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A Role for Brain Stress Systems in Addiction

2008; Cell Press; Volume: 59; Issue: 1 Linguagem: Inglês

10.1016/j.neuron.2008.06.012

1097-4199

George F. Koob,

Heart Rate Variability and Autonomic Control

Drug addiction is a chronically relapsing disorder characterized by compulsion to seek and take drugs and has been linked to dysregulation of brain regions that mediate reward and stress. Activation of brain stress systems is hypothesized to be key to the negative emotional state produced by dependence that drives drug seeking through negative reinforcement mechanisms. This review explores the role of brain stress systems (corticotropin-releasing factor, norepinephrine, orexin [hypocretin], vasopressin, dynorphin) and brain antistress systems (neuropeptide Y, nociceptin [orphanin FQ]) in drug dependence, with emphasis on the neuropharmacological function of extrahypothalamic systems in the extended amygdala. The brain stress and antistress systems may play a key role in the transition to and maintenance of drug dependence once initiated. Understanding the role of brain stress and antistress systems in addiction provides novel targets for treatment and prevention of addiction and insights into the organization and function of basic brain emotional circuitry. Drug addiction is a chronically relapsing disorder characterized by compulsion to seek and take drugs and has been linked to dysregulation of brain regions that mediate reward and stress. Activation of brain stress systems is hypothesized to be key to the negative emotional state produced by dependence that drives drug seeking through negative reinforcement mechanisms. This review explores the role of brain stress systems (corticotropin-releasing factor, norepinephrine, orexin [hypocretin], vasopressin, dynorphin) and brain antistress systems (neuropeptide Y, nociceptin [orphanin FQ]) in drug dependence, with emphasis on the neuropharmacological function of extrahypothalamic systems in the extended amygdala. The brain stress and antistress systems may play a key role in the transition to and maintenance of drug dependence once initiated. Understanding the role of brain stress and antistress systems in addiction provides novel targets for treatment and prevention of addiction and insights into the organization and function of basic brain emotional circuitry. Drug addiction is a chronically relapsing disorder characterized by compulsive drug use and loss of control over drug intake. Addiction comprises three stages: preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect, in which impulsivity often dominates at the early stages, and compulsivity dominates at terminal stages. As an individual moves from impulsivity to compulsivity, a shift occurs from positive reinforcement driving the motivated behavior to negative reinforcement driving the motivated behavior (Koob, 2004Koob G.F. Allostatic view of motivation: implications for psychopathology.in: Bevins R.A. Bardo M.T. Motivational Factors in the Etiology of Drug Abuse (series title: Nebraska Symposium on Motivation, vol. 50). University of Nebraska Press, Lincoln NE2004: 1-18Google Scholar). These three stages are conceptualized as feeding into one other, becoming more intense, and ultimately leading to the pathological state known as addiction (Koob and Le Moal, 1997Koob G.F. Le Moal M. Drug abuse: hedonic homeostatic dysregulation.Science. 1997; 278: 52-58Crossref PubMed Scopus (1239) Google Scholar). The preoccupation/anticipation (craving) stage of the addiction cycle has long been hypothesized to be a key element of relapse in humans and defines addiction as a chronic relapsing disorder (Table 1, Table 2). Different drugs produce different patterns of addiction that engage different components of the addiction cycle, depending on dose, length of use, and even cultural factors. With opioids, the classic drugs of addiction, a pattern of compulsive intravenous or smoked drug taking evolves that includes intense intoxication, the development of tolerance, escalation in intake, and profound dysphoria, physical discomfort, and somatic and emotional withdrawal signs during abstinence. A pattern develops in which the drug must be obtained to avoid the severe dysphoria and discomfort experienced during abstinence. Alcohol addiction or alcoholism can follow a similar trajectory, but the pattern of oral drug taking often is characterized by binges of alcohol intake that can be daily episodes or prolonged days of heavy drinking and is characterized by a severe somatic and emotional withdrawal syndrome. Nicotine addiction contrasts with the above patterns, with little obvious signs of the binge/intoxication stage, and has a pattern of intake characterized by highly titrated intake of the drug except during periods of sleep and negative emotional states during abstinence, including dysphoria, irritability, and intense craving. Marijuana addiction follows a pattern similar to opioids and tobacco, with a significant intoxication stage, but as chronic use continues, subjects begin to show a pattern of use characterized by chronic intoxication during waking hours followed by a withdrawal that includes dysphoria, irritability, and sleep disturbances. Psychostimulant addiction (cocaine and amphetamines) shows a pattern with a salient binge/intoxication stage. Such binges can be hours or days in duration and often are followed by a withdrawal (“crash”) characterized by extreme dysphoria and inactivity. Intense craving for all drugs can anticipate withdrawal (i.e., with opioids, alcohol, nicotine) or often occurs after acute withdrawal when craving is driven by both environmental cues signifying the availability of the drug and internal states linked to negative emotional states and stress. Animal models of the symptoms of addiction on specific drugs such as stimulants, opioids, alcohol, nicotine, and Δ9-tetrahydrocannabinol can be defined by models relevant to different stages of the addiction cycle (Shippenberg and Koob, 2002Shippenberg T.S. Koob G.F. Recent advances in animal models of drug addiction and alcoholism.in: Davis K.L. Charney D. Coyle J.T. Nemeroff C. Neuropsychopharmacology: The Fifth Generation of Progress. Lippincott Williams and Wilkins, Philadelphia2002: 1381-1397Google Scholar) (Table 2). Animal models for the binge/intoxication stage of the addiction cycle can be conceptualized as measuring acute drug reward, in which reward can be defined as a positive reinforcer with some additional emotional value, such as pleasure (Table 1). Animal models of reward and reinforcement are extensive and well validated and include intravenous drug self-administration, conditioned place preference, and decreased brain reward thresholds. Animal models of the withdrawal/negative affect stage include conditioned place aversion (rather than preference) to precipitated withdrawal or spontaneous withdrawal from chronic administration of a drug, increases in brain reward thresholds, and dependence-induced increases in drug seeking (Table 2). Rodents will increase intravenous or oral self-administration of drugs with extended access to the drugs and during withdrawal from the dependent state, measured both by increased drug administration and increased work to obtain the drug. Such increased self-administration in dependent animals has been observed with cocaine, methamphetamine, nicotine, heroin, and alcohol (Ahmed et al., 2000Ahmed S.H. Walker J.R. Koob G.F. Persistent increase in the motivation to take heroin in rats with a history of drug escalation.Neuropsychopharmacology. 2000; 22: 413-421Crossref PubMed Scopus (170) Google Scholar, Ahmed and Koob, 1998Ahmed S.H. Koob G.F. Transition from moderate to excessive drug intake: change in hedonic set point.Science. 1998; 282: 298-300Crossref PubMed Scopus (472) Google Scholar, Kitamura et al., 2006Kitamura O. Wee S. Specio S.E. Koob G.F. Pulvirenti L. Escalation of methamphetamine self-administration in rats: a dose-effect function.Psychopharmacology (Berl.). 2006; 186: 48-53Crossref PubMed Scopus (90) Google Scholar, O'Dell and Koob, 2007O'Dell L.E. Koob G.F. ‘Nicotine deprivation effect’ in rats with intermittent 23-hour access to intravenous nicotine self-administration.Pharmacol. Biochem. Behav. 2007; 86: 346-353Crossref PubMed Scopus (29) Google Scholar, Roberts et al., 2000Roberts A.J. Heyser C.J. Cole M. Griffin P. Koob G.F. Excessive ethanol drinking following a history of dependence: animal model of allostasis.Neuropsychopharmacology. 2000; 22: 581-594Crossref PubMed Scopus (200) Google Scholar). This model will be a key element for the evaluation of the role of brain stress systems in addiction outlined below. Animal models of craving (preoccupation/anticipation stage) involve reinstatement of drug seeking following extinction from the drugs themselves, by cues linked to the drug, and from exposure to stressors (Shaham et al., 2003Shaham Y. Shalev U. Lu L. De Wit H. Stewart J. The reinstatement model of drug relapse: history, methodology and major findings.Psychopharmacology (Berl.). 2003; 168: 3-20Crossref PubMed Scopus (731) Google Scholar) (Table 1). Drug-induced reinstatement first involves extinction and then a priming injection of the drug. Latency to reinitiate responding or the amount of responding on the previously extinguished lever are hypothesized to reflect the motivation for drug-seeking behavior. Similarly, drug-paired or drug-associated stimuli can reinitiate drug-seeking behavior (cue-induced reinstatement). Stress-induced reinstatement involves the application of acute stressors that reinitiate drug-seeking behavior in animals that have been extinguished from the drug. These stressors can include physical stressors such as footshock, psychological stressors such as restraint, or pharmacological stressors such as yohimbine (Shaham et al., 2003Shaham Y. Shalev U. Lu L. De Wit H. Stewart J. The reinstatement model of drug relapse: history, methodology and major findings.Psychopharmacology (Berl.). 2003; 168: 3-20Crossref PubMed Scopus (731) Google Scholar). In rats with a history of dependence, protracted abstinence can be defined as a period after acute physical withdrawal has disappeared in which elevations in ethanol intake over baseline and increased stress responsivity persist (e.g., 2–8 weeks postwithdrawal from chronic ethanol). Protracted abstinence has been linked to increased brain reward thresholds and increases in sensitivity to anxiety-like behavior that have been shown to persist after acute withdrawal in animals with a history of dependence. Stress-induced reinstatement of drug seeking and stress-induced reinstatement of anxiety-like states during protracted abstinence will be used in the present review to explore the role of the brain stress systems in the preoccupation-anticipation (craving) stage of the addiction cycle (Table 2). The thesis of this review is that a key element of the addiction process involves a profound interaction with brain stress systems and dysregulation of brain antistress systems to produce the negative emotional state that becomes the powerful motivation for drug seeking associated with compulsive use in the withdrawal/negative affect and preoccupation/anticipation (craving) stages of the addiction cycle. Chronic use of drugs of abuse has long been associated with exaggerated responses to stressors, and these exaggerated responses contribute to addiction (Himmelsbach, 1941Himmelsbach C.K. Studies on the relation of drug addiction to the autonomic nervous system: results of cold pressor tests.J. Pharmacol. Exp. Ther. 1941; 73: 91-98Google Scholar). Delineation of key elements of not only hormonal but also brain stress neurocircuits have laid the foundation for new insights into the pathophysiology of addiction. Motivation is a state that guides behavior in relationship to changes in the environment (Hebb, 1949Hebb D.O. Organization of Behavior: A Neuropsychological Theory. Wiley, New York1949Google Scholar) and shares key common characteristics with our concepts of arousal (Pfaff, 2006Pfaff D. Brain Arousal and Information Theory: Neural and Genetic Mechanisms. Harvard University Press, Cambridge, MA2006Crossref Google Scholar). Motivational states gain energy both from the external milieu (incentives) or internal milieu (central motive states or drives). As such, motivation or motivational states are not constant and vary over time but have long been hypothesized to have homeostatic constraints. In the context of temporal dynamics, Solomon and Corbit inextricably linked the concept of motivation with hedonic, affective, or emotional states in addiction by the opponent process theory of motivation (Solomon and Corbit, 1974Solomon R.L. Corbit J.D. An opponent-process theory of motivation: 1. Temporal dynamics of affect.Psychol. Rev. 1974; 81: 119-145Crossref PubMed Scopus (531) Google Scholar) (Table 1). More recently, opponent process theory has been expanded into the domains of the neurocircuitry and neurobiology of drug addiction from a physiological perspective (Koob and Le Moal, 2008Koob G.F. Le Moal M. Addiction and the brain antireward system.Annu. Rev. Psychol. 2008; 59: 29-53Crossref PubMed Scopus (345) Google Scholar). Counteradaptive processes such as opponent process that are part of the normal homeostatic limitation of reward function are hypothesized to fail to return to the normal homeostatic range and thus produce the reward deficits that are prominent in addiction. These counteradaptive processes were hypothesized to be mediated by two processes: within-system neuroadaptations and between-system neuroadaptations (Koob and Bloom, 1988Koob G.F. Bloom F.E. Cellular and molecular mechanisms of drug dependence.Science. 1988; 242: 715-723Crossref PubMed Google Scholar) (Table 1). For the present review, the systems activated as between-system neuroadaptations are hypothesized to involve the brain stress systems and the brain antistress systems. These circuits also can be conceptualized as an antireward homeostatic mechanism (Koob and Le Moal, 2008Koob G.F. Le Moal M. Addiction and the brain antireward system.Annu. Rev. Psychol. 2008; 59: 29-53Crossref PubMed Scopus (345) Google Scholar). In this framework, addiction is conceptualized as a cycle of spiraling dysregulation of brain reward/antireward mechanisms that progressively increases, resulting in the compulsive use of the drug. The purpose of this review is to explore the neuroadaptational changes that occur in the brain stress and antistress systems to account for the negative emotional state that provides motivation for the compulsivity of addiction. The hypothalamic-pituitary-adrenal (HPA) axis is defined by three major structures: the paraventricular nucleus of the hypothalamus, the anterior lobe of the pituitary gland, and the adrenal gland (for review, see Turnbull and Rivier, 1997Turnbull A.V. Rivier C. Corticotropin-releasing factor (CRF) and endocrine responses to stress: CRF receptors, binding protein, and related peptides.Proc. Soc. Exp. Biol. Med. 1997; 215: 1-10Crossref PubMed Google Scholar). Neurosecretory neurons in the medial parvocellular subdivision of the paraventricular nucleus synthesize and release CRF into the portal blood vessels that enter the anterior pituitary gland. Binding of CRF to the CRF1 receptor on pituitary corticotropes induces the release of adrenocorticotropic hormone (ACTH) into the systemic circulation. ACTH, in turn, stimulates glucocorticoid synthesis and secretion from the adrenal cortex. Vasopressin released from parvocellular neurons of the paraventricular nucleus produces synergistic effects on ACTH release that are mediated by vasopressin V1b receptors. The HPA axis is finely tuned via negative feedback from circulating glucorticoids that act on the glucocorticoid receptor, a cytosolic protein that acts via the nucleus and transcriptional mechanisms, in two main brain areas: the paraventricular nucleus and the hippocampus. The hypophysiotropic neurons of the paraventricular nucleus of the hypothalamus are innervated by numerous afferent projections, including from brainstem, other hypothalamic nuclei, and forebrain limbic structures. New functional observations have provided support for the hypothesis that the neuroanatomical substrates for many of the motivational effects of opponent processes associated with drug dependence may involve a common neural circuitry that forms a separate entity within the basal forebrain, termed the “extended amygdala” (Koob and Le Moal, 2001Koob G.F. Le Moal M. Drug addiction, dysregulation of reward, and allostasis.Neuropsychopharmacology. 2001; 24: 97-129Crossref PubMed Scopus (1140) Google Scholar). The extended amygdala represents a macrostructure that is composed of several basal forebrain structures: the bed nucleus of the stria terminalis, the central medial amygdala, and a transition zone in the posterior part of the medial nucleus accumbens (i.e., posterior shell) (Heimer and Alheid, 1991Heimer L. Alheid G. Piecing together the puzzle of basal forebrain anatomy.in: Napier T.C. Kalivas P.W. Hanin I. The Basal Forebrain: Anatomy to Function (series title: Advances in Experimental Medicine and Biology, vol. 295). Plenum Press, New York1991: 1-42Google Scholar). These structures have similarities in morphology, immunohistochemistry, and connectivity, and they receive afferent connections from limbic cortices, hippocampus, basolateral amygdala, midbrain, and lateral hypothalamus. The efferent connections from this complex include the posterior medial (sublenticular) ventral pallidum, ventral tegmental area, various brainstem projections, and perhaps most intriguing from a functional point of view, a considerable projection to the lateral hypothalamus (Heimer and Alheid, 1991Heimer L. Alheid G. Piecing together the puzzle of basal forebrain anatomy.in: Napier T.C. Kalivas P.W. Hanin I. The Basal Forebrain: Anatomy to Function (series title: Advances in Experimental Medicine and Biology, vol. 295). Plenum Press, New York1991: 1-42Google Scholar). Key elements of the extended amygdala include not only neurotransmitters associated with the positive reinforcing effects of drugs of abuse but also major components of the brain stress systems associated with the negative reinforcement of dependence (Koob and Le Moal, 2005Koob G.F. Le Moal M. Plasticity of reward neurocircuitry and the ‘dark side’ of drug addiction.Nat. Neurosci. 2005; 8: 1442-1444Crossref PubMed Scopus (267) Google Scholar). The role of specific neuropharmacological mechanisms associated with the brain stress systems and the extended amygdala will be explored in the sections below. Corticotropin-releasing factor is a 41 amino acid polypeptide that controls hormonal, sympathetic, and behavioral responses to stressors. Substantial CRF-like immunoreactivity is present in the neocortex, extended amygdala, medial septum, hypothalamus, thalamus, cerebellum, and autonomic midbrain and hindbrain nuclei (Swanson et al., 1983Swanson L.W. Sawchenko P.E. Rivier J. Vale W. The organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: an immunohistochemical study.Neuroendocrinology. 1983; 36: 165-186Crossref PubMed Google Scholar) (Figure 1). The CRF1 receptor has abundant, widespread expression in the brain that overlaps significantly with the distribution of CRF and urocortin 1. The discovery of other peptides with structural homology, notably the urocortin family (urocortins 1, -2, and -3), has suggested broad neurotransmitter roles for the CRF systems in behavioral and autonomic responses to stress (Bale and Vale, 2004Bale T.L. Vale W.W. CRF and CRF receptors: role in stress responsivity and other behaviors.Annu. Rev. Pharmacol. Toxicol. 2004; 44: 525-557Crossref PubMed Scopus (558) Google Scholar) (see Supplemental Data available online). Urocortin 1 binds both to CRF1 and CRF2 receptors and has a different neuroanatomical distribution than CRF. The type 2 urocortins, urocortin 2 (Reyes et al., 2001Reyes T.M. Lewis K. Perrin M.H. Kunitake K.S. Vaughan J. Arias C.A. Hogenesch J.B. Gulyas J. Rivier J. Vale W.W. Sawchenko P.E. Urocortin II: A member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors.Proc. Natl. Acad. Sci. USA. 2001; 98: 2843-2848Crossref PubMed Scopus (603) Google Scholar) and urocortin 3 (Lewis et al., 2001Lewis K. Li C. Perrin M.H. Blount A. Kunitake K. Donaldson C. Vaughan J. Reyes T.M. Gulyas J. Fischer W. et al.Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor.Proc. Natl. Acad. Sci. USA. 2001; 98: 7570-7575Crossref PubMed Scopus (607) Google Scholar), differ from urocortin 1 and CRF in their neuroanatomical, neuropharmacological, and distribution profiles and are endogenous selective CRF2 agonists. (A) The major CRF-stained cell groups (dots) and fiber systems in the rat brain. Most of the immunoreactive cells and fibers appear to be associated with systems that regulate the output of the pituitary and the autonomic nervous system and with cortical interneurons. Most of the longer central fibers course either ventrally through the medial forebrain bundle and its caudal extension in the reticular formation, or dorsally through a periventricular system in the thalamus and brainstem central gray. The direction of fibers in these systems is unclear because they appear to interconnect regions that contain CRF-stained cell bodies. Three adjacent CRF-stained cell groups—laterodorsal tegmental nucleus, locus coeruleus, parabrachial nucleus—lie in the dorsal pons. Uncertain is which of these cell groups contributes to each of the pathways shown, and which of them receives inputs from the same pathways. Modified with permission from Swanson et al., 1983Swanson L.W. Sawchenko P.E. Rivier J. Vale W. The organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: an immunohistochemical study.Neuroendocrinology. 1983; 36: 165-186Crossref PubMed Google Scholar. ac, anterior commissure; BST, bed nucleus of the stria terminalis; cc, corpus callosum; CeA, central nucleus of the amygdala; CG, central gray; DR, dorsal raphe; DVC, dorsal vagal complex; HIP, hippocampus; LDT, laterodorsal tegmental nucleus; LHA, lateral hypothalamic area; ME, median eminence; mfb, medial forebrain bundle; MID THAL, midline thalamic nuclei; MPO, medial preoptic area; MR, median raphe; MVN, medial vestibular nucleus; PB, parabrachial nucleus; POR, perioculomotor nucleus; PP, peripeduncular nucleus; PVN, paraventricular nucleus; SEPT, septal region; SI, substantia innominata; st, stria terminalis. (B) Role of corticotropin-releasing factor in dependence. CRF in the paraventricular nucleus of the hypothalamus controls the pituitary adrenal response to stress (Turnbull and Rivier, 1997Turnbull A.V. Rivier C. Corticotropin-releasing factor (CRF) and endocrine responses to stress: CRF receptors, binding protein, and related peptides.Proc. Soc. Exp. Biol. Med. 1997; 215: 1-10Crossref PubMed Google Scholar). Progressive changes in the HPA axis are observed during the transition from acute administration to chronic administration of drugs of abuse. Acute administration of most drugs of abuse in animals activates the HPA axis and may first facilitate activity in the brain motivational circuits, facilitate drug reward, and as a result facilitate acquisition of drug-seeking behavior (Piazza et al., 1993Piazza P.V. Deroche V. Deminière J.M. Maccari S. Le Moal M. Simon H. Corticosterone in the range of stress-induced levels possesses reinforcing properties: implications for sensation-seeking behaviors.Proc. Natl. Acad. Sci. 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Thus, while activation of the HPA axis may characterize initial drug use and the binge/intoxication stage of addiction, the HPA activation also can lead to subsequent activation of extrahypothalamic brain stress systems that characterize the withdrawal/negative affect stage of addiction (Kreek and Koob, 1998Kreek M.J. Koob G.F. Drug dependence: Stress and dysregulation of brain reward pathways.Drug Alcohol Depend. 1998; 51: 23-47Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar, Koob and Le Moal, 2005Koob G.F. Le Moal M. Plasticity of reward neurocircuitry and the ‘dark side’ of drug addiction.Nat. Neurosci. 2005; 8: 1442-1444Crossref PubMed Scopus (267) Google Scholar, Koob and Kreek, 2007Koob G.F. Kreek M.J. Stress, dysregulation of drug reward pathways, and the transition to drug dependence.Am. J. Psychiatry. 2007; 164: 1149-1159Crossref PubMed Scopus (292) Google Scholar) (Figure 2). (A) Effects of ethanol withdrawal on CRF-like immunoreactivity in the rat amygdala determined by microdialysis. Dialysate was collected over four 2 hr periods regularly alternated with nonsampling 2 hr periods. The four sampling periods corresponded to the basal collection (before removal of ethanol), and 2–4 hr, 6–8 hr, and 10–12 hr after withdrawal. Fractions were collected every 20 min. Data are represented as mean ± SEM (n = 5 per group). ANOVA confirmed significant differences between the two groups over time (p < 0.05). Taken with permission from Merlo-Pich et al., 1995Merlo-Pich E. Lorang M. Yeganeh M. Rodriguez de Fonseca F. Raber J. Koob G.F. Weiss F. Increase of extracellular corticotropin-releasing factor-like immunoreactivity levels in the amygdala of awake rats during restraint stress and ethanol withdrawal as measured by microdialysis.J. Neurosci. 1995; 15: 5439-5447PubMed Google Scholar. (B) Mean (±SEM) dialysate CRF concentrations collected from the central nucleus of the amygdal