CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 7, Issue 5, 2008

Drug addiction is a complex neurological disorder affecting millions of people around the world [1]. This relapsing disease not only affects the individual, but also their family and community at large with severe medical and economic consequences [2]. In the past decades, groundbreaking scientific discoveries about the brain have revolutionized our understanding of drug addiction, enabling us to respond more effectively to the disease [3]. Current scientific information on the neurobiology of drug addiction has expanded significantly and the number of technological breakthroughs has also increased our understanding about the pathophysiology of drug addiction [1, 3]. However, limitations exist on the therapeutic frontier for treatment of many forms of drug addiction and abuse as current medications are not fully efficacious or devoid of side effects that limit compliance. Moreover, therapeutic strategies are not currently available for all forms of drug addiction. Thus, there is a need to translate the current knowledge derived from preclinical research into the discovery and development of effective and safe pharmacotherapeutic strategies. This hot topic issue, Drug Addiction and Brain Targets from Preclinical Research to Pharmacotherapy, consists of seven reviews written by eminent experts in the field. The issue covers important aspects of neuroscience research on drug addiction associated with the primary central nervous system neurotransmitter receptors implicated in drug addiction. The reviews in this themed issue describe some of the latest concepts in preclinical research, analyze breakthrough findings, define approaches and target multiple brain substrates including, dopamine transporters, dopamine D3 receptors, neuronal nicotinic receptors, opioid receptors, serotonergic (5-HT3) receptors, cannabinoid receptors and the glutamate receptor system for discovery of medications for the clinical management of drug addictions. Zhu and Reith have provided an extensive description of the dopamine transporter as an important target for the central nervous system actions of psychostimulants, nicotine, and other drugs of abuse such as ethanol, heroin, and morphine. They focus their review on multiple factors that regulate dopamine transporter function associated with reinforcing effects of psychostimulants and other classes of abused drugs. They also discuss current research on dopamine transporter activity in relation to novel environmental factors that might be critical to psychostimulant abuse. The latest findings on dopamine transporter function highlighted in this review provide a solid framework for understanding effects of commonly abused drugs related to dopamine transporter function. Implications of this scientific insight for the discovery of novel anti-addiction medications are discussed. Heidbreder reviews preclinical evidence that selective antagonism of dopamine D3 receptors are a viable potential target for drug addiction pharmacotherapy. The author has provided a comprehensive review focused on dopamine D3 receptor expression in the rodent and human brain, changes in expression of the dopamine D3 receptor following exposure to drugs of abuse, and efficacy of selective dopamine D3 receptor antagonists in preclinical models assessing the abuse-related behavioral effects of drugs such as cocaine, nicotine, alcohol, methamphetamine and heroin. The translational value of the extensive preclinical work reviewed in this article provides great value in understanding both the function of this dopamine receptor subtype in the actions of abused drugs and the potential of antagonists of this site for the therapeutic management of addictive disorders. Rahman et al. have described the important role of brain nicotinic receptors as potential targets for pharmacotherapy of nicotine addiction and other addictive disorders. The authors discuss the heterogeneity of brain nicotinic receptors and their function in the presence of nicotine. They cover the potential role of nicotinic receptors in mediating nicotine-induced addictive behavior in preclinical models. Current knowledge and understanding on the neurochemical basis of nicotine and other forms of drug addiction are also discussed. The progress and latest lines of research in the nicotinic receptor field reviewed in this chapter shed new light for future translational research and act as platform for therapeutic discovery in the management of nicotine and other forms of drug addiction, including alcoholism. Shippenberg et al. focus their review on mu-and delta-opioid receptors as targets for the treatment of opiate and other drug addiction. The authors discuss critical roles of mu-opioid and delta opioid receptors in mediating the rewarding effects produced by several classes of abused drugs. They also review the potential contribution of delta opioid receptors to mu opioid receptor function in various drug addiction processes. This comprehensive review highlights and documents the functional interactions of mu-opioid receptor and delta-opioid receptor as new targets for the treatment of opiate and psychostimulant addiction. Thus, in addition to discussing current data on these important molecular mechanisms of drug action, this chapter also provides a data-based understanding of the use of these mechanisms for defining strategies for the discovery of new opiate analgesics with reduced side effects.

A number of studies over the last two decades have demonstrated the critical importance of dopamine (DA) in the behavioral pharmacology and addictive properties of abused drugs. The DA transporter (DAT) is a major target for drugs of abuse in the category of psychostimulants, and for methylphenidate (MPH), a drug used for treating attention deficit hyperactivity disorder (ADHD), which can also be a psychostimulant drug of abuse. Other drugs of abuse such as nicotine, ethanol, heroin and morphine interact with the DAT in more indirect ways. Despite the different ways in which drugs of abuse can affect DAT function, one evolving theme in all cases is regulation of the DAT at the level of surface expression. DAT function is dynamically regulated by multiple intracellular and extracellular signaling pathways and several protein-protein interactions. In addition, DAT expression is regulated through the removal (internalization) and recycling of the protein from the cell surface. Furthermore, recent studies have demonstrated that individual differences in response to novel environments and psychostimulants can be predicted based on individual basal functional DAT expression. Although current knowledge of multiple factors regulating DAT activity has greatly expanded, many aspects of this regulation remain to be elucidated; these data will enable efforts to identify drugs that might be used therapeutically for drug dependence therapeutics.

The focal distribution of the dopamine (DA) D3 receptor in brain regions implicated in emotional and cognitive functions has made this target a main focus of drug discovery efforts. This paper will review the most recent lines of research in support of the use of selective DA D3 receptor antagonists for the pharmacotherapeutic management of drug addiction: (1) expression of the DA D3 receptor in the rodent and human brain; (2) changes in expression of the DA D3 receptor following exposure to drugs of abuse, and (3) efficacy of selective DA D3 receptor antagonists in preclinical paradigms assessing the behavioral effects of drugs such as cocaine, nicotine, alcohol, methamphetamine, and heroin. This manuscript, however, will not review the effects of nonselective DA D2/D3 receptor antagonists or partial D3 receptor agonists. Growing evidence suggests that selective DA D3 receptor antagonists do not affect the primary reinforcing effects of drugs of abuse, but rather seem to regulate the motivation to self-administer drugs under schedules of reinforcement that require an increase in work demand. In addition, selective antagonism at DA D3 receptors appears to disrupt significantly the responsiveness to drug-associated stimuli that play a key role in reinstatement of drug-seeking behavior. These preclinical findings will be discussed in the context of translational research relevant to the design of early clinical trials and hypothesis testing in humans.

Nicotine addiction and other forms of drug addiction continue to be significant public health problems in the United States and the rest of the world. Accumulated evidence indicates that brain nicotinic acetylcholine receptors (nAChRs) are a heterogenous family of ion channels expressed in the various parts of the brain. A growing body of preclinical studies suggests that brain nAChRs are critical targets for the development of pharmacotherapies for nicotine and other drug addictions. In this review, we will discuss the nAChR subtypes, their function in response to endogenous brain transmitters, and how their functions are regulated in the presence of nicotine. Furthermore, we will discuss the role of nAChRs in mediating nicotine-induced addictive behavior in animal models. Additionally, we will provide an overview of the effects of nicotine and nicotinic compounds on the mesolimbic dopamine system, part of the reinforcement/reward circuitry of the brain, as an example of the neurochemical basis of nicotine addiction and other drug addictions. An appreciation of the complexity of nicotinic receptors and their regulation will be necessary for the development of nicotinic receptor modulators as potential pharmacotherapy for drug addiction.

Drug addiction is a chronic, relapsing disorder that is characterized by a compulsion to take drug regardless of the adverse consequences that may ensue. Although the involvement of mesoaccumbal dopamine neurons in the initiation of drug abuse is well-established, neuroadaptations within the limbic cortical- striatopallidal circuit that occur as a consequence of repeated drug use are thought to lead to the behavioral dysregulation that characterizes addiction. Opioid receptors and their endogenous ligands are enriched in brain regions comprising this system and are, thus, strategically located to modulate neurotransmission therein. This article will review data suggesting an important role of mu-opioid receptor (MOPr) and delta opioid receptor (DOPr) systems in mediating the rewarding effects of several classes of abused drugs and that aberrant activity of these opioid systems may not only contribute to the behavioral dysregulation that characterizes addiction but to individual differences in addiction vulnerability.

Alcohol and drug abuse continue to be a major public health problem in the United States and other industrialized nations. Extensive preclinical research indicates the mesolimbic dopamine (DA) pathway and associated regions mediate the rewarding and reinforcing effects of drugs of abuse and natural rewards, such as food and sex. The serotonergic (5-HT) system, in concert with others neurotransmitter systems, plays a key role in modulating neuronal systems within the mesolimbic pathway. A substantial portion of this modulation is mediated by activity at the 5-HT3 receptor. The 5- HT3 receptor is unique among the 5-HT receptors in that it directly gates an ion channel inducing rapid depolarization that, in turn, causes the release of neurotransmitters and/or peptides. Preclinical findings indicate that antagonism of the 5- HT3 receptor in the ventral tegmental area, nucleus accumbens or amygdala reduces alcohol self-administration and/or alcohol- associated effects. Less is known about the effects of 5-HT3 receptor activity on the self-administration of other drugs of abuse or their associated effects. Clinical findings parallel the preclinical findings such that antagonism of the 5- HT3 receptor reduces alcohol consumption and some of its subjective effects. This review provides an overview of the structure, function, and pharmacology of 5-HT3 receptors, the role of these receptors in regulating DA neurotransmission in mesolimbic brain areas, and discusses data from animal and human studies implicating 5-HT3 receptors as targets for the development of new pharmacological agents to treat addictions.

Tobacco addiction is one of the leading preventable causes of mortality in the world and nicotine appears to be the main critical psychoactive component in establishing and maintaining tobacco dependence. Several lines of evidence suggest that the rewarding effects of nicotine, which underlie its abuse potential, can be modulated by manipulating the endocannabinoid system. For example, pharmacological blockade or genetic deletion of cannabinoid CB1 receptors reduces or eliminates many behavioral and neurochemical effects of nicotine that are related to its addictive potential. This review will focus on the recently published literature about the role of the endocannabinoid system in nicotine addiction and on the endocannabinoid system as a novel molecular target for the discovery of medications for tobacco dependence.

Considerable research into the neurobiology of cocaine addiction has shed light on the role of glutamate. Findings from models of relapse to cocaine-seeking indicate that the glutamatergic system is critically involved, as glutamate levels in the nucleus accumbens increase during reinstatement and glutamate receptor activation is necessary for reinstatement to drug-seeking. Thus, it would seem beneficial to block the increased glutamate release, but full antagonists of ionotropic glutamate receptors produce undesirable side effects. Therefore, modulation of glutamatergic transmission would be advantageous and provide novel pharmacotherapeutic avenues. Pharmacotherapies have been developed that have the potential to modulate excessive glutamatergic transmission through ionotropic and metabotropic (mGluR) glutamate receptors. Compounds that modulate glutamatergic transmission through ionotropic glutamate receptors include the non-competitive N-methyl-D-aspartic acid antagonists, amantadine and memantine, and the partial N-methyl-D-aspartic acid agonist d-cycloserine. They have shown promise in preclinical models of cocaine addiction. The mGluR2/3 agonist LY379268 is effective in inhibiting cocaine seeking in preclinical animal models and could decrease stress-induced relapse due to its anxiolytic effects. Similarly, the mGluR1/5 antagonists, 2-methyl-6-(phenylethynyl)pyridine and 3-[2- methyl-4-thiazolyl)ethynyl]pyridine, have shown to be effective in preclinical models of cocaine addiction. The cysteine pro-drug, N-acetylcysteine, restores the inhibitory tone on presynaptic glutamate receptors and has been effective in reducing cue-induced craving and cocaine use in humans. Furthermore, anticonvulsants, such as topiramate or lamotrigine, have shown efficacy in treating cocaine dependence or reducing relapse in humans. Future pharmacotherapy may focus on manipulating signal transduction proteins and pathways, which include Homer/N-methyl-D-aspartic acid complexes, to provide effective treatment for cocaine addiction.