gestation as the only source of nutrition. The rats consume on average 12  g ethanol/kg/day (and up to 18  g/kg/day) (Gil-Mohapel, Boehme, Kainer, & Christie, 2010). Pair-fed control groups are used to manage and compare the weight gain by the dams. This group receives an isocaloric diet, with maltose dextrin substituting the ethanol calories. The delivery of the diet usually begins on GD1 of pregnancy and over 3, or sometimes more, days the ethanol is added to the diet gradually (i.e., one-third final ethanol concentration on GD1, two-thirds of final ethanol concentration on GD2, and final ethanol concentration on GD3 and for the remainder of the pregnancy). The BAC produced by the liquid diet depends on the ethanol concentration chosen; it usually fluctuates between 80 and 180  mg/dL in rats.

Voluntary drinking. There are other kinds of oral administration similar to the liquid diet model; ethanol can also be administered through the drinking water. In this case the animal keeps receiving the laboratory food (rat chow), and the ethanol is added to the water bottle. This method is stressless; however, the female rats have to be trained to voluntarily consume a saccharin-sweetened 10% ethanol solution prior to pregnancy. The control group receives saccharin-sweetened water only. Using this paradigm, rodents consume an average of 14  g ethanol/kg/day and the BAC achieved is 120  mg/dL (Choi, Allan, & Cunningham, 2005). Another voluntary drinking model is the beer model, as an alternative to oral self-administration of ethanol without stress. In this method the control group receives near beer and the treated group receives near beer with an added ethanol dose. Near beer makes the solution more palatable than plain water, and it is easier to make rats drink higher doses during the whole pregnancy. It is important to choose a near beer that guarantees 0.0% of ethanol to ensure the correct dose chosen for the study. Using this model the BAC can reach between 80 and 150  mg/dL (Brolese et al., 2014; Samson, Denning, & Chappelle, 1996).

Figure 2.1  Animal models of ethanol exposure. Different kinds of animal models are used to administer ethanol to the rodents. (1) liquid diet; (2) voluntary drinking; (3) injection; (4) intubation (gavage); and (5) chamber with vaporized ethanol.

One of the advantages of the dietary or voluntary drinking models is that much less stress (i.e., less handling) is involved for the dams. Additionally, the techniques are simple; there is less risk of fatality with the dose, and it is less labor-intensive when compared to other methods. However, there are some disadvantages; with these methods it is not possible to be precise with the dose and timing of ethanol administration, and this can lead to variability in the BAC achieved. Also, administration during the extrauterine time, equivalent to the third trimester of pregnancy, could be continued on a liquid diet or voluntary drinking during the suckling period, but it is not possible to control how much ethanol crosses into the breast milk. Thus, dams exposed to ethanol drinking during the suckling period may not engage in appropriate maternal behavior. Nevertheless, this model has been very well used to expose dams to moderate doses and still has validity and significant legitimacy, mimicking the human condition.

Injection

When the study needs to control the exact dose administered and the acute ethanol effects during development, subcutaneous (s.c.) (Ikonomidou et al., 2000) or intraperitoneal (i.p.) (De Licona et al., 2009) ethanol injection, either acutely or across multiple days during gestation, can be useful. This method of administration allows a rapid increase in BAC, reaching an average between 180 and 200  mg/dL, with limited handling-induced stress. However, this method of administration far from resembles ethanol consumption in human beings and may not accurately replicate several important aspects of human PEE.

Intragastric Intubation (Gavage)

Ethanol can also be delivered directly to the stomach of the pregnant dam using an intubation