- Email: [email protected]
Sponsor's foreword: NIDA at forty
Neuropharmacology 76 (2014) 195–197
Contents lists available at ScienceDirect
Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm
Foreword
Sponsor’s foreword: NIDA at forty
In 1974, the United States Congress established the National Institute on Drug Abuse (NIDA) as the responsible Federal agency for conducting basic, clinical, and epidemiological research to improve the understanding, prevention, and treatment of drug abuse and addiction and their health consequences. Throughout its 40 year history, NIDA’s mission has been to bring the power of science to bear on the problem of drug abuse and addiction. NIDA’s intramural research program (now in Baltimore MD) grew out of the Addiction Research Center in Lexington, KY, and, at the time of its establishment, NIDA assumed control of the Drug Abuse Warning Network and the National Household Survey on Drug Abuse. Early on, NIDA-supported research focused on opiate addiction and its treatment, which led to the discovery of the opiate receptors and their binding sites. NIDA-supported research continues at a rapid pace and some of the more recent and exciting opiate research is highlighted in three articles in this special issue. Pasternak’s (2014) article reveals the complexity of the mu opioid receptor gene and its many splice variants, which may provide drug targets for new opiate analgesics without abuse liability or risk of respiratory depression. Charbogne et al. (2014) champion the use of mutant mice in exploring the role of the mu, delta and kappa receptors in drug abuse, and the viability of the receptors as targets for medications development. Hutchinson and Watkins (2014) review the unique role of opioid activation of central immune signaling and they present ground-breaking evidence that drug-induced activation of central immune mechanisms can increase activation of mesolimbic dopamine reward pathways. Moving beyond opioids, Piomelli (2014) reviews what we know about lipid-derived signaling molecules that activate cannabinoid receptors (i.e., endocannabinoids) and their involvement in stress, pain, emotion, motivation and energy balance. He describes what is known about the molecules themselves, receptors, and enzyme-mediated cleavage, and what is needed to understand their role in drug abuse and addiction. Volkow and Baler (2014) give an excellent summary of many of the advances that NIDA-sponsored research has produced, from the development of brain imaging technology to new tools that can identify genes, epigenetic marks, and neuronal circuits (e.g., optogenetics and designer drug receptors). These advances have stimulated unprecedented growth in our understanding of drug abuse and addiction. The review by Parker et al. (2014) discusses recent advances that are making it possible to fine-map quantitative trait loci (QTLs) and to study “knocked-out” genes in rats, which will improve the ability of addiction scientists to study the genetic basis of addiction using robust animal models. Research reviewed by several eminent investigators in this special issue describes in exquisite detail the functional role of 0028-3908/$ – see front matter Ó 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.neuropharm.2013.08.020
neurotransmitter systems, receptors, and molecular, genetic and epigenetic mechanisms in addiction. In his review, Nestler (2014) explores the role of epigenetic regulatory changes following exposure to drugs of abuse. He demonstrates that repeated exposure to drugs of abuse results in changes in histone acetylation, DNA methylation, and non-coding RNAs in the brain’s reward regions. This work holds great promise for developing new diagnostic tests and for effective selective epigenetic-based treatments for addiction. The review by Vassoler et al. (2014) goes further, suggesting that some of these epigenetic changes can be trans-generational with parental use of drugs influencing the next generation in the absence of prenatal drug exposure. While further work is needed, the research reviewed raises the concern that the epigenetic consequences from drug exposure can produce transmittable changes that may bias the physiology and behavior of the offspring. The review by Gipson et al. (2014) considers the transition from occasional and controlled usage to the pattern of compulsive drug taking that characterizes addiction. Addiction involves a variety of neuroadaptations and dysregulations in the central nervous system. Gipson et al. consider these dynamic drug-induced morphological and electrophysiological changes in glutamatergic synapses in the nucleus accumbens (NA) that can lead to compulsive drug seeking and relapse. Loweth et al. (2014) explore the underlying mechanisms of cue-induced relapse. By focusing on the “incubation” phenomenon, they suggest that the accumulation and trafficking of Ca2þpermeable AMPA receptors (AMPAR) during withdrawal may be responsible for regulating AMPAR plasticity in the NA among other mechanisms discussed in their review. Neisewander et al. (2014) argue that the role of the serotonin 5-HT1B and D3 receptors in cocaine-associated behaviors depends on the stage of the addiction cycle (i.e., initiation, maintenance, escalation, and relapse) and that treatment strategies must consider the possibility that drug targets also may change depending on the stage of addiction. Stamatakis et al. (2014) look beyond the NA to consider the neurotransmitter and neuropeptide systems involved in motivated behavior and in relapse to drug seeking. They suggest that the use of optogenetic tools to explore the connectivity of regions such as the basolateral amygdala (BLA) and the bed nucleus of the stria terminalis (BNST) will lead to fundamental insights into the critical role for BLA and BNST connectivity in addiction. Ikemoto and Bonci (2014) also suggest going beyond well-mapped circuitry such as the ventral tegmental area (VTA)-NA system to explore other circuits mediating drug reward and drug seeking. They review intracranial selfadministration and optogenetic studies implicating a diversity of brain regions and neurotransmitter systems involved in drugreward-related behaviors. One such region, the insular cortex, is discussed by Paulus and Stewart (2014) who emphasize the role of
196
Foreword / Neuropharmacology 76 (2014) 195–197
body-relevant information and its associated neural circuits in drug addiction. They describe how the insular cortex integrates interoceptive signals with the external stimuli that direct motivated behavior, thus highlighting the role of interoception in drug addiction. Lammel et al. (2014) suggest that the mesocorticolimbic circuit is more complex than first described. They provide evidence that VTA dopamine (DA) neurons are heterogeneous with regard to their anatomical, molecular, and electrophysiological properties. These neurons respond to both appetitive and aversive stimuli, an important property considering that drug abuse is motivated by both positive and negative reinforcement. Carelli and West (2014) expand on the heterogeneity and dynamic changes in the NA, by noting a shift in cell firing to a sweet taste following its pairing and “devaluation” by cocaine, which results in the emergence of negative affective states. The key neuroanatomical and neurochemical components driving the negative affective state thus motivate drug seeking through negative reinforcement, an idea which is reviewed thoroughly by Koob et al. (2014). Their model proposes that cycles of drug taking and withdrawal recruit a stressful, fear-like state in the extended amygdala that indirectly activates depressed affect by suppressing dopamine. Mantsch et al. (2014) describe additional aspects of the neural circuitry and neurochemicals involved in stress-induced relapse and propose that behavioral treatment for stress management plus medications targeting multiple receptors are needed to prevent stress-induced relapse. In a related review, Calu et al. (2014) explain that similar mechanisms may underlie stress-induced food seeking and stress-induced drug seeking. Specifically, they describe the role of the medial prefrontal cortex, stress and food related peptides in reinstatement of food intake. Drugs of abuse affect more than motivational systems of the brain. They can also affect regions of the brain involved in decision making. Lucantonio et al. (2014) draw the distinction between two systems – model-based and model-free reinforcement learning. These systems are mediated by different neurocircuitry and are differentially affected by drugs of abuse. The model-based system relies on the orbitofrontal cortex and provides information about reward, including its sensory characteristics and unique value. It is impaired by drugs of abuse such as cocaine. The model-free system relies on the ventral striatum (VS), is involved in reward prediction, and is enhanced by exposure to cocaine. Chronic drug exposure leads to maladaptive, less flexible decision making, more habitual learning, and a failure to learn from new or unexpected outcomes – hallmarks of drug addiction. Overall these contributors are bringing us closer to a complete understanding of the circuitry, receptors, neurotransmitters, neuropeptides, and brain regions as well as the dynamic changes that occur at various phases of addiction. Not everyone who takes a drug of abuse becomes addicted. Through twin and family studies we know there are critical genetic and environmental factors in the development of substance use disorders. In addition, adolescence is a crucial period for the initiation of, and experimentation with drugs of abuse, suggesting that substance use disorders can be influenced by developmental stage, in concert with genetic variants, and environmental factors. Hurd et al. (2014) address these issues by reviewing data that show that adolescent cannabis exposure can increase vulnerability to addiction and psychiatric disorders for some individuals. As they point out, the mechanisms by which cannabis affects the organization and structure of the brain during adolescent development is unknown, but it undoubtedly involves the direct pharmacological effects of the drug along with genetic factors. These studies are particularly important with the recent rise in marijuana use among adolescents in the United States. Flagel et al. (2014) use a selective breeding strategy to explore genetic factors. They report that rats bred for high versus low locomotor activity are differentially susceptible to addiction and show differences in hippocampal gene expression during
development, as well as differences in adult neurogenesis following cocaine exposure. Deroche-Gamonet and Piazza (2014) confirm that etiology to addiction varies and depends on a variety of complex, multidimensional personality traits such as sensation seeking and impulsivity. Moreover, addiction itself may be multidimensional at both the behavioral and neurobiological levels such that vulnerability to addiction might be associated with a number of complex neurobehavioral attributes. Robinson et al. (2014) explore the variation in behavioral responses to cues with motivational value for food (sign-tracking vs. goal-tracking). They posit that individual differences in sign-tracking vs. goal-tracking can be used to predict behavior directed toward drug cues and “vulnerability” to drug seeking. Cunningham and Anastasio (2014) look at the role of serotonin neurotransmission in impulsivity and drug cue reactivity. They argue that the serotonin system may be involved in many aspects of vulnerability to, and phases of, addiction suggesting it is a prime target not only for medication development but potentially an important prognostic and diagnostic biomarker, particularly specific serotonin receptor subtypes involved in corticostriatal function. The review by Jentsch and Pennington (2014) explores the role of individual differences in inhibitory control as an antecedent risk factor for substance abuse, which they describe as linked to low brain dopamine, other neurotransmitter systems such as serotonin, and specific gene variants. Jupp and Dally (2014) elaborate on this idea by identifying, studying, and postulating that predisposing neural and behavioral endophenotypes are risk factors that show remarkable convergence across species from rat to human. Trifilieff and Martinez (2014) expand on the impact of impulsivity in human drug addiction, showing that D2 receptor binding and dopamine release revealed in human imaging studies correlate with impulsive, motivated behavior in animals. Nader and Banks (2014) describe the interaction between D2 receptors and social rank in determining rates of cocaine self-administration in non-human primates. In their work, brain imaging and behavioral observations combine to reveal the mechanisms underlying the effects of the social environment and reinforcement on drug taking. Bickel et al. (2014) describe a behavioral economics approach to drug addiction and suggest that delay discounting might be a useful biobehavioral marker reflecting vulnerability to addiction and possibly predicting treatment outcome. McNally (2014) explores the many facets of extinction learning as a potential behavioral treatment for drug addiction showing that the brain can be “retuned” to reduce drug seeking, implicating the cortical–striatal–hypothalamic and cortical–hypothalamic–thalamic pathways in the process. Addiction to nicotine/tobacco is one of the most devastating diseases in terms of its world-wide impact on public health. It accounts for a wide range of illnesses, including cancer, chronic obstructive pulmonary disease, coronary heart disease, stroke, peripheral vascular disease, peptic ulcer disease, and it can adversely affect neonatal development. It is estimated that global mortality from tobacco use will rise to 10 million annually by 2030. NIDA continues to support a large research portfolio on nicotine/tobacco addiction, including the development of smoking cessation treatments that are preventing premature death and many chronic illnesses. Work conducted and reviewed by Fowler and Kenny (2014) delves into the complex neurobiological mechanisms and functional significance of genetic variants of the acetylcholine receptor subunits that are involved both in the rewarding and aversive effects of nicotine. They show how insights from genetics can lead to new targets for medications development and can provide a conceptual framework for research that can be translated into effective smoking cessation strategies. Picciotto and Mineur (2014) explore the molecular mechanisms and anatomical regions responsible for nicotine reinforcement and its other effects on appetite suppression, stressrelated behavior, depression, and neuronal development. Li et al.
Foreword / Neuropharmacology 76 (2014) 195–197
(2014) discuss nicotine’s role in the release of the neurotransmitters glutamate and g-aminobutyric acid (GABA) and explain how these neurotransmitters and their specific receptor subunits can be important “druggable” targets for treating nicotine dependence and withdrawal in the development of novel smoking cessation medications. There are important sex and gender differences in vulnerability to drug addiction, in relapse rates, and in treatment success. O’Dell and Torres (2014) look at nicotine’s effects in female and male rats. They are interested in identifying mechanisms to explain why women are more sensitive to the positive rewarding effects of nicotine than men, and are more likely than men to relapse following stress. They suggest that a combination of anxiolytic medications with smoking cessation medications may be an effective approach for treating women smokers. Ashare et al. (2014) focus on neurocognitive effects associated with nicotine withdrawal that can be measured in animals and humans, that are predictive of relapse, and that have important clinical relevance in treatment-seeking smokers. They suggest that improved treatment strategies (both pharmacological and behavioral) need to target negative cognitive symptoms associated with withdrawal. Finally, Bierut et al. (2014) review the genetic contribution to individual differences in nicotine dependence, focusing on the role of the a5-a3-b4 nicotinic receptor subunit gene variants. They explain that new research suggests that these same variants are associated with a differential response to pharmacologic treatment and thus can be used to improve and guide smoking cessation by “personalizing” treatment. This special issue provides a comprehensive overview of the state of addiction science covering many advances and highlighting new research opportunities that will further our understanding of drug addiction. During the past forty years, the field of addiction science has progressed along many research fronts and NIDA is committed to continuing to support these efforts well into the future. Forty years of research is showing us the path forward and the need to marshal resources to translate these discoveries, and those to come, into the development of more effective addiction treatment interventions. Only in this way will NIDA’s mission be completely fulfilled as a public health agency dedicated to bringing science to bear on the understanding of and providing effective treatment for drug abuse and addiction. For further information on the NIDA neuroscience initiatives and translational research, visit http://www.drugabuse.gov. References Ashare, R.L., Falcone, M., Lerman, C., 2014. Cognitive function during nicotine withdrawal: Implications for nicotine dependence treatment. Neuropharmacology 76, 581–591. Bickel, W.K., Koffarnus, M.N., Moody, L., Wilson, A.G., 2014. The behavioral- and neuro-economic process of temporal discounting: A candidate behavioral marker of addiction. Neuropharmacology 76, 518–527. Bierut, L.J., Johnson, E.O., Saccone, N.L., 2014. A glimpse into the future – personalized medicine for smoking cessation. Neuropharmacology 76, 592–599. Calu, D.J., Chen, Y.-W., Kawa, A.B., Nair, S.G., Shaham, Y., 2014. The use of the reinstatement model to study relapse to palatable food seeking during dieting. Neuropharmacology 76, 395–406. Carelli, R.M., West, E.A., 2014. When a good taste turns bad: Neural mechanisms underlying the emergence of negative affect and associated natural reward devaluation by cocaine. Neuropharmacology 76, 360–369. Charbogne, P., Kieffer, B.L., Befort, K., 2014. 15 years of genetic approaches in vivo for addiction research: Opioid receptor and peptide gene knockout in mouse models of drug abuse. Neuropharmacology 76, 204–217. Cunningham, K.A., Anastasio, N.C., 2014. Serotonin at the nexus of impulsivity and cue reactivity in cocaine addiction. Neuropharmacology 76, 460–478. Deroche-Gamonet, V., Vincenzo Piazza, P., 2014. Psychobiology of cocaine addiction: Contribution of a multisymptomatic animal model of loss of control. Neuropharmacology 76, 437–449. Flagel, S.B., Waselus, M., Clinton, S.M., Watson, S.J., Akil, H., 2014. Antecedents and consequences of drug abuse in rats selectively bred for high and low response to novelty. Neuropharmacology 76, 425–436. Fowler, C.D., Kenny, P.J., 2014. Nicotine aversion: Neurobiological mechanisms and relevance to tobacco dependence vulnerability. Neuropharmacology 76, 533–544.
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Gipson, C.D., Kupchik, Y.M., Kalivas, P.W., 2014. Rapid, transient synaptic plasticity in addiction. Neuropharmacology 76, 276–286. Hurd, Y.L., Michaelides, M., Miller, M.L., Jutras-Aswad, D., 2014. Trajectory of adolescent cannabis use on addiction vulnerability. Neuropharmacology 76, 416–424. Hutchinson, M.R., Watkins, L.R., 2014. Why is Neuroimmunopharmacology crucial for the future of addiction research? Neuropharmacology 76, 218–227. Ikemoto, S., Bonci, A., 2014. Neurocircuitry of drug reward. Neuropharmacology 76, 329–341. Jentsch, J.D., Pennington, Z.T., 2014. Reward, interrupted: Inhibitory control and its relevance to addictions. Neuropharmacology 76, 479–486. Jupp, B., Dalley, J.W., 2014. Behavioral endophenotypes of drug addiction: Etiological insights from neuroimaging studies. Neuropharmacology 76, 487–497. Koob, G.F., Buck, C.L., Cohen, A., Edwards, S., Park, P.E., Schlosburg, J.E., Schmeichel, B., Vendruscolo, L.F., Wade, C.L., Whitfield Jr., T.W., George, O., 2014. Addiction as a stress surfeit disorder. Neuropharmacology 76, 370–382. Lammel, S., Lim, B.K., Malenka, R.C., 2014. Reward and aversion in a heterogeneous midbrain dopamine system. Neuropharmacology 76, 351–359. Li, X., Semenova, S., D’Souza, M.S., Stoker, A.K., Markou, A., 2014. Involvement of glutamatergic and GABAergic systems in nicotine dependence: Implications for novel pharmacotherapies for smoking cessation. Neuropharmacology 76, 554–565. Loweth, J.A., Tseng, K.Y., Wolf, M.E., 2014. Adaptations in AMPA receptor transmission in the nucleus accumbens contributing to incubation of cocaine craving. Neuropharmacology 76, 287–300. Lucantonio, F., Caprioli, D., Schoenbaum, G., 2014. Transition from ‘model-based’ to ‘model-free’ behavioral control in addiction: Involvement of the orbitofrontal cortex and dorsolateralstriatum. Neuropharmacology 76, 407–415. Mantsch, J.R., Vranjkovic, O., Twining, R.C., Gasser, P.J., McReynolds, J.R., Blacktop, J.M., 2014. Neurobiological mechanisms that contribute to stressrelated cocaine use. Neuropharmacology 76, 383–394. McNally, G.P., 2014. Extinction of drug seeking: Neural circuits and approaches to Augmentation. Neuropharmacology 76, 528–532. Nader, M.A., Banks, M.L., 2014. Environmental modulation of drug taking: Nonhuman primate models of cocaine abuse and PET neuroimaging. Neuropharmacology 76, 510–517. Neisewander, J.L., Cheung, T.H.C., Pentkowski, N.S., 2014. Dopamine D3 and 5-HT1B receptor dysregulation as a result of psychostimulant intake and forced abstinence: Implications for medications development. Neuropharmacology 76, 301–319. Nestler, E.J., 2014. Epigenetic mechanisms of drug addiction. Neuropharmacology 76, 259–268. O’Dell, L.E., Torres, O.V., 2014. A mechanistic hypothesis of the factors that enhance vulnerability to nicotine use in females. Neuropharmacology 76, 566–580. Parker, C.C., Chen, H., Flagel, S.B., Geurts, A.M., Richards, J.B., Robinson, T.E., Solberg Woods, L.C., Palmer, A.A., 2014. Rats are the smart choice: Rationale for a renewed focus on rats in behavioral genetics. Neuropharmacology 76, 250–258. Pasternak, G.W., 2014. Opioids and their receptors: Are we there yet? Neuropharmacology 76, 198–203. Paulus, M.P., Stewart, J.L., 2014. Interoception and drug addiction. Neuropharmacology 76, 342–350. Picciotto, M.R., Mineur, Y.S., 2014. Molecules and circuits involved in nicotine addiction: The many faces of smoking. Neuropharmacology 76, 545–553. Piomelli, D., 2014. More surprises lying ahead. The endocannabinoids keep us guessing. Neuropharmacology 76, 228–234. Robinson, T.E., Yager, L.M., Cogan, E.S., Saunders, B.T., 2014. On the motivational properties of reward cues: Individual differences. Neuropharmacology 76, 450–459. Stamatakis, A.M., Sparta, D.R., Jennings, J.H., McElligott, Z.A., Decot, H., Stuber, G.D., 2014. Amygdala and bed nucleus of the stria terminalis circuitry: Implications for addiction-related behaviors. Neuropharmacology 76, 320–328. Trifilieff, P., Martinez, D., 2014. Imaging addiction: D2 receptors and dopamine signaling in the striatum as biomarkers for impulsivity. Neuropharmacology 76, 498–509. Vassoler, F.M., Byrnes, E.M., Pierce, R.C., 2014. The impact of exposure to addictive drugs on future generations: Physiological and behavioral effects. Neuropharmacology 76, 269–275. Volkow, N.D., Baler, R.D., 2014. Addiction science: Uncovering neurobiological complexity. Neuropharmacology 76, 235–249.
David Shurtleff, Cathrine Sasek*, Mary Kautz National Institute on Drug Abuse, National Institutes of Health, United States * Corresponding author. Office of Science Policy and Communications, National Institute on Drug Abuse, 6001 Executive Boulevard, Rm 5230, MSC 9991, Bethesda, MD 20892-9555, United States. Tel.: þ1 301 443 6071; fax: þ1 301 443 6277. E-mail address: [email protected] (C. Sasek) 2 August 2013
Contents lists available at ScienceDirect
Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm
Foreword
Sponsor’s foreword: NIDA at forty
In 1974, the United States Congress established the National Institute on Drug Abuse (NIDA) as the responsible Federal agency for conducting basic, clinical, and epidemiological research to improve the understanding, prevention, and treatment of drug abuse and addiction and their health consequences. Throughout its 40 year history, NIDA’s mission has been to bring the power of science to bear on the problem of drug abuse and addiction. NIDA’s intramural research program (now in Baltimore MD) grew out of the Addiction Research Center in Lexington, KY, and, at the time of its establishment, NIDA assumed control of the Drug Abuse Warning Network and the National Household Survey on Drug Abuse. Early on, NIDA-supported research focused on opiate addiction and its treatment, which led to the discovery of the opiate receptors and their binding sites. NIDA-supported research continues at a rapid pace and some of the more recent and exciting opiate research is highlighted in three articles in this special issue. Pasternak’s (2014) article reveals the complexity of the mu opioid receptor gene and its many splice variants, which may provide drug targets for new opiate analgesics without abuse liability or risk of respiratory depression. Charbogne et al. (2014) champion the use of mutant mice in exploring the role of the mu, delta and kappa receptors in drug abuse, and the viability of the receptors as targets for medications development. Hutchinson and Watkins (2014) review the unique role of opioid activation of central immune signaling and they present ground-breaking evidence that drug-induced activation of central immune mechanisms can increase activation of mesolimbic dopamine reward pathways. Moving beyond opioids, Piomelli (2014) reviews what we know about lipid-derived signaling molecules that activate cannabinoid receptors (i.e., endocannabinoids) and their involvement in stress, pain, emotion, motivation and energy balance. He describes what is known about the molecules themselves, receptors, and enzyme-mediated cleavage, and what is needed to understand their role in drug abuse and addiction. Volkow and Baler (2014) give an excellent summary of many of the advances that NIDA-sponsored research has produced, from the development of brain imaging technology to new tools that can identify genes, epigenetic marks, and neuronal circuits (e.g., optogenetics and designer drug receptors). These advances have stimulated unprecedented growth in our understanding of drug abuse and addiction. The review by Parker et al. (2014) discusses recent advances that are making it possible to fine-map quantitative trait loci (QTLs) and to study “knocked-out” genes in rats, which will improve the ability of addiction scientists to study the genetic basis of addiction using robust animal models. Research reviewed by several eminent investigators in this special issue describes in exquisite detail the functional role of 0028-3908/$ – see front matter Ó 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.neuropharm.2013.08.020
neurotransmitter systems, receptors, and molecular, genetic and epigenetic mechanisms in addiction. In his review, Nestler (2014) explores the role of epigenetic regulatory changes following exposure to drugs of abuse. He demonstrates that repeated exposure to drugs of abuse results in changes in histone acetylation, DNA methylation, and non-coding RNAs in the brain’s reward regions. This work holds great promise for developing new diagnostic tests and for effective selective epigenetic-based treatments for addiction. The review by Vassoler et al. (2014) goes further, suggesting that some of these epigenetic changes can be trans-generational with parental use of drugs influencing the next generation in the absence of prenatal drug exposure. While further work is needed, the research reviewed raises the concern that the epigenetic consequences from drug exposure can produce transmittable changes that may bias the physiology and behavior of the offspring. The review by Gipson et al. (2014) considers the transition from occasional and controlled usage to the pattern of compulsive drug taking that characterizes addiction. Addiction involves a variety of neuroadaptations and dysregulations in the central nervous system. Gipson et al. consider these dynamic drug-induced morphological and electrophysiological changes in glutamatergic synapses in the nucleus accumbens (NA) that can lead to compulsive drug seeking and relapse. Loweth et al. (2014) explore the underlying mechanisms of cue-induced relapse. By focusing on the “incubation” phenomenon, they suggest that the accumulation and trafficking of Ca2þpermeable AMPA receptors (AMPAR) during withdrawal may be responsible for regulating AMPAR plasticity in the NA among other mechanisms discussed in their review. Neisewander et al. (2014) argue that the role of the serotonin 5-HT1B and D3 receptors in cocaine-associated behaviors depends on the stage of the addiction cycle (i.e., initiation, maintenance, escalation, and relapse) and that treatment strategies must consider the possibility that drug targets also may change depending on the stage of addiction. Stamatakis et al. (2014) look beyond the NA to consider the neurotransmitter and neuropeptide systems involved in motivated behavior and in relapse to drug seeking. They suggest that the use of optogenetic tools to explore the connectivity of regions such as the basolateral amygdala (BLA) and the bed nucleus of the stria terminalis (BNST) will lead to fundamental insights into the critical role for BLA and BNST connectivity in addiction. Ikemoto and Bonci (2014) also suggest going beyond well-mapped circuitry such as the ventral tegmental area (VTA)-NA system to explore other circuits mediating drug reward and drug seeking. They review intracranial selfadministration and optogenetic studies implicating a diversity of brain regions and neurotransmitter systems involved in drugreward-related behaviors. One such region, the insular cortex, is discussed by Paulus and Stewart (2014) who emphasize the role of
196
Foreword / Neuropharmacology 76 (2014) 195–197
body-relevant information and its associated neural circuits in drug addiction. They describe how the insular cortex integrates interoceptive signals with the external stimuli that direct motivated behavior, thus highlighting the role of interoception in drug addiction. Lammel et al. (2014) suggest that the mesocorticolimbic circuit is more complex than first described. They provide evidence that VTA dopamine (DA) neurons are heterogeneous with regard to their anatomical, molecular, and electrophysiological properties. These neurons respond to both appetitive and aversive stimuli, an important property considering that drug abuse is motivated by both positive and negative reinforcement. Carelli and West (2014) expand on the heterogeneity and dynamic changes in the NA, by noting a shift in cell firing to a sweet taste following its pairing and “devaluation” by cocaine, which results in the emergence of negative affective states. The key neuroanatomical and neurochemical components driving the negative affective state thus motivate drug seeking through negative reinforcement, an idea which is reviewed thoroughly by Koob et al. (2014). Their model proposes that cycles of drug taking and withdrawal recruit a stressful, fear-like state in the extended amygdala that indirectly activates depressed affect by suppressing dopamine. Mantsch et al. (2014) describe additional aspects of the neural circuitry and neurochemicals involved in stress-induced relapse and propose that behavioral treatment for stress management plus medications targeting multiple receptors are needed to prevent stress-induced relapse. In a related review, Calu et al. (2014) explain that similar mechanisms may underlie stress-induced food seeking and stress-induced drug seeking. Specifically, they describe the role of the medial prefrontal cortex, stress and food related peptides in reinstatement of food intake. Drugs of abuse affect more than motivational systems of the brain. They can also affect regions of the brain involved in decision making. Lucantonio et al. (2014) draw the distinction between two systems – model-based and model-free reinforcement learning. These systems are mediated by different neurocircuitry and are differentially affected by drugs of abuse. The model-based system relies on the orbitofrontal cortex and provides information about reward, including its sensory characteristics and unique value. It is impaired by drugs of abuse such as cocaine. The model-free system relies on the ventral striatum (VS), is involved in reward prediction, and is enhanced by exposure to cocaine. Chronic drug exposure leads to maladaptive, less flexible decision making, more habitual learning, and a failure to learn from new or unexpected outcomes – hallmarks of drug addiction. Overall these contributors are bringing us closer to a complete understanding of the circuitry, receptors, neurotransmitters, neuropeptides, and brain regions as well as the dynamic changes that occur at various phases of addiction. Not everyone who takes a drug of abuse becomes addicted. Through twin and family studies we know there are critical genetic and environmental factors in the development of substance use disorders. In addition, adolescence is a crucial period for the initiation of, and experimentation with drugs of abuse, suggesting that substance use disorders can be influenced by developmental stage, in concert with genetic variants, and environmental factors. Hurd et al. (2014) address these issues by reviewing data that show that adolescent cannabis exposure can increase vulnerability to addiction and psychiatric disorders for some individuals. As they point out, the mechanisms by which cannabis affects the organization and structure of the brain during adolescent development is unknown, but it undoubtedly involves the direct pharmacological effects of the drug along with genetic factors. These studies are particularly important with the recent rise in marijuana use among adolescents in the United States. Flagel et al. (2014) use a selective breeding strategy to explore genetic factors. They report that rats bred for high versus low locomotor activity are differentially susceptible to addiction and show differences in hippocampal gene expression during
development, as well as differences in adult neurogenesis following cocaine exposure. Deroche-Gamonet and Piazza (2014) confirm that etiology to addiction varies and depends on a variety of complex, multidimensional personality traits such as sensation seeking and impulsivity. Moreover, addiction itself may be multidimensional at both the behavioral and neurobiological levels such that vulnerability to addiction might be associated with a number of complex neurobehavioral attributes. Robinson et al. (2014) explore the variation in behavioral responses to cues with motivational value for food (sign-tracking vs. goal-tracking). They posit that individual differences in sign-tracking vs. goal-tracking can be used to predict behavior directed toward drug cues and “vulnerability” to drug seeking. Cunningham and Anastasio (2014) look at the role of serotonin neurotransmission in impulsivity and drug cue reactivity. They argue that the serotonin system may be involved in many aspects of vulnerability to, and phases of, addiction suggesting it is a prime target not only for medication development but potentially an important prognostic and diagnostic biomarker, particularly specific serotonin receptor subtypes involved in corticostriatal function. The review by Jentsch and Pennington (2014) explores the role of individual differences in inhibitory control as an antecedent risk factor for substance abuse, which they describe as linked to low brain dopamine, other neurotransmitter systems such as serotonin, and specific gene variants. Jupp and Dally (2014) elaborate on this idea by identifying, studying, and postulating that predisposing neural and behavioral endophenotypes are risk factors that show remarkable convergence across species from rat to human. Trifilieff and Martinez (2014) expand on the impact of impulsivity in human drug addiction, showing that D2 receptor binding and dopamine release revealed in human imaging studies correlate with impulsive, motivated behavior in animals. Nader and Banks (2014) describe the interaction between D2 receptors and social rank in determining rates of cocaine self-administration in non-human primates. In their work, brain imaging and behavioral observations combine to reveal the mechanisms underlying the effects of the social environment and reinforcement on drug taking. Bickel et al. (2014) describe a behavioral economics approach to drug addiction and suggest that delay discounting might be a useful biobehavioral marker reflecting vulnerability to addiction and possibly predicting treatment outcome. McNally (2014) explores the many facets of extinction learning as a potential behavioral treatment for drug addiction showing that the brain can be “retuned” to reduce drug seeking, implicating the cortical–striatal–hypothalamic and cortical–hypothalamic–thalamic pathways in the process. Addiction to nicotine/tobacco is one of the most devastating diseases in terms of its world-wide impact on public health. It accounts for a wide range of illnesses, including cancer, chronic obstructive pulmonary disease, coronary heart disease, stroke, peripheral vascular disease, peptic ulcer disease, and it can adversely affect neonatal development. It is estimated that global mortality from tobacco use will rise to 10 million annually by 2030. NIDA continues to support a large research portfolio on nicotine/tobacco addiction, including the development of smoking cessation treatments that are preventing premature death and many chronic illnesses. Work conducted and reviewed by Fowler and Kenny (2014) delves into the complex neurobiological mechanisms and functional significance of genetic variants of the acetylcholine receptor subunits that are involved both in the rewarding and aversive effects of nicotine. They show how insights from genetics can lead to new targets for medications development and can provide a conceptual framework for research that can be translated into effective smoking cessation strategies. Picciotto and Mineur (2014) explore the molecular mechanisms and anatomical regions responsible for nicotine reinforcement and its other effects on appetite suppression, stressrelated behavior, depression, and neuronal development. Li et al.
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(2014) discuss nicotine’s role in the release of the neurotransmitters glutamate and g-aminobutyric acid (GABA) and explain how these neurotransmitters and their specific receptor subunits can be important “druggable” targets for treating nicotine dependence and withdrawal in the development of novel smoking cessation medications. There are important sex and gender differences in vulnerability to drug addiction, in relapse rates, and in treatment success. O’Dell and Torres (2014) look at nicotine’s effects in female and male rats. They are interested in identifying mechanisms to explain why women are more sensitive to the positive rewarding effects of nicotine than men, and are more likely than men to relapse following stress. They suggest that a combination of anxiolytic medications with smoking cessation medications may be an effective approach for treating women smokers. Ashare et al. (2014) focus on neurocognitive effects associated with nicotine withdrawal that can be measured in animals and humans, that are predictive of relapse, and that have important clinical relevance in treatment-seeking smokers. They suggest that improved treatment strategies (both pharmacological and behavioral) need to target negative cognitive symptoms associated with withdrawal. Finally, Bierut et al. (2014) review the genetic contribution to individual differences in nicotine dependence, focusing on the role of the a5-a3-b4 nicotinic receptor subunit gene variants. They explain that new research suggests that these same variants are associated with a differential response to pharmacologic treatment and thus can be used to improve and guide smoking cessation by “personalizing” treatment. This special issue provides a comprehensive overview of the state of addiction science covering many advances and highlighting new research opportunities that will further our understanding of drug addiction. During the past forty years, the field of addiction science has progressed along many research fronts and NIDA is committed to continuing to support these efforts well into the future. Forty years of research is showing us the path forward and the need to marshal resources to translate these discoveries, and those to come, into the development of more effective addiction treatment interventions. Only in this way will NIDA’s mission be completely fulfilled as a public health agency dedicated to bringing science to bear on the understanding of and providing effective treatment for drug abuse and addiction. For further information on the NIDA neuroscience initiatives and translational research, visit http://www.drugabuse.gov. References Ashare, R.L., Falcone, M., Lerman, C., 2014. Cognitive function during nicotine withdrawal: Implications for nicotine dependence treatment. Neuropharmacology 76, 581–591. Bickel, W.K., Koffarnus, M.N., Moody, L., Wilson, A.G., 2014. The behavioral- and neuro-economic process of temporal discounting: A candidate behavioral marker of addiction. Neuropharmacology 76, 518–527. Bierut, L.J., Johnson, E.O., Saccone, N.L., 2014. A glimpse into the future – personalized medicine for smoking cessation. Neuropharmacology 76, 592–599. Calu, D.J., Chen, Y.-W., Kawa, A.B., Nair, S.G., Shaham, Y., 2014. The use of the reinstatement model to study relapse to palatable food seeking during dieting. Neuropharmacology 76, 395–406. Carelli, R.M., West, E.A., 2014. When a good taste turns bad: Neural mechanisms underlying the emergence of negative affect and associated natural reward devaluation by cocaine. Neuropharmacology 76, 360–369. Charbogne, P., Kieffer, B.L., Befort, K., 2014. 15 years of genetic approaches in vivo for addiction research: Opioid receptor and peptide gene knockout in mouse models of drug abuse. Neuropharmacology 76, 204–217. Cunningham, K.A., Anastasio, N.C., 2014. Serotonin at the nexus of impulsivity and cue reactivity in cocaine addiction. Neuropharmacology 76, 460–478. Deroche-Gamonet, V., Vincenzo Piazza, P., 2014. Psychobiology of cocaine addiction: Contribution of a multisymptomatic animal model of loss of control. Neuropharmacology 76, 437–449. Flagel, S.B., Waselus, M., Clinton, S.M., Watson, S.J., Akil, H., 2014. Antecedents and consequences of drug abuse in rats selectively bred for high and low response to novelty. Neuropharmacology 76, 425–436. Fowler, C.D., Kenny, P.J., 2014. Nicotine aversion: Neurobiological mechanisms and relevance to tobacco dependence vulnerability. Neuropharmacology 76, 533–544.
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David Shurtleff, Cathrine Sasek*, Mary Kautz National Institute on Drug Abuse, National Institutes of Health, United States * Corresponding author. Office of Science Policy and Communications, National Institute on Drug Abuse, 6001 Executive Boulevard, Rm 5230, MSC 9991, Bethesda, MD 20892-9555, United States. Tel.: þ1 301 443 6071; fax: þ1 301 443 6277. E-mail address: [email protected] (C. Sasek) 2 August 2013