- Email: [email protected]
Introduction to the Neural Basis of Addiction
Chapter 1
Introduction to the Neural Basis of Addiction Mary M. Torregrossa Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
Drug addiction is a devastating illness characterized by repeated cycles of uncontrolled consumption, periods of abstinence or withdrawal, and relapse to use. According to the latest survey by the Substance Abuse and Mental Health Services Administration, in the United States, 7.8% of the adult population met the criteria for diagnosis of a substance use disorder for alcohol, prescription drugs, or illicit substances in 2016. Lifetime prevalence rates are even higher, and many children and adolescents under the age of 18 also suffer from substance use disorders/addiction, making the actual number of people affected by addiction much higher. Moreover, substance abuse produces a huge cost to society, with a reported $740 billion dollars lost annually due to crime, health care, and lost productivity. Thus, drug addiction is a serious and growing public health problem in our society, but unfortunately very few effective treatments exist. In order to develop effective treatment strategies, a substantial amount of clinical and preclinical research has been conducted over the past several decades. However, for many years, addiction research suffered from the popularly held belief that the “addict” was to blame for their problem, and that individuals could quit using if they simply had enough will power. With the advent of animal models of addiction in nonhuman primates and in rodents, where the animal could choose to perform a behavior to receive the drug, scientists began to understand that drugs of abuse exert powerful control over behavior in a manner that cannot simply be attributed to a character flaw. Animal models allowed researchers to recognize addiction as a progressive disease that has a biological basis in the brain. Early studies used pharmacological and biochemical approaches to determine which biological molecules were targeted by different classes of drugs of abuse, which allowed researchers to identify the receptors and transporters that were responsible for the euphoric effects of drugs like heroin, cocaine, and amphetamine. Research was further advanced by the development of in vivo microdialysis, which allowed scientists to measure changes in extracellular neurotransmitter release in response to drug exposure. Dopamine was found to increase dramatically in several brain regions, most notably the nucleus accumbens, in response to the administration of most classes of abused substances. The rodent studies were supported by neuroimaging studies in human drug users, providing evidence for cross-species mechanisms of action and the translational value of the animal models. Henceforth, research into the neuroscience of addiction rapidly expanded. Initial neuroscience research in addiction focused on the dopamine system due to its obvious importance in mediating the reinforcing or rewarding effects of abused drugs. Studies using electrical stimulation or lesions also began to isolate the specific brain regions that mediated the ability of drugs to motivate behavior. Over the years, numerous scientific advances, particularly in genomics and molecular biology, further increased our understanding of the long-term effects of drugs of abuse on the brain and the body. In particular, the identification of long-lasting changes in gene expression and synaptic function across multiple brain regions further confirmed that addiction is a progressive and chronic brain disorder. Unfortunately, despite this increase in our understanding of the biology of addiction, there still has been little advance in developing effective treatments. In more recent years, however, there has been an astoundingly rapid increase in our understanding of the neural mechanisms of addiction, which is providing hope that better addiction treatments may be on the horizon. First, the sophistication of our animal models has increased exponentially in the past 10 years. Many recent studies have used animal models that better reproduce the core features of addiction, including progressive increases in intake, negative affect, and use despite adverse consequences. In other words, instead of simply studying the neural mechanisms underlying the initial reinforcing effects of drugs that are observed in almost all animals (and humans), animal models now study the development of uncontrolled and compulsive drug use. Second, many studies now recognize that there are large individual differences in the
Neural Mechanisms of Addiction. https://doi.org/10.1016/B978-0-12-812202-0.00001-4 Copyright © 2019 Elsevier Inc. All rights reserved.
1
2 Neural Mechanisms of Addiction
propensity for animals to exhibit an addiction phenotype. These studies have improved our understanding of the genetic vulnerabilities and brain mechanisms that lead some people to develop addiction, while others can use socially without problem. Furthermore, there have been substantial technological advances that have allowed scientists to investigate the neural mechanisms of addiction with finer detail and precision than was possible even 5 years ago. These technological advances in research tools are beginning to lead to completely novel methods for treating neurological diseases that may not require the development of a “magic pill,” but rather will allow us to rewire disrupted brain circuits. Thus, the purpose of this book is to provide the reader an updated view on our understanding of the neural mechanisms underlying addiction, with a focus on how emerging technologies, applied to improved animal models, is leading to a new understanding of this complex disorder. Each chapter was written by an expert in addiction neuroscience, who provides a unique perspective on emerging themes in the field based on their own ongoing research. The first chapter provides a comprehensive overview of the most common animal models used in addiction neuroscience, including a description of the most recently developed models, which are leading to an increased understanding of the neural mechanisms underlying the core features required for diagnosis of a substance use disorder. Subsequent chapters focus on the latest developments in our understanding of how the brain is altered by drug exposure with descriptions of changes in molecules, synaptic function, neuronal morphology, circuits, and systems. In addition, several chapters discuss how drugs of abuse influence specific systems such as learning and memory, decision making, and even circadian rhythms to further perpetuate the disease. Finally, the book includes chapters describing novel treatment strategies, such as neuropeptide and stimulation-based therapies. Several chapters included discussion of drug class-specific neuroadaptations, such as effects that are specific to alcohol, opioids, or cocaine, which will clearly be an important consideration for determining effective treatment strategies for each individual. However, much work still needs to be done to compare across classes of drugs, and a substantial number of recent and exciting findings in the field may only apply to one type of drug. As technologies continue to emerge and their application to the neuroscience of addiction progresses, it is clear that our understanding of the disorder will improve. Thus, this is an exciting time to be investigating such a critical health problem in our society, and the developments described in this book are paving the way for true progress in tackling this devastating disease.
Introduction to the Neural Basis of Addiction Mary M. Torregrossa Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
Drug addiction is a devastating illness characterized by repeated cycles of uncontrolled consumption, periods of abstinence or withdrawal, and relapse to use. According to the latest survey by the Substance Abuse and Mental Health Services Administration, in the United States, 7.8% of the adult population met the criteria for diagnosis of a substance use disorder for alcohol, prescription drugs, or illicit substances in 2016. Lifetime prevalence rates are even higher, and many children and adolescents under the age of 18 also suffer from substance use disorders/addiction, making the actual number of people affected by addiction much higher. Moreover, substance abuse produces a huge cost to society, with a reported $740 billion dollars lost annually due to crime, health care, and lost productivity. Thus, drug addiction is a serious and growing public health problem in our society, but unfortunately very few effective treatments exist. In order to develop effective treatment strategies, a substantial amount of clinical and preclinical research has been conducted over the past several decades. However, for many years, addiction research suffered from the popularly held belief that the “addict” was to blame for their problem, and that individuals could quit using if they simply had enough will power. With the advent of animal models of addiction in nonhuman primates and in rodents, where the animal could choose to perform a behavior to receive the drug, scientists began to understand that drugs of abuse exert powerful control over behavior in a manner that cannot simply be attributed to a character flaw. Animal models allowed researchers to recognize addiction as a progressive disease that has a biological basis in the brain. Early studies used pharmacological and biochemical approaches to determine which biological molecules were targeted by different classes of drugs of abuse, which allowed researchers to identify the receptors and transporters that were responsible for the euphoric effects of drugs like heroin, cocaine, and amphetamine. Research was further advanced by the development of in vivo microdialysis, which allowed scientists to measure changes in extracellular neurotransmitter release in response to drug exposure. Dopamine was found to increase dramatically in several brain regions, most notably the nucleus accumbens, in response to the administration of most classes of abused substances. The rodent studies were supported by neuroimaging studies in human drug users, providing evidence for cross-species mechanisms of action and the translational value of the animal models. Henceforth, research into the neuroscience of addiction rapidly expanded. Initial neuroscience research in addiction focused on the dopamine system due to its obvious importance in mediating the reinforcing or rewarding effects of abused drugs. Studies using electrical stimulation or lesions also began to isolate the specific brain regions that mediated the ability of drugs to motivate behavior. Over the years, numerous scientific advances, particularly in genomics and molecular biology, further increased our understanding of the long-term effects of drugs of abuse on the brain and the body. In particular, the identification of long-lasting changes in gene expression and synaptic function across multiple brain regions further confirmed that addiction is a progressive and chronic brain disorder. Unfortunately, despite this increase in our understanding of the biology of addiction, there still has been little advance in developing effective treatments. In more recent years, however, there has been an astoundingly rapid increase in our understanding of the neural mechanisms of addiction, which is providing hope that better addiction treatments may be on the horizon. First, the sophistication of our animal models has increased exponentially in the past 10 years. Many recent studies have used animal models that better reproduce the core features of addiction, including progressive increases in intake, negative affect, and use despite adverse consequences. In other words, instead of simply studying the neural mechanisms underlying the initial reinforcing effects of drugs that are observed in almost all animals (and humans), animal models now study the development of uncontrolled and compulsive drug use. Second, many studies now recognize that there are large individual differences in the
Neural Mechanisms of Addiction. https://doi.org/10.1016/B978-0-12-812202-0.00001-4 Copyright © 2019 Elsevier Inc. All rights reserved.
1
2 Neural Mechanisms of Addiction
propensity for animals to exhibit an addiction phenotype. These studies have improved our understanding of the genetic vulnerabilities and brain mechanisms that lead some people to develop addiction, while others can use socially without problem. Furthermore, there have been substantial technological advances that have allowed scientists to investigate the neural mechanisms of addiction with finer detail and precision than was possible even 5 years ago. These technological advances in research tools are beginning to lead to completely novel methods for treating neurological diseases that may not require the development of a “magic pill,” but rather will allow us to rewire disrupted brain circuits. Thus, the purpose of this book is to provide the reader an updated view on our understanding of the neural mechanisms underlying addiction, with a focus on how emerging technologies, applied to improved animal models, is leading to a new understanding of this complex disorder. Each chapter was written by an expert in addiction neuroscience, who provides a unique perspective on emerging themes in the field based on their own ongoing research. The first chapter provides a comprehensive overview of the most common animal models used in addiction neuroscience, including a description of the most recently developed models, which are leading to an increased understanding of the neural mechanisms underlying the core features required for diagnosis of a substance use disorder. Subsequent chapters focus on the latest developments in our understanding of how the brain is altered by drug exposure with descriptions of changes in molecules, synaptic function, neuronal morphology, circuits, and systems. In addition, several chapters discuss how drugs of abuse influence specific systems such as learning and memory, decision making, and even circadian rhythms to further perpetuate the disease. Finally, the book includes chapters describing novel treatment strategies, such as neuropeptide and stimulation-based therapies. Several chapters included discussion of drug class-specific neuroadaptations, such as effects that are specific to alcohol, opioids, or cocaine, which will clearly be an important consideration for determining effective treatment strategies for each individual. However, much work still needs to be done to compare across classes of drugs, and a substantial number of recent and exciting findings in the field may only apply to one type of drug. As technologies continue to emerge and their application to the neuroscience of addiction progresses, it is clear that our understanding of the disorder will improve. Thus, this is an exciting time to be investigating such a critical health problem in our society, and the developments described in this book are paving the way for true progress in tackling this devastating disease.