This collection of six articles is targeted towards specialists in the field, and will be largely inaccessible to a general audience. Experimental methodologies are front and center, and despite substantial reviews and discussions of highly important results, these are somewhat secondary, often serving primarily as illustrations of the application of various experimental techniques. In some cases, this is due to the fact that the techniques are so new or have only been adopted in a small number of laboratories. In this review I will discuss the general topics addressed in each chapter, as well as a small selection of some of the most important findings or issues presented by each chapter, trying to make them as accessible as possible to a general reader.
One major theme running throughout many of the articles is the crucial and comparatively understudied phenomenon of relapse. This is the central focus of Chapter 1, "Advances in Animal Models of Relapse for Addiction Research", which covers three factors well known to contribute to relapse. First, associations between the rewarding effects of drugs and various environmental stimuli due to classical conditioning can serve to reinstate desire for and use of drugs in abstinent animals and humans; e.g., re-exposure to contexts or cues that have been historically predictive of drug reward. This phenomenon has been comparatively well studied in both humans and animals. Second, stress has been shown to consistently reinstate drug seeking and taking. Third, long term changes in neural function that are less well understood can contribute to the potential for relapse which outlasts physical withdrawal for a long and indeterminate period of time. One of the primary advances discussed by the author is the incorporation of the importance of dependence history, including especially the incorporation of repeated negative reinforcement resulting from withdrawal as a factor in relapse, and the subsequent relief when use is resumed, creating an association between drug use and the alleviation of withdrawal symptoms. This factor constitutes a distinct but synergistic form of conditioning that is relevant to understanding relapse.
Chapter 2, "Application of Chronic Extracellular Recording Method to Studies of Cocaine Self-Administration: Methods and Progress" is primarily concerned with advances made possible through extended extracellular recording by means of implanted recording arrays, in particular the short- and long-term effects of cocaine self-administration on activity within the nucleus accumbens. The chapter includes a review of various electrophysiological recording techniques, and their advantages and disadvantages relative to the chronic extracellular recording method, and attempting to provide an "integrated electrophysiological approach" that combines the virtues of the various measures The primary advantages of the chronic extracellular recording method center around the ability to study neural activity in freely behaving animals (rather than, e.g., in anesthetized animals or post-mortem preparations). This is important insofar as many of the effects of drugs depend on the specific behavioral patterns involved during conditioning or drug acquisition. The chronic extracellular recording method allows us to observe both short-term (1 msec) and long-term (hours to days) changes in neural activity within single neurons in a single animal. This permits the dissociation of various stages and components of drug-related behavior, e.g., acute and chronic effects of various drugs, and the pharmacological v. non-pharmacological effects of drugs.
Chapter 3, "Neurochemistry of Addiction: Monitoring Essential Neurotransmitters of Addiction" is a review of current and future directions in techniques for measuring neurotransmitter activity associated with drug use. Methodologically, the focus is on voltammetry (chemical analysis of neurotransmitters via the use of electrical probes) and microdialysis (chemical analysis via the extraction of neurotransmitters from the brain), with some discussion of the use of enzyme-linked biosensors (the use of neurotransmitter- or receptor-specific binding biochemicals). The chapter discusses the trade-offs between these methods with respect to sensitivity, selectivity, speed, and size with a focus on improvements in temporal resolution of both voltammetry (where these enable real-time monitoring), as well as microdialysis.
Chapter 4, "Alcohol Craving and Relapse Prediction: Imaging Studies" is concerned with the use of imaging methods to discern the predictive neural factors specifically involved in relapse. Again, the chapter contains a review of the trade-offs between different imaging methods with respect to selectivity and temporal and spatial resolution. Methods examined include functional magnetic imaging (fMRI), positron emission tomography (PET) and single photon emission computed tomography (SPECT). The author places an emphasis on the co-application of multiple techniques of imaging and other methods to characterize under-researched system properties involved in addiction, such as the distinct contributions of various neurotransmitters to different aspects of the relapse process, e.g. the role of opioids in "liking" (i.e., drug reward) v. the role of dopamine in "wanting" (drug craving), highlighting that relapse can be driven either by cravings resulting from dopaminergic dysregulation, or by the prospect for opioid-mediated reward, and can be blocked by interventions that modulate these systems, e.g., the use of the opioid antagonist naltrexone to block the rewarding effects of drugs.
Among the important results discussed by the author include the fact that long-term use of drugs is associated with various compensatory mechanisms in the brain, believed to be neuroadaptations designed to down-regulate the effects of drugs and restore the system to a state of balance. Such long-term changes likely underlie the fact that exposure to drug-related cues can precipitate anticipatory homeostatic compensations resembling withdrawal, even well beyond the point of acute detoxification, which can in turn reactivate drug seeking in order to alleviate these symptoms. Also discussed is how imaging studies have demonstrated that dysregulation in GABA and glutamate systems that can lead to reduced ability of frontal cortex to control drug-related behavior, and how DA dysfunction during or following detoxification can undermine a return to natural rewards, an essential component of recovery.
Chapter 5, "Integrating Behavioral and Molecular Approaches in Mouse: Self-Administration Studies" focuses on methods for determining the contributions of single genes to addiction, which allows researchers to target addiction-related changes to intracellular proteins inaccessible to pharmacological manipulations, and to examine protein synthesis in specific cell types in specific regions. Advances in methodology discussed include the use of inducible knockout (removal of genes) and transgenic (addition of DNA) modifications, permitting the ability to selectively turn genes on or off at particular times, avoiding widespread confounding developmental adaptations to the induction of gene alterations early in life. The author also emphasizes the importance of species and strain differences among experimental animals in modeling addictive processes, with different strains of mice, for example, showing markedly distinct responses to various stages and types of addictive behavior such as rates and dosages required for the acquisition of self-administration and drug seeking behavior during abstinence, different responses to different types of drugs, different patterns of response to natural rewards, and different learning mechanisms. Studies of such strain differences indicate that there is separate neurobiological regulation of drug-taking and drug-seeking.
Chapter 6, "Neuroeconomics: Implications for Understanding the neurobiology of Addiction" addresses the intersection of behavioral economics and neuroscience to understand decision-making. These techniques (such as the measurement of future discounting) are applied to discern similarities in the underlying processing of economic rewards to processing of other rewards, as well as the study of decision making in addiction and other pathological conditions, some of which bear a strong resemblance to addictive behavior. The authors specifically focus on situating addictive behavior within its social context. Social rewards are intrinsically rewarding, and are as motivating to humans as other natural rewards, such as food, sometimes even more so. Considering the social aspects of addiction provides insight into the ways in which addiction can be facilitated by social contexts associated with drug use, the way in which addiction can cause dysregulation in the usual reward systems associated with social relations, as well as the ways in which social reward can be used to treat addiction.
In short, this volume introduces a host of important advances in the measurement of addictive processes at the genetic, physiological, neural, behavioral and psychological levels, as well as a wide variety of fascinating findings that will certainly play a major future role in both pure research and the pragmatics of treating addiction. Researchers at the forefront of addiction research will certainly want to consider the potential applications of these tools and findings for their own research.
© 2011 Jason Clark
Jason Clark studied philosophy and neuroscience at Syracuse University, where he received a PhD in philosophy in 2009. His main interests are in the evolution of human emotions, and emotion theory more generally. From 2009-2012, he will be a post-doc in the animal emotionale project at the University of Osnabrueck in Germany.