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Pathways of Addiction: Opportunities in Drug Abuse Research 3 Neuroscience Over the past 20 years, drug abuse research has contributed to impressive gains in the neurosciences and in our understanding of brain function. Neuroscience research as it relates to drug abuse has advanced knowledge about neurotransmitters and neural pathways, and has yielded information about brain mechanisms both under normal conditions and when affected by drugs of abuse. That knowledge has already been translated into improved clinical care and has had significant impacts on other scientific disciplines. The goal of neuroscience research in the area of drug dependence is to determine the actions of abusable drugs on the brain that result in dependence and to determine the neural substrates that make one individual inherently vulnerable to such actions and others relatively resistant. That knowledge can have an impact on the ways in which drug abuse and dependence are managed clinically and on the way they are viewed by our society. Neuroscience research can add to the knowledge base in the science of addiction and provide information for the development of more effective medications to treat drug dependence. New pharmacotherapies will significantly improve the effectiveness of psychosocial interventions. It must be emphasized that it is impossible to predict all of the benefits of ongoing fundamental neuroscience research in the drug abuse field. Many of the advances that will be discussed throughout this chapter were unanticipated, yet clearly improved public health in many ways. The interface between basic neurobiology and the applied neuroscience of drug abuse research has been a rich and fruitful part of the approach termed integrative neuroscience. Drug abuse research has con-
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Pathways of Addiction: Opportunities in Drug Abuse Research tributed to many discoveries in neuroendocrinology and the neurobiology of stress including the discovery of opioid peptides and stress neurotransmitters, the neurochemical control of stress hormone, and reproductive hormone release. In addition, drug abuse research impacts on disciplines as diverse as molecular biology, the neurobiology of emotional behavior, and the neurobiology of cognitive function in the effort to understand the complex phenomena associated with a course of drug dependence. The following chapter contains a technical overview illustrating the complexity of the neurotransmission processes involved in the neurobiology of drug dependence, a description of the many advances in understanding the neurobiological basis for drug dependence, a summary of gaps and needs, and finally recommendations for future research. The technical overview provides the vocabulary and basic concepts necessary to understand how drugs can interact at many different functional levels including the molecular, cellular, and systems levels. The section on accomplishments details the significant advances in understanding the neurobiology of drug reinforcement and the beginnings of our understanding of the processes of neuroadaptation to these systems associated with dependence. In addition, the chapter describes progress in human imaging research and the recent developments in understanding brain mechanisms of pain and analgesia. Gaps and needs are identified that focus on the chronic consequences of drug exposure in brain systems implicated in the motivational effects of drug dependence at the molecular, cellular, and system levels of analysis. Finally, the chapter identifies numerous areas for research opportunities that will aid in our understanding of the neurobiology of drug dependence and help integrate this basic research with the applied problems of vulnerability, treatment, and prevention of drug abuse. These areas include molecular neurobiology, genetics research, animal models of dependence, brain imaging, co-occurring psychiatric disorders, HIV models, neurotoxicity of drug dependence, immunology, analgesia and pain, and relapse and prolonged abstinence. NEUROTRANSMISSION AND ITS EFFECTS The human brain is composed of an enormous number of neurons, with estimates ranging from 10 billion to 10 trillion (reviewed by Kandel et al., 1991; Hyman and Nestler, 1993). These neurons are organized in such a way that they communicate with one another in a highly intricate and specific manner. This process of communication is referred to as synaptic transmission. In a simplified scheme, neurons consist of a cell body or soma; mul-
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Pathways of Addiction: Opportunities in Drug Abuse Research tiple dendrites that arise from the cell body to receive incoming signals; and usually a single axon that also arises from the cell body. Axons can be very long and give rise to outgoing signals through their branched ends (terminals). A single neuron can possess thousands of axon terminals and thereby form connections (called synapses) with up to thousands of other neurons. The brain utilizes a chemical process of neurotransmission to transfer information across synapses. Briefly, an electrochemical impulse produced by changes in concentrations of ions across the axon membrane travels down the axon of one neuron, invades the axon's nerve terminals, and triggers the release of a chemical substance, called a neurotransmitter, from the terminals. The neurotransmitter diffuses across the synaptic cleft (the space between the two neurons) and binds to specific receptor proteins located on the surface of the cell, or plasma membrane, of the next neuron. The binding of a neurotransmitter to its receptor activates the receptor and causes a change in the flow of ions across the cell membrane, which can either lead to or inhibit the generation of electrical impulses in that next neuron. The neurotransmitter stimulus is then "turned off" either by enzymatic degradation in the synaptic cleft or by proteinmediated reuptake of neurotransmitter into the nerve terminal. Neurons receive incoming signals from hundreds or thousands of nerve terminals. Whether a neuron fires an impulse is determined by the summation of those numerous inputs. Neuronal membranes contain classes of proteins, termed ion pumps, that maintain unequal concentrations of ions (e.g., Na+, K+, Ca2+, C1-) between the outside and inside of the cell. The most important pump is termed the Na+-K+ ATPase (adenosine triphosphatase). Neurons are polarized, meaning that the inside of the cell is negatively charged with respect to the outside. Neurons also possess other proteins in their plasma membrane, termed ion channels, that allow passage of specific ions across the cell membrane. Neurotransmitters regulate the electrical properties of neurons by activating or inhibiting the activity of specific types of ion channels. Neurotransmitters and Their Receptors The majority of neurotransmission in the brain is performed by amino acid neurotransmitters, which are contained in two-thirds of all synapses in the brain. Glutamate is the major excitatory neurotransmitter in the brain because its receptor channel permits Na+ (and in some cases Ca2+) to flow into the cell; the major inhibitory neurotransmitter in the brain is gamma-aminobutyric acid (GABA) (GABA's receptor channel carries C1 into the cell). Most other neurotransmitters in the brain bind to receptor proteins
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Pathways of Addiction: Opportunities in Drug Abuse Research that do not contain ion channels within their structures. Rather, these receptors produce their physiological effects by interacting with a special class of proteins, called G proteins, which are composed of three variable molecules, called alpha, beta, and gamma subunits. When a neurotransmitter binds to a G protein-coupled receptor, the G protein dissociates into a free alpha and free beta-gamma subunit, which then interacts with many other cellular proteins to produce a variety of physiological effects. For example, specific types of ion channels can be induced to increase or decrease their activity by the action of G protein subunits. Second Messengers and Protein Phosphorylation The G protein-coupled receptors also influence many other neural processes through complex pathways of intracellular messengers. The first steps in these pathways are "second messengers" (the neurotransmitter is considered the first messenger, and the G protein a coupling factor). Prominent second messengers in the brain are cAMP (cyclic adenosine monophosphate), cGMP (cyclic guanosine monophosphate), Ca2+, nitric oxide, and metabolites of arachidonic acid (e.g., prostaglandins) and phosphatidylinositol. The G protein-coupled receptors control the levels of these second messengers by regulating the activity of enzymes that catalyze the synthesis and degradation of second messengers, with different effects produced depending on the G protein involved.1 For example, neurotransmitters that increase cAMP levels act through Gs, which binds to and stimulates adenylyl cyclase, the enzyme that catalyzes the synthesis of cAMP. Other neurotransmitters decrease cAMP levels by acting through Gi, which binds to and inhibits adenylyl cyclase. Still other neurotransmitters do not affect cAMP, but instead increase the generation of phosphatidylinositol-derived second messengers. The next step in these intracellular pathways is the regulation, by second messengers, of protein phosphorylation, the process by which phosphate groups are added to or removed from specific amino acid residues by protein kinases and protein phosphatases, respectively. Phosphate groups, because of their large size and negative charge, affect the conformation and charge of proteins, which in turn affect their physiological function. For example, phosphorylation of ion channels and pumps affects their ability to open or close or to allow ions to pass through them. Phosphorylation of receptors affects their ability to bind to their 1 There are three subtypes of G proteins (guanine nucleotide-binding membrane proteins). Gs is stimulatory in that it stimulates adenylyl cyclase, and Gi is inhibitory in that it inhibits adenylyl cyclase. Gq is the third subtype but the "q" has no implicit meaning.
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Pathways of Addiction: Opportunities in Drug Abuse Research neurotransmitters or interact with their G proteins. Phosphorylation of enzymes affects their catalytic activity (e.g., phosphorylation of adenylyl cyclase can increase its capacity to synthesize cAMP). The brain contains many types of protein kinases and protein phosphatases that exhibit differential regulation. For example, cAMP activates cAMP-dependent protein kinases, Ca2+ activates Ca2+-dependent protein kinases, etc. Each type of protein kinase then phosphorylates a specific array of target proteins and thereby produces many additional effects of the original neurotransmitter-G protein-second messenger stimulus. Due to the multiple effects of phosphorylation on a number of important intracellular processes, a neurotransmitter stimulus can influence virtually every chemical process that occurs within its target neurons. Some effects, such as alterations in electrical activity, are very rapid (within seconds) and short-lived. Other effects, such as alterations in gene expression, can develop more slowly (over minutes or hours) and last for a long time. These more long-lasting effects of a neurotransmitter stimulus alter the manner in which the target neuron responds to subsequent stimuli—both the original neurotransmitter and others—and presumably represent the basis of neural adaptation and change, called plasticity. Together, these types of responses of widely differing time courses allow neurons to exert very complex control over other neurons operating within neural circuits. Neurotrophic Factor Signaling Pathways Second-messenger–regulated protein phosphorylation is just one component of a neuron's complex intracellular regulatory mechanisms. Neurons contain many protein kinases and protein phosphatases in addition to those regulated by second messengers, and these enzymes also contribute to the diverse effects that a neurotransmitter stimulus exerts on its target neurons. For example, neurotrophic factors were first studied for their important role in neural development and differentiation. However, it is now known that neurotrophic factors also play an important role in the regulation of the fully differentiated adult brain. One important family of neurotrophic factors, called neurotrophins, binds to a class of receptor that contains a special type of protein kinase within its structure, a protein tyrosine kinase, which phosphorylates proteins specifically on tyrosine residues. Binding of neurotrophin to its protein tyrosine kinase receptor activates the kinase activity and leads to the phosphorylation of specific cellular proteins and, eventually, to a cascade of protein kinase activity. Thus, neurotrophic factor-related signaling pathways are another example of the complexity of a neuron's intracellular regulatory machinery, and serve to highlight the complex types of effects that a
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Pathways of Addiction: Opportunities in Drug Abuse Research neurotransmitter stimulus produces in its target neurons which ultimately contributes to the short- and long-term effects of neurotransmitters on the brain. Understanding Drug Dependence in the Context of Neurotransmission All drugs of abuse interact initially with receptor or reuptake proteins, summarized in Table 3.1 (Nestler et al., 1995). For example, opiates activate opioid receptors, and cocaine inhibits reuptake proteins for the monoamine neurotransmitters (which include dopamine, norepinephrine, and serotonin). These initial effects lead to alterations in the levels of specific neurotransmitters, or to different activation states of specific neurotransmitter receptors, in the brain. Opiate activation of opioid receptors, for example, leads to recruitment of inhibitory and related G proteins. This, in turn, leads to activation of K+ channels and inhibition of Ca2+ channels. Both are inhibitory actions, because more K+ flows out of the cell and less Ca2+ flows into the cell. Thus, the electrical properties of the target neurons are affected relatively rapidly by opiates. Recruitment of the inhibitory G protein also inhibits adenylyl cyclase, and reductions in cellular Ca2+ levels decrease Ca2+-dependent protein phosphorylation cascades, altering the activity of still additional ion channels. These effects, along with changes in many other neural processes within target neurons, contribute further to the acute effects of opiates. The sum of such TABLE 3.1 Acute Effects of Abused Drugs on Neurotransmitters Drug Action Opiates Agonist at opioid receptors Cocaine Inhibits monoamine reuptake transporters Amphetamine Stimulates monoamine release Alcohol Facilitates GABAA receptor function and inhibits N-methyl-D-aspartate (NMDA) glutamate receptor functiona Nicotine Agonist at nicotinic acetylcholine receptors Cannabinoids Agonist at cannabinoid receptorsb Hallucinogens Partial agonist at 5-HT2c serotonin receptors Phencyclidine (PCP) Antagonist at NMDA glutamate receptors a The mechanism by which alcohol produces these effects has not been established but would not appear to involve direct alcohol binding to the receptors as is the case for the other drugs listed in this table. b Although a specific receptor for cannabinoids has been identified in the brain, the endogenous ligand for this receptor has not yet been identified with certainty. c 5-Hydroxytryptamine-2.
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Pathways of Addiction: Opportunities in Drug Abuse Research changes presumably triggers the longer-term effects of the drugs that eventually lead to abuse, dependence, tolerance, and withdrawal. ACCOMPLISHMENTS Significant advances in understanding the neurobiological basis of drug dependence in the past 25 years are now beginning to provide a strong scientific basis for drug abuse treatment, prevention, and etiology. Drug dependence has long been associated with some perturbation of the brain reward systems. At the systems level, specific neural circuits within the midbrain-forebrain connection of the medial forebrain bundle have been identified that mediate the acute reinforcing effects of drugs (Figure 3.1) (Koob, 1992a). These neural circuits are composed of specific chemical neurotransmitters and include the midbrain dopamine systems, the endogenous opioid peptide systems, and other neurotransmitters such as serotonin, GABA, and glutamate. These systems appear to be modified during the development of dependence and appear to remain sensitive to future perturbations. Cellular studies have identified specific changes in the function of different components of that midbrain-forebrain system and are beginning to provide a framework for the adaptive changes within neurons that are associated with withdrawal and sensitization (Nestler, 1992). Molecular studies not only have identified the specific neurotransmitter receptors and receptor subtypes important for mediating those reinforcement actions, but also have begun to provide a molecular basis for the long-term plasticity associated with relapse and vulnerability (Nestler, 1994). The remainder of this section highlights some of the neurobiological advances resulting from research on individual differences; neural substrates of reinforcement, withdrawal, tolerance, and relapse; pharmacotherapy; and brain imaging. Individual Differences It is widely presumed that individuals differ in their predilection for drug dependence (see Chapter 5). This has been demonstrated in epidemiological studies of alcoholism, but it remains largely unproven for other addictive disorders. There is, however, growing evidence of individual differences in responsiveness to drugs of abuse in laboratory animals. Genetic Factors Genetically inbred strains of mice and rats exhibit clearly different behavioral responses to one or another drug of abuse (Li and Lumeng, 1984; Pickens and Svikis, 1988; George and Goldberg, 1989; Guitart et al.,
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Pathways of Addiction: Opportunities in Drug Abuse Research 1993; Kosten et al., 1994). Such strain differences have been demonstrated with respect to numerous behavioral measures, including locomotor activity and sensitization, physical dependence, drug self-administration, conditioned place preference, and brain stimulation reward (Li et al., 1986; Crabbe et al., 1994). These observations suggest that there are likely genetic determinants of diverse aspects of drug action, including drug reinforcement. Researchers have also observed that genetically inbred strains of mice and rats differ not only in acute responses to drugs of abuse but also in responses to repeated drug exposure (e.g., George and Goldberg, 1989; Nestler, 1992; Guitart et al., 1993; Kosten et al., 1994), indicating that pharmacodynamic differences may reside in part at the level of gene expression. This research has implications for the treatment of drug abuse discussed later in the chapter. Environmental Factors In animal models, environmental factors also contribute to an individual's responses to drugs of abuse. First, exposure to a drug of abuse itself influences an animal's subsequent responses to the drug, including the reinforcing effects of a drug (Piazza et al., 1989; Horger et al., 1992). Second, other types of environmental factors have been shown to influence an animal's responses to drugs of abuse. One prominent example is stress, which can enhance the reinforcing and locomotor activating effects of several drugs of abuse, including cocaine and other stimulants, opiates, and alcohol (Volpicelli et al., 1986; Piazza et al., 1989; Vezina and Stewart, 1990; Cunningham and Kelley, 1992; Hamamura and Fibiger, 1993; Koob and Cador, 1993; Sorg and Kalivas, 1993; Goeders and Guerin, 1994; Shaham and Stewart, 1994). The effects of stress may be mediated, at least in part, via stress systems such as the hypothalamic-pituitary-adrenal axis, which is known to be activated by stress, and extrahypothalmic stress systems because mediators of those systems, including corticotropin-releasing factor (CRF) and glucocorticoids, alter drug reinforcement and drug-induced locomotor activity (Cole et al., 1990; Piazza et al., 1991). These findings have relevance in the clinical setting for the treatment of drug dependence since continued exposure to environmental factors increases an individual's risk for drug abuse and dependence (see Chapter 2). More work is needed, however, in the area of environmental factors on drug dependence and their neurobiological impact. Genetic-Environmental Interactions One way to understand these observations is that genes determine an individual animal's potential responses to drugs of abuse, whereas envi-
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Pathways of Addiction: Opportunities in Drug Abuse Research ronmental factors shape that genetic potential. That is, environmental exposures (e.g., a drug or stress) alter the brain in different ways depending on the genetic template of the brain. Particularly powerful environmental exposures (e.g., high levels of a drug of abuse) may lead to the same types of changes in the brain despite genetic differences (Nestler, 1992). Together, genetic and environmental factors combine to set an individual's responses to drugs of abuse. Identification of the specific genetic and environmental factors that influence the actions of drugs of abuse in animal models can provide insight into the types of genetic factors that contribute to an individual vulnerability for drug dependence in humans (Hilbert et al., 1991). Neural Substrates of Drug Abuse Neural Substrates of Reinforcement A multineurotransmitter system called the medial forebrain bundle, which courses from the ventral midbrain to the basal forebrain, has long been associated with reinforcement and reward (Olds and Milner, 1954; Olds, 1962; Stein, 1968; Wise, 1989). Electrical stimulation through electrodes implanted along this bundle is considered to be pleasurable or rewarding because animals will perform certain tasks repeatedly (e.g., pressing a bar) to trigger the stimulation (self-stimulation). Thresholds for that intracranial self-stimulation are lowered by drugs of abuse, suggesting that they ''sensitize" the brain reward system. Recent advances exploring the neurobiological basis for the positive reinforcing effects of drugs of abuse have focused on specific neurochemical systems that make up the medial forebrain bundle reward system. Psychomotor stimulants, such as cocaine and amphetamine, appear to depend on an increase in the synaptic release of dopamine in the mesolimbic dopamine system (Koob, 1992b). This system has its cell bodies of origin in the ventral tegmental area and projects to the nucleus accumbens, olfactory tubercle, frontal cortex, and amygdala. Cocaine is thought to act mainly to block reuptake of dopamine by binding to a specific protein, the dopamine transporter protein, involved in reuptake; amphetamines both enhance dopamine release and block its reuptake. Three of the five cloned dopamine receptor subtypes have been implicated in the reinforcing actions of cocaine (Woolverton, 1986; Koob, 1992b; Caine and Koob, 1993). Opiate drugs bind to opioid receptors to produce their reinforcing effects.2 The mu receptor appears to be most important for the reinforc- 2 Three known receptor subtypes have been cloned: mu, delta, and kappa.
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Pathways of Addiction: Opportunities in Drug Abuse Research ing effects of heroin and morphine, and the most important brain sites for the acute reinforcing actions of those drugs appear to be in the ventral tegmental area and the nucleus accumbens. Opiates stimulate the release of dopamine in the terminal areas of the mesolimbic dopamine system, and there also appears to be a dopamine-independent action in the region of the nucleus accumbens on neuronal systems that receive a dopaminergic input (Koob, 1992a). Ethanol and other sedative hypnotics clearly have multiple sites of action for their acute reinforcing effects, which depend on facilitation of GABAergic neurotransmission, stimulation of dopamine release at low doses, activation of endogenous opioid peptide systems, and antagonism of serotonergic and glutamatergic neurotransmission. The exact sites for these actions are under study but appear again to involve the mesolimbic dopamine system and its connections in the basal forebrain, particularly in limbic areas such as the amygdala. Nicotine is a direct agonist at brain nicotinic acetylcholine receptors, which are widely distributed throughout the brain. Nicotine self-administration is blocked by dopamine antagonists and opioid peptide antagonists, and both a nicotinic acetylcholine antagonist and an opiate antagonist have been shown to precipitate nicotine withdrawal in rodents (Malin et al., 1993, 1994). Nicotine is thus thought to activate both the mesolimbic dopamine system and opioid peptide systems in the same neural circuitry associated with other drugs of abuse (Corrigall et al., 1992). The neurobiological substrates for the acute reinforcing actions of psychedelic drugs are less well understood. Indeed, rodents and nonhuman primates will not self-administer psychedelic drugs. Lysergic acid diethylamide (LSD) clearly involves a serotonergic action, possibly as a postsynaptic agonist. However, the brain sites and specific subtypes involved are still under study. Little is known about the neurobiology of the acute reinforcing actions of marijuana, but the cloning of the tetrahydrocannabinol (THC) receptor and the discovery of endogenous THC compounds in the brain offer exciting new approaches to this question, discussed below (Matsuda et al., 1990; Devane et al., 1992). Neural Substrates for Drug Tolerance The neural substrates for drug tolerance overlap significantly with those associated with dependence because tolerance and dependence may be components of the same neuroadaptive process. Tolerance also involves associative processes (processes of learning where previously neutral stimuli come to acquire significance through pairing with biologically significant events), however, and the role of associative processes has been most explored in the context of opiate drugs and sedative-hypnotics
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Pathways of Addiction: Opportunities in Drug Abuse Research such as alcohol (Young and Goudie, 1995). Both operant (behavioral tolerance) and classical (context-dependent tolerance) conditioning have been shown to play a role in drug tolerance, and mechanisms for these associative processes may involve several neurotransmitters independent of their role in dependence. Norepinephrine and serotonin have long been known to be involved in the development of tolerance to ethanol and barbiturates (Tabakoff and Hoffman, 1992). More recently, administration of glutamate antagonists has been shown to block the development of tolerance, again consistent with an associative component of tolerance (Trujillo and Akil, 1991). Mechanisms of tolerance at the molecular level often overlap with those of dependence (Nestler et al., 1993).3 For example, up-regulation of the cAMP pathway could be a mechanism of tolerance; the changes would be expected to oppose the acute actions of opiates of inhibiting adenylyl cyclase. In addition, tolerance seems to involve the functional uncoupling of opioid receptors from their G proteins. The mechanisms underlying this uncoupling remain unknown but could involve drug-induced changes in the phosphorylation state of the receptors or G proteins that reduce their affinity for each other. Another possible mechanism of tolerance involves drug-induced changes in the ion channels that mediate the acute effects of drugs. For example, alterations in the phosphorylation state, amount, or even type of channel conceivably could contribute to drug tolerance (Nestler, 1992). Neural Substrates of Withdrawal Withdrawal from chronic use of drugs of abuse is characterized by a dependence syndrome that is made up of two elements. The objectively observable physical signs of alcohol withdrawal are tremor and autonomic hyperactivity; abdominal discomfort and pain are associated with opiate withdrawal. The self-reported "psychological" signs of drug withdrawal, which may be considered more motivational, are usually different components of a negative emotional state including dysphoria, depression, anxiety, and malaise (Koob et al., 1993) and are difficult to measure directly in animals. Behavioral history is a primary determinant of whether withdrawal and the negative affective state associated with it produce drug-seeking behavior. For individuals with a history of selfmedication of opiates and alcohol, physical dependence is an important 3 Tolerance and dependence can be separated operationally at the molecular level in vitro, but at the systems level they are usually related when the same dependent variable is measured for both constructs.
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Pathways of Addiction: Opportunities in Drug Abuse Research clear because both serotonergic and adrenergic medications are helpful. Dopaminergic medications have little antidepressant efficacy, however, although dopamine seems so critical for hedonic tone or at least euphoria. Direct evidence for neurobiological connections between drug dependence and psychiatric disorders remains to be elucidated and may be studied with newly developed tools (e.g., functional brain imaging). HIV Models The utility of an animal model rests in its ability to permit the study of a disease process under controlled conditions. Animal models that recapitulate the pathogenic and functional outcomes seen with HIV infection in humans can then be used to examine the influence of drugs of abuse on HIV disease progression. Direct neurotoxic effects of drugs, in addition to their effects on immunocompetence, may contribute to an enhancement of neurological sequelae of AIDS (called neuroAIDS disease) or accelerate its onset. These studies also will help determine the nature of viral neuropathogenesis to specific brain systems relevant to drug reward. That may have significant clinical outcomes related to risk reduction in terms of altered behavioral and pharmacological sensitivity to drugs of abuse in infected individuals. Thus, behavioral analysis in animal models of viral neuropathogenesis provides a unique opportunity to study the interaction between drugs of abuse and the immune system and should go far in identifying critical viral- and host-derived factors associated with increased susceptibility to the pathobiological effects of drugs of abuse and consequent synergistic neurotoxicity. Continued development of animal models of the effects of HIV infection on the brain would be useful for studying the links between AIDS and drug abuse—e.g., effects of drugs on disease progression, and the effect of HIV on brain reward systems and behaviors relevant to risk. Neurotoxicity of Drug Dependence There were early reports that chronic exposure to drugs of abuse led to neuronal death. Most reports proved to be spurious, however this is still a controversial area. One example of drug-induced neurotoxicity remains well established, namely the ability of certain amphetamine derivatives to kill central monoaminergic neurons. Methamphetamine and to a lesser extent amphetamine are toxic to midbrain dopamine neurons (Seiden et al., 1975), and methylenedioxymethamphetamine (MDMA, also known as Ecstasy) is toxic to midbrain serotonin neurons (Ricaurte et al., 1988). More recently, subtler forms of neural injury have been detected in
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Pathways of Addiction: Opportunities in Drug Abuse Research the brain under a variety of conditions. Chronic stress, perhaps mediated by glucocorticoids, causes pruning of dendritic spines in certain hippocampal neurons (Sapolsky, 1992). Recent work raises the possibility that neural adaptation, perhaps forms of learning, may be associated with changes in the numbers of dendrites and dendritic spines (Woolley and McEwen, 1995; Yuste and Denk, 1995). Recent evidence suggests that such subtle forms of neural injury may be induced in midbrain dopamine neurons by chronic exposure to drugs of abuse (Sklair-Tavron et al., 1995). Further work is needed to better characterize these adaptations in animal models of drug dependence and eventually to extend these studies to people by using evolving brain imaging procedures. Thus, cell loss and more subtle forms of neural injury should be studied in animal models of drug dependence. Neurobiology of Relapse After Prolonged Abstinence There is evidence in the clinical literature for physiological changes in people with a history of drug abuse that persist for years following the last drug exposure (Jaffe, 1990). These changes have been referred to as ''prolonged abstinence" or "protracted abstinence syndrome." Individuals who have been abstinent for years can return to a place associated with past drug exposure and quickly relapse to drug abuse (O'Brien, 1976). Individuals who took years to develop a hard-core dependence can, even after years of abstinence, descend back to that hard-core addicted state far more rapidly than before. There are relatively few preclinical studies of such types of phenomena; however, one example reports that sensitization to the locomotor activating effects of stimulants can persist for several months in rats (Robinson and Berridge, 1993). Given the clinical importance of prolonged abstinence, more preclinical research on this phenomenon is needed. One difficulty is that it is not at all clear that the same brain regions that mediate acute drug reinforcement and, perhaps, some motivational aspects of drug dependence are involved in prolonged abstinence. Such persisting adaptations may be more likely to reside in cortical, hippocampal, and amygdaloid regions as opposed to the mesolimbic dopamine system. Again the first step in this process must be the development of animal models of prolonged abstinence. However, we may not yet have the neurobiological resolution necessary to reveal the kinds of adaptations responsible for such long-lived phenomena as prolonged abstinence. Prolonged abstinence can be considered a form of long-term memory, and very little progress indeed has been made in establishing the neurobiological basis of long-term memory in general. Long-term memory may involve changes in the numbers or
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Pathways of Addiction: Opportunities in Drug Abuse Research sizes of dendritic spines of certain hippocampal and cortical neurons, or changes in the numbers and even types of synaptic terminals that innervate those neurons. Although the work is very tedious, it is possible to investigate such types of adaptation once behavioral models are developed and the relevant brain regions are identified. A Role for Immunology in Drug Treatment Another approach to drug abuse treatment is the development of antidrug vaccination, by which an immune response is induced in the organism that would effectively remove the drug from circulation and thus block its actions in the brain. Early work showed that immunizations can be used to blunt the reinforcing effects of morphine or heroin (Bonese et al., 1974; Killian et al., 1978). Recent evidence in cocaine abuse research suggests that synthetic analogues of cocaine can be used to produce active immunization in animals against the parent compound sufficient to block its stimulant effects (Carrera et al., 1995). Unknown at this time is how long such treatments will last and how they would affect other aspects of models of dependence. Other immunotherapies now being pursued include the development of passive immunizations (e.g., monoclonal antibodies or even catalytic antibodies could be injected into a subject to prevent a drug's action) (Landry et al., 1993). Again, the efficacy, duration of action, and impact of monoclonal or catalytic antibodies on drug dependence models remain to be explored. Research in Analgesia and Pain Finally, research in analgesia and pain has both informed neuroscience research on drug abuse and benefited from advances in drug abuse research. Four areas in analgesia and pain research have been highlighted for future research. Molecular Substrates of Analgesia and Tolerance New molecular research techniques are allowing investigators to identify some of the genes and intracellular messenger systems that are activated or suppressed by pain and analgesics (Hunt et al., 1987; Draisci et al., 1991; Gogas et al., 1991; Abbadie and Besson, 1994). These new techniques will allow a new level of analysis of the action of the body's many endogenous pain-modulating systems mediated by endorphins, enkephalins, serotonin, norepinephrine, GABA, acetylcholine, and other transmitters (Fields and Liebeskind, 1994). This in turn could lead to novel treatments for pain and make possible the prevention of tolerance to and
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Pathways of Addiction: Opportunities in Drug Abuse Research dependence on opioids. For example, evidence from animal models suggests that excitatory amino acid neurotransmission plays a role in tolerance to analgesia, which can be reversed or prevented by coadministration with NMDA antagonists (Elliott et al., 1994). Clinical trials of NMDA antagonist-opioid combinations in humans are just beginning. Development of Analgesics Acting at Opioid Receptors Other than the Mu Receptor In animals, agonists at delta, kappa, and epsilon receptors provide analgesia. In humans, such drugs might have fewer side effects or abuse liability than conventional analgesics (which act predominantly at the mu receptor). Animal studies suggest that opioids acting at different receptors may produce analgesic synergism if combined (Miaskowski et al., 1992). Research to clone receptor subtypes, develop specific drugs, and investigate their basic and clinical pharmacology will promote that goal. Functional Brain Imaging Studies of Pain and Opioid Analgesia Although our knowledge of pain physiology has emerged largely from studies in small animals, pain and opioid analgesia are complex human phenomena. PET and MRI are beginning to provide unique maps of the involvement of higher human brain centers in pain (Casey et al., 1994; Coghill et al., 1994; Iadarola et al., 1995). These techniques could potentially identify the areas in the brain mediating opioid analgesia and the pain-related effects on emotion, movement, and the endocrine and immune systems. Imaging methods may also be invaluable for predicting the actions of novel analgesic compounds. Treatment of Chronic Nonmalignant Pain by Opioids There is a consensus that acute pain and chronic cancer pain should be treated with opioids (Carr et al., 1992; Jacox et al., 1994). However, there is great controversy about the benefits and risks of long-term opioid treatment of various types of nonmalignant pain conditions such as neuropathic pain, low back pain, myofascial pain, and arthritic pain (Wall and Melzack, 1994). There are almost no data on the responsiveness of each type of pain to opioids, the rate of development of analgesic tolerance and physical dependence, and the risk of true abuse and dependence. There is a particular need for data about the risks and outcome of opioid treatment of former addicts with pain, as well as patients with pain related to human immunodeficiency virus (HIV) infection.
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Pathways of Addiction: Opportunities in Drug Abuse Research CONCLUSION AND RECOMMENDATION Significant progress has been made in understanding the neural substrates of drug dependence, and yet—due to the complexity of the brain and the difficulties inherent in studying the pathogenesis of any brain disease—there is still much more work to be done. Although physical withdrawal from drugs can now be managed well, all currently available treatments for the behavioral aspects of dependence remain inadequately effective for most people. By utilizing increasingly sophisticated research techniques and methods, future neurobiological studies at all levels of inquiry—molecular, cellular, and systems—will provide essential information for developing drug abuse treatment and prevention measures. The committee recommends continued support for fundamental investigations in neuroscience on the molecular, cellular, and systems levels. Research should be supported in the following areas: developing better animal models of the motivational aspects of drug dependence (with particular emphasis on protracted abstinence and propensity to relapse); genetics research; brain imaging; the neurobiology of co-occurring psychiatric disorders and drug abuse; animal models of the effects of HIV infection on the brain; the neurotoxicity of drug dependence; immunological approaches to drug abuse treatment; and pain and analgesia. REFERENCES Abbadie C, Besson J-M. 1994. Chronic treatment with aspirin or acetaminophen reduces both the development of polyarthritis and fos-like immunoreactivity in rat lumbar spinal cord. Pain 57:45-54. Aghajanian GK. 1978. Tolerance of locus coeruleus neurons to morphine and suppression of withdrawal response by clonidine. Nature 276:186-188. Aguzzi A, Brandner S, Sure U, Ruedi D, Isenmann S. 1994. Transgenic and knock-out mice: Models of neurological disease. Brain Pathology 4:3-20. Akaoka A, Aston-Jones G. 1991. Opiate withdrawal-induced hyperactivity of locus coeruleus neurons is substantially mediated by augmented excitatory amino acid input. Journal of Neuroscience 11:3830-3839. Baldo BA, Heyser CJ, Griffin P, Schulteis G, Stinus L, Koob GF. 1995. Effects of chlordiazepoxide and acamprosate on the conditioned place aversion induced by ethanol withdrawal. Neuroscience Abstracts 21:1701. Baxter LR, Schwartz JM, Phelps ME, Mazziotta JC, Barrio J, Rawson RA, Engel J, Guze BH, Selin C, Sumida R. 1988. Localization of neurochemical effects of cocaine and other stimulants in the human brain. Journal of Clinical Psychiatry 49:23-26. Belknap JK, Metten P, Helms ML, O'Toole LA, Angeli-Gade S, Crabbe JC, Phillips TJ. 1993. Quantitative trait lock (QTL) applications to substances of abuse: Physical dependence studies with nitrous oxide and ethanol in BXD mice. Behavior Genetics 23:213-222.
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