ABSTRACT

In recent years, gene knock-out studies have greatly expanded understanding of the molecular basis of drug reward and drug addiction. One of the consequences of these studies has been to produce a more pluralistic view of the underlying neurochemical mechanisms that mediate drug reward after the development of a strongly dopamine-centered view in the 1980s. This is not to say that dopamine does not have a central role in drug reward and drug addiction, but rather a fuller examination of these mechanisms involves the complex neurocircuitry of which dopamine systems are a part. This view is not new, but has been expressed from a variety of perspectives. Gene knock-out studies have indicated a particular approach to examining the nature of interactions between different parts of this circuitry. This chapter will focus on the role of serotonin, and in particular the serotonin transporter (SERT), in drug reward. This more pluralistic perspective became apparent in gene knock-out studies of the rewarding effects of drugs of abuse which demonstrated that deletion of the dopamine transporter (DAT) did not eliminate the rewarding effects of cocaine, and subsequent findings that implicated a critical role of SERT in a variety of circumstances. These studies also validated the central role of dopamine in drug reward, and consequently the role of SERT must be considered largely from the point of view of interactions with dopamine systems.

ABSTRACT

The serotonin transporter (SERT), a membrane protein responsible for the reuptake of extracellular serotonin, is a prominent target of antidepressants. Moreover, a polymorphism of this gene that decreases serotonin uptake has been linked to depression. However, the role of SERT in depression is poorly understood. Several functional impairments, notably in behavior, sleep, and response to stress, are consistently found in animal models of depression, but consistent correlation with serotonergic dysfunction has not been demonstrated. Nevertheless, in certain genetic backgrounds, the same impairments are also found in mutant rodents in which serotonin transport has been abolished. These impairments are also observed in adult rodents after a transient disruption of serotonin transport during the first postnatal month. Conversely, they may be prevented in mutant rodents by normalizing serotonergic transmission postnatally. Therefore, the function of the serotonin transporter during postnatal development is critical for the proper maturation of brain circuits, while susceptibility to depression caused by reduced serotonin transporter function may be determined, in part, during development.

INTRODUCTION

Depression is one of the most common psychiatric disorders in developed countries. This disease affects mood, psychomotor activity, neurovegetative functions, and cognition (Fava and Kendler,2000). Estimates indicate a lifetime prevalence up to 20% for major depression (Blazer, 2000; Fava and Kendler, 2000; Kornstein et al., 2000), and the likelihood of experiencing this disorder is twice as high in women as in men (Kornstein et al., 2000). Depression can be a lifelong episodic disorder with multiple recurrences.

The serotonin transporter (SERT) has gained research popularity due to its prominent role in normal and aberrant brain processes. This key brain protein reuptakes serotonin from the synaptic cleft into presynaptic neurons, thereby modulating serotonergic neurotransmission. An entire class of psychotropic drugs, the serotonin reuptake inhibitors (SRIs), is dedicated to the action of this single protein. The fact that selective SRIs are becoming the world's most prescribed psychotropic medication emphasizes the utmost importance of SERT research for clinical psychiatry. The growing body of knowledge on SERT's role in the brain also emphasizes the need for experimental models of SERT function. Collectively, this has stimulated the compilation of this book, the aim of which is to provide a comprehensive update spanning the breadth of SERT research from animal models to their clinical parallels.

Although the exact functional mechanisms of SERT are not yet fully elucidated, it is thought to contain 12 hydrophobic transmembrane domains and to bind Na+, Cl−, and serotonin simultaneously. This results in a conformational change in the molecule, forming a barrier against the exterior of the cell, and opens the protein inwardly to the cytoplasmic membrane. The serotonin then disassociates from SERT, and the transporter returns to its original conformation receptive to extracellular serotonin once again. This process is the main mechanism of serotonin modulation in the brain, and the dysregulation of this system can affect brain and behavior markedly.

MIND-BODY: WHAT IS THE PROBLEM?

The mind-body problem has been under discussion for more than 2000 years, and it is still a live issue. One might even go further and say that with the advent of the neurosciences it has become a more hotly debated issue than ever. This is explained by a simple fact. Although the mind-body problem is fundamentally a philosophical one, the progress made in solving it is to a large extent dependent on the progress of neuroscientific knowledge. The philosophical debate is essentially about how to interpret the facts in the light of undisputed or at least widely accepted criteria of rationality and coherence. But these facts are primarily provided by the neurosciences. As new facts come to light, interpretations must be reconsidered. Several of the models of the mind under discussion today can be found as early as in the dialogue Phaedo, in which Plato defends a substantialist conception of the mind against a number of “materialist” conceptions that leave no room for immortality and knowledge of eternal forms. But only the remarkable progress, since its beginnings in the eighteenth century, of empirical investigations into the working of the mind and its substrate, the brain, has provided the resources necessary for a realistic assessment of these models and for leaving behind speculation and wishful thinking. Of course, the converse is also true.

The field of neuroscience has “evolved” as an inter-disciplinarity of neurobiology, anatomy, physiology, pharmacology, and psychology, to focus upon the structure and function of nervous systems (in both human and non-human organisms). Growing from older iterations of experimental and physiological psychology, neuroscience initially addressed mechanisms of neural function as related to sensory and motor systems, learning and memory, cognition, and ultimately consciousness. These basic approaches fostered subsequent studies that were specifically relevant to medicine (e.g. neurology, psychiatry, and pain care), and, more recently, social practices (such as consumer behavior, and spiritual and religious practices and experiences).

In the United States, the congressionally dedicated Decade of the Brain (1990–2000) provided political incentive to support neuroscientific research with renewed intensity. As a result, significant discoveries were achieved in a variety of areas including neurogenetics, neuro- and psychopharmacology, and neuroimaging. This progress was not limited to the United States; rather, the Decade of the Brain served to provide a funding base that catalyzed international cooperation. We feel that this was the beginning of a “culture of neuroscience” that was created from, and continues to engage a world-wide “think tank” atmosphere that facilitates academic, medical, and technological collaboration, rapid scientific developments, and widely distributed effects in research, health care, and public life.

In addition, neuroscience has become a venue for the employment of cutting edge biotechnology that is extending the capabilities and boundaries of both investigation and intervention.

THE HUMAN CONDITION: STRIVINGS TO FLOURISH

From a naturalistic perspective, humans, like any species, are defined both by their biology and by how this biology has established certain capabilities and limitations. In inhabiting diverse environments, the human species has been forced to confront such limitations (of form and function), and develop resourcefulness to survive in the niche(s) we occupy. And, as in other species, our survival is dependent, at least in part, upon the ability to maximally adapt to, and/or compensate for, both biological and environmental constraint(s). Yet, as evidenced by history, human beings are achievers. This is shown by the artifacts of our existence: social structures, tools, and implements that represent a striving to overcome our (self-apparent and/or self-declared) frailties and shortcomings. In short, humans show a trend toward not merely surviving, but flourishing (Gow 2002).

We propose that one neuroanthropologic view of human history could depict a species specific tendency toward enhancing our function, so as to occupy and subordinate increasingly broader niche(s) (Havercamp & Reiss 2003). Thus, human history is punctuated by our attempts to break the bonds of biological restrictions, and “be more than we are”; our relative dependence has been overcome by forming sociocultural cooperatives, our fears appeased by myth and assuaged by knowledge, and our weakness(es) compensated by intellect and invention. In this way, we can (and perhaps should) view our history as defined by its artifacts of biology, society, and machination (BioSoMa), in interaction.

Neuroethics is a truly exciting endeavor. For a very long time, human beings have puzzled over questions concerning the fundamental nature of the world in which we live and of ourselves. Why be moral? Do we have free will? How should we behave towards one another? Can we know anything? These are the questions of the discipline that has come to be called philosophy. For most of human history, these questions were pursued using the full range of tools available, but sometime in the recent past – perhaps as late as the nineteenth century – the philosophical questions became separated from scientific questions. Each was seen to have its own distinctive methodology, its own tools and conceptual resources; philosophers thought it was a mistake to think that science could shed much light on their research.

Neuroethics, along with a number of related developments (experimental philosophy; philosophy of biology; cognitive science) is part of a backlash against this separation. Science is the crowning achievement of human epistemology; its distinctive methods help to compensate for our cognitive limitations and to build a cumulative and reliable body of knowledge to an extent unprecedented in human history. For philosophers to cut themselves off from this body of knowledge would be madness. But philosophers have skills, in conceptual analysis and logic, that prove invaluable in understanding the human significance of science.

INTRODUCTION

The extraordinary increase in scientific knowledge achieved in the past century has generated numerous challenges for ethics. As a result, the field of bioethics has expanded, with an increased emphasis on a need for scientific advances to be accompanied by an examination of the humanistic implications of biomedical research.

In this regard, the intersection of ethics and neurogenetics is exceptionally significant because it connects the tensions found in discussions regarding brain–mind distinctions with the difficulties encountered in delineating mental health. At this intersection, epistemological issues arise as researchers and health care professionals attempt to relate human experiences – such as pain, suffering, illness, conscience, or even the awareness of self-existence – to physical correlates – such as genetic sequence variations and protein deposits – and vice versa. Hence, this intersection of ethics and neurogenetics involves a combination of issues that cannot be adequately interpreted, understood, or addressed from any single vantage point.

To explicate the dynamics of this intersection of ethics and neurogenetics, this chapter will focus on certain specific areas of neurogenetics – behavioral genetics, pharmacogenomics, and genetic testing – in order to reveal how scientific understanding and its accompanying assumptions can better facilitate the ethical decisionmaking process. Particular attention will be given to the problematic effects and consequences a reductionistic scientific framework can have at this intersection of neurogenetics and ethics, and to how a more integrative approach, such as an emergentistic framework, can be used to address these issues more completely.

Can we read minds? Can neuroimaging serve as a new form of liedetector or reveal the essence of who we are? Should we be fearful that in the near future our personal thoughts will become publicly available through neuroimaging? Popular science and the media in particular have emphasized the mind-reading powers of neuroimaging. Questionable practices relying on such beliefs have begun to surface. Although appealing, these beliefs expose functional neuroimaging to potential abuse, and the equation between neuroimaging and mindreading betrays the sophisticated nature of tools such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET). At stake is a potential misunderstanding of the true capabilities of functional neuroimaging – a misunderstanding that can be perpetuated if the mind-reading paradigm is not thoroughly examined.

The goal of this chapter is not to consider the numerous ethical challenges in neuroimaging research in detail, since many general overviews have been published (Downie & Marshall 2007; Illes et al. 2007; Marshall et al. 2007; Racine & Illes 2007a). Instead, it specifically reviews ethical and social challenges related to the interpretation of functional neuroimaging research, in and outside of clinical care, in order to critically examine the mind-reading potential of functional neuroimaging. This popular portrayal of neuroimaging must be addressed in the context of a balanced discussion of risks and ethical issues related to neuroimaging and neuroscience.

In this nascent age of “neurolaw”, “neuromarketing”, “neuropolicy”, “neuroethics”, “neurophilosophy”, “neuroeconomics”, and even “neurotheology”, it becomes necessary to disentangle the science from the scientism. There is a host of cultural entrepreneurs currently grasping at various forms of authority through appropriations of neuroscience, presented to us in the corresponding dialects of neurotalk. Such talk is often accompanied by a picture of a brain scan, that fast-acting solvent of critical faculties.

Elsewhere in this issue, O. Carter Snead offers a critique of the use of brain scans in the courtroom in which he alludes to, but ultimately brackets, questions about the scientific rigor of such use. For the sake of argument, he proceeds on the assumption that neuroimaging is competent to do what it is often claimed to do, namely, provide a picture of human cognition.

But there are some basic conceptual problems hovering about the interpretation of brain scans as pictures of mentation. In parsing these problems, it becomes apparent that the current “neuro” enthusiasm should be understood in the larger context of scientism, a pervasive cultural tendency with its own logic.

INTRODUCTION

Functional neuroimaging techniques, such as functional MRI (fMRI), positron emission tomography, and others have proven to be powerful methods for examining brain function that have led to major advances in our understanding of the brain and various neurological conditions. fMRI has provided researchers with a non-invasive tool to delineate basic neurophysiological processes and found use in clinical applications such as pre-surgical mapping of important functional areas that can guide neurosurgical cases. More thought-provoking examples include identifying a distinct response to romantic love, different from sexual arousal (Aron et al. 2005) and the development of an fMRI-based neural feedback system to improve management of pain (deCharms et al. 2005).

Since 1992 there has been an exponential increase in the number of papers published on fMRI (Bandettini 2007). This is in part due to the fact that fMRI as a technique only began to be used in the early 1990s but also due to the ready availability of MRI scanners capable of conducting these studies. Correspondingly, there has been an explosion of media coverage of this branch of neuroscience, driven in part by the compelling portrayal of these results with the pictures and movies to which these techniques readily lend themselves (Racine et al. 2005). Neuroscientific explanations combined with richly detailed and beautiful pictures depicting the results from fMRI experiments have been shown to increase the perceived validity of a finding even when the underlying science is questionable (McCabe & Castel 2008; Weisberg et al. 2008).

The past twenty years have seen remarkable progress in theoretical and clinical neuroscience. Functional neuroimaging can display realtime activation in brain regions correlating with cognitive and affective processes. Brain scans have improved the diagnosis of a range of neurological and psychiatric disorders. They can also be used to monitor the progression of these disorders and the metabolic effects of drugs used to treat them. Psychopharmacology has developed generally safer and more effective therapeutic agents for diseases of the brain and mind. Some of these agents can be used to enhance normal cognitive functions. Electrical and magnetic stimulation of the brain can control symptoms of neurological and psychiatric disorders that have not responded to other treatments. Stem-cell-based neurotransplantation in the field of restorative neurosurgery holds promise for reversing damage from neurodegenerative diseases, stroke, and spinal cord injury. Neural prostheses may enable people immobilized by paralysis to translate their intentions into actions. All of these measures and interventions in the brain have great potential to benefit a significant number of people, enabling them to become more independent and have better quality of life.

There is also a dark side to these drugs and techniques. Atypical antipsychotics can increase the risk of patients dying from sudden heart failure. Brain scans are visualizations of statistical analyses based on a large number of images and are inaccurately described as pictures of what actually occurs in the brain.

INTRODUCTION

Although adult-to-adult organ transplantation has developed in the past 50 years in the surgical arenas, neurosurgeons have had no options to take out damaged brain areas and to implant new tissue from adult donors. Adult neurons do not survive isolation and transplantation. The neurosurgeon, moreover, cannot take out malfunctioning brain tissue or cells without severely damaging the nervous system in its still intact parts. However, the possibility of neural tissue repair by implantation rather than by transplantation became an option, with observations in animal research that has shown that immature nerve cells not only survive and mature following implantation in the adult nervous system, but also integrate and become functionally active in existing networks. Implantation of neurons to supplement lost neurons in cases of neurodegenerative diseases and neurotrauma thus became a challenging perspective for the neurosurgeon.

Parkinson's disease (PD) was the test bed disease for this approach, as it is primarily characterized by a defined loss of neurons in the substantia nigra serving a dopaminergic input in the striatum of the central nervous system (CNS). Grafting fetal substantia nigra dopaminergic cells into the striatum of substantia nigra-lesioned rats reversed the motor disturbances, and similar studies in non-human primate models were successful as well. These results prompted clinical trials with human fetal dopaminergic neurons implanted into the striatum of PD patients. The grafted neurons indeed survived and became active cells as shown by functional brain scans.

INTRODUCTION

With the Age of Enlightenment, a sociocultural transformation process began on a large scale. This process can defined concisely by the triple trends of individualization, secularization, and scientification (Kohls 2004; Benedikter 2001; 2005). As a consequence, rational and scientific concepts replaced those of religion and spirituality in social life. This was especially true for the role of institutionalized religion as a genuine compass for social values and an epistemological framework as well as for morally and socially acceptable behavior. In the main, religious adherence was gradually substituted by a pluralism of scientific concepts and by philosophical systems. With the rise of academic psychology in the 1880s as a new, independent scientific field of inquiry, the explaining of consciousness and its underlying mechanisms became the focus of science in accordance with the aforementioned Zeitgeist as predicted by French thinker Auguste Comte. Psychology as a secular, rational, and “measuring” science overtook religion and philosophy as the new center of intellectual and perhaps social gravity. It was within this new paradigm that the “essence of the human being” was now to be studied.

These developments had enormous impact on the explicit and implicit interpretational frameworks for explaining consciousness and the scientific theories of mind that emerged of the time. Of note is that, in the first half of the nineteenth century, a paradigm shift also occurred in biology and medicine. The focus of studies about the nature of mind moved from anatomy to physiology.

INTRODUCTION

A major characteristic of the information era is the continuous increase in interconnectedness created by a worldwide electronic network: the Internet. Thus, through such electronic linkage, our minds move closely together even if spatially separated by thousands of miles. In this scenario the computer usually creates an interface between us and the digital world. An ultimate connectedness between our minds and the information pool of the Internet can be fantasized within a science fiction scenario as represented in the movie The Matrix. Brain–mind operation could be connected to a computer, which might afford an opportunity to enter a direct interaction with a virtual world. Such brain – machine interfaces would have to fulfill a two-directional task: one is to give the human user the opportunity to communicate with the system by sending signals to the computer (which can be achieved either by voluntary control of a computer, or by a computer's ability to engage and interpret our thoughts); the other is brain stimulation by a device in order to let us experience the virtual world. Whereas the first task attempts to replace the keyboard and mouse of a computer, the second tries to substitute the computer screen and audio system. Current multimedia consumer technology already offers great possibilities available in the modern home cinema. In terms of the information transfer rate of such visual and auditory stimulating systems, one should note that they require a far higher information flow compared with the control devices (e.g. mouse and keyboard) of a computer.