Plasticity of Reward Neurocircuitry and the 'Dark Side' of Drug Addiction

COMMENTARY NEUROBIOLOGY OF ADDICTION

Plasticity of reward neurocircuitry and the ‘dark side’ of drug addiction

George F Koob & Michel Le Moal

Drug seeking is associated with activation of reward neural circuitry. Here we argue that drug addiction also involves a ‘dark side’—a decrease in the function of normal reward-related neurocircuitry and persistent recruitment of anti-reward systems. Understanding the neuroplasticity of the dark side of this circuitry is the key to understanding vulnerability to addiction.

Drug addiction has been conceptualized as tive and sensitization framework) can be super- theoretical positions favor models from each of http://www.nature.com/natureneuroscience a progression from impulsive to compulsive imposed on the stages of the addiction cycle2. the three stages, although in our view, models behavior, ending in chronic, relapsing drug These stages are thought to feed into each other, of the transition to dependence have the most taking. Patients with impulse control disor- becoming more intense and ultimately leading heuristic value for the human condition. ders experience an increasing sense of tension to the pathological state known as addiction. For the binge-intoxication stage, studies of or arousal before committing an impulsive Our thesis is that addiction involves a long- the acute reinforcing effects of drugs of abuse act; pleasure, gratification or relief at the time term, persistent plasticity in the activity of per se have identified key neurobiological sub- of committing the act; and then regret, self- neural circuits mediating two different moti- strates. Important anatomical circuits include reproach or guilt after the act1. In contrast, vational systems: decreased function of brain the mesocorticolimbic dopamine system patients with compulsive disorders experience reward systems driven by natural rewards, and originating in the ventral tegmental area and anxiety and stress before committing a com- recruitment of anti-reward systems that drive projecting to the nucleus accumbens and the pulsive repetitive behavior, then relief from the aversive states. The concept of anti-reward is extended amygdala. The extended amygdala stress by performing the behavior1. In addic- based on the hypothesis that there are brain comprises the central nucleus of the amygdala,

2005 Nature Publishing Group Group 2005 Nature Publishing tion, drug-taking behavior progresses from systems in place to limit reward (see footnote the bed nucleus of the stria terminalis and a

© impulsivity to compulsivity in a three-stage in ref. 2), an ‘opponent process’ concept that is transition area in the medial (shell) part of the cycle: binge/intoxication, withdrawal/negative a general feature of biological systems3. nucleus accumbens and a major projection to affect and preoccupation/anticipation2. In the From a neurobiological perspective, progres- the lateral hypothalamus. Neurotransmitter/ impulsive stage, the drive for the drug-taking sion through the three stages of the addiction neuromodulator systems implicated in the behavior is positive reinforcement, in which cycle induces plasticity in neural circuitry that acute reinforcing effects of drugs of abuse in stimuli increase the probability of the response. drives compulsive drug taking, narrowing the these neuroanatomical sites include dopamine, As individuals move to the compulsive stage, the behavioral repertoire to drug seeking. Animal opioid peptides, γ-aminobutyric acid (GABA), drive transitions to negative reinforcement, in models have been developed that have face glutamate, neuropeptide Y and glucocorticoids which removal of the aversive state increases the validity (resembles the human condition) and of the hypothalamic-pituitary-adrenal (HPA) probability of the response. Different theoreti- some construct validity (possesses explanatory axis5. There is strong evidence for a role of cal perspectives from experimental psychology power) for all three stages of the addiction cycle dopamine in the acute reinforcing actions of (positive and negative reinforcement frame- and the transition to drug addiction. Acute self- psychostimulants, for opioid peptide receptors work), social psychology (self-regulation failure administration of drugs (intravenous and oral) in the acute reinforcing effects of opioids, and framework) and neurobiology (counteradap- has construct validity for drug intoxication and for GABA and opioid peptides in the acute rein- elements of drug binges in humans. Self-stim- forcing actions of alcohol. Although acute drug ulation and place conditioning (learning to use is not, in and of itself, addiction, the study George F. Koob is in the Molecular and Integrative avoid a location previously paired with an aver- of the neuropharmacological mechanisms for Neurosciences Department, The Scripps sive stimulus or state) are sensitive measures the acute reinforcing effects of drugs of abuse Research Institute, La Jolla, California, 92037, of ‘motivational’ withdrawal. Cue-induced or has had heuristic value in two major domains. USA, and Michel Le Moal is at the Laboratoire de stress-induced reinstatement has face validity Such studies provide a framework for examin- Physiopathologie des Comportements, Institut and is currently under test for construct valid- ing neuroadaptive changes in the reward circuits National de la Santé et de la Recherche Médicale, ity. Although more construct validation rela- with the development of addiction, and they Unite 588, Université Victor Segalen Bordeaux 2, tive to the human condition is needed, neural also provide a valid model for development of Bordeaux, France. substrates for each of the stages have already medications to treat excessive drug intake (such e-mail: [email protected] been identified using these models4. Different as naltrexone for excessive drinking).

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For the purposes of this opinion piece, the provides a powerful source of negative rein- source of potential allostatic changes that drive withdrawal/negative affect stage can be defined forcement that defines compulsive drug-seek- and maintain addiction2. In this context, ‘allo- as the presence of motivational signs of with- ing behavior and addiction. The development stasis’ is defined as the process of achieving drawal in humans: chronic irritability, emo- of the aversive emotional state that drives the stability of the reward system through change. tional pain, malaise, dysphoria, alexithymia negative reinforcement of addiction is here An allostatic state is a state of chronic deviation and loss of motivation for natural rewards. It is termed the ‘dark side’ of addiction. We further of the reward system from its normal (homeo- characterized in animals by increases in reward hypothesize that this chronic aversive state static) operating level, which ultimately leads thresholds during withdrawal from all major manifested by motivational signs of withdrawal to the pathological state of addiction. More drugs of abuse. Significant plasticity occurs in in humans is produced in part by recruitment specifically, in drug addiction, allostasis is the the neurotransmitter circuits identified above of the brain anti-reward systems. We believe process of attempting to maintain apparent as critical for the acute reinforcing effects of that research in this domain has been largely reward function stability by changes in reward drugs of abuse. In animal models of the tran- neglected by the field, mainly because of an and anti-reward system neurocircuitry5. sition to addiction, similar changes in brain excessive focus on psychostimulant drugs and Neuroplasticity in the natural reward sys- reward threshold occur that temporally precede reward pathways (largely misattributed to the tem is highlighted by decreased dopaminergic and highly correlate with escalation in drug mesolimbic dopamine system). activity and hypofrontality. Neuroplasticity intake6. During such acute withdrawal, there A critical problem in drug addiction is in the anti-reward system is highlighted by is decreased activity of the mesocorticolimbic chronic relapse, in which addicts return to increased CRF function and is hypothesized dopamine system as measured by electrophysi- compulsive drug taking long after acute with- to be particularly slow to return to homeosta- ological recordings and in vivo microdialysis, drawal. This corresponds to the preoccupation/ sis. This makes the system that drives the dark and there is also decreased activity in opioid anticipation stage of the addiction cycle, out- side potentially more important for driving peptide, GABA, glutamate and neuropeptide Y lined above. Both animal and human neuro- dependence than decreases in natural reward in elements of the extended amygdala and/or imaging studies show that the prefrontal cortex function. For example, there is evidence of nucleus accumbens. Human imaging studies system (orbitofrontal, medial prefrontal, pre- residual dysregulation of the HPA axis16 and of http://www.nature.com/natureneuroscience of addicts during withdrawal or protracted limbic/cingulate) and the basolateral amygdala the brain CRF system weeks after acute with- abstinence give results that are consistent are key mediators of drug- and cue-induced drawal from alcohol17. Similar observations with the animal studies, including decreases reinstatement in animal models and craving are made in human addicts18. In contrast, in dopamine D2 receptors (hypothesized to and relapse in humans. Neurotransmitter withdrawal-induced decreases in dopaminer- reflect hypodopaminergic functioning) and systems implicated in drug- and cue- or con- gic function are relatively transient10. Thus, hypoactivity of the orbitofrontal-infralimbic text-induced craving again include dopa- the drug addict, futilely in the short term, cortex system7. These neurotransmitter/neuro- mine, opioid peptides, glutamate and GABA. attempts to misregulate these drug-induced modulator system changes may persist during Neurotransmitter/neuromodulator systems neuroplasticities by taking more drug, which protracted abstinence and include hypofunc- implicated in stress-induced relapse include only serves in the long-term to dysregulate the tioning of the HPA axis8. CRF, glucocorticoids and norepinephrine, sug- system further, leading to a worsening of the More importantly for the present thesis, as gesting that there is reactivation of both reward condition. The most prominent functional dependence and withdrawal develop, brain and anti-reward systems during relapse12–14. increase of the anti-reward system identified

2005 Nature Publishing Group Group 2005 Nature Publishing anti-reward systems such as corticotropin- Although the relapse models have face validity, to date involves activation of the CRF-HPA

© releasing factor (CRF), norepinephrine there remain serious concerns about construct axis and subsequent activation of the CRF– and dynorphin are recruited. For example, validity relative to the human condition. Most extended amygdala system, but other neuro- extracellular CRF in the extended amygdala reinstatement studies to date have been done adaptive processes associated with behavioral is increased during acute withdrawal from with nondependent animals and may be of responses to stressors also may have potential drugs of abuse, and critically, CRF receptor little more relevance to the study of addiction roles such as neuropeptide Y, dynorphin and antagonists block excessive drug taking during than studies of reinstatement of responding for norepinephrine. The allostatic dysregulated dependence8. These neurotransmitter systems a nondrug, high-incentive stimulus such as a reward state not only produces the motiva- are activated during the development of exces- saccharin solution, a control rarely explored tional symptoms of acute withdrawal and sive drug taking, and this activation is manifest in reinstatement studies. In other words, do protracted abstinence, but also provides the when the drug in removed (acute withdrawal the neuropharmacological substrates for the background by which drug priming, drug cues and protracted abstinence). The observation reinstatement of responding for saccharin—or and acute stressors acquire even more power that CRF receptor antagonists in the amyg- any other nondrug reinforcer of high incentive to elicit drug-seeking behavior. dala can block excessive drug intake associ- value—parallel those of the neural substrates Clearly appropriate, construct-validated ated with the development of dependence for nondependent doses of cocaine or heroin? animal models for the stages of the addiction provides a compelling example of a key player We also hypothesize that the dysregulations cycle, the motivational aspects of drug-seek- in the plasticity of the extended amygdala in that constitute the dark side of drug addiction ing and genetic vulnerability to addiction the development of addiction. We hypoth- persist during protracted abstinence to set are critical to test these hypotheses. Recently, esize that anti-reward circuits are recruited as the tone for vulnerability to ‘craving’ by acti- animal models with excellent face validity for between-system neuroadaptations9 during the vation of the drug-, cue- and stress-induced the transition to addiction have been devel- development of addiction, producing aversive reinstatement neurocircuits now driven by a oped, which include escalated drug intake or stress-like states8,10,11. We further hypoth- reorganized and hypofunctioning prefrontal driven by dependence6,15, responding for esize that within the motivational circuits of system15. A reward allostasis model is proposed drug despite adverse consequences19,20 and the extended amygdala, the combination of to explain how dysregulation of the reward a narrowing of the behavioral repertoire for decreases in reward neurotransmitter func- system associated with the development of drug19,20. These models have strong face valid- tion and recruitment of anti-reward systems motivational aspects of withdrawal is a major ity for the Diagnostic and Statistical Manual of

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Mental Disorders1 and International Statistical ACKNOWLEDGMENTS 9. Koob, G.F. & Bloom, F.E. Science 242, 715–723 Classification of Diseases21 criteria for addic- We thank M. Arends for his assistance with the (1988). preparation of this manuscript. 10. Nestler, E.J. Nat. Rev. Neurosci. 2, 119–128 (2001). tion, are currently under test for construct 11. Aston-Jones, G., Delfs, J.M., Druhan, J. & Zhu, Y. Ann. validity and show promise for measuring the NY Acad. Sci. 877, 486–498 (1999). COMPETING INTERESTS STATEMENT 12. Piazza, P.V. & Le Moal, M. Annu. Rev. Pharmacol. genetic and environmental contributions to The authors declare that they have no competing Toxicol. 36, 359–378 (1996). vulnerability to addiction. financial interests. 13. Shaham, Y., Erb, S. & Stewart, J. Brain Res. Brain Res. Thus, in our view, a perspective often over- Rev. 33, 13–33 (2000). 1. American Psychiatric Association. Diagnostic and 14. See, R.E., Fuchs, R.A., Ledford, C.C. & McLaughlin, J. looked in the drug abuse field is that there is Statistical Manual of Mental Disorders 4th edn. Ann. NY Acad. Sci. 985, 294–307 (2003). a long-term persistent decrease in function of (American Psychiatric Press, Washington, D.C., 15. Le Moal, M. in Psychopharmacology: The Fourth 1994). Generation of Progress (eds. Bloom, F.E. & Kupfer, normal motivational systems driven by two 2. Koob, G.F. & Le Moal, M. Science 278, 52–58 D.J.) 283–294 (Raven, New York, 1995). sources: decreased function of brain reward sys- (1997). 16. Rasmussen, D.D. et al. Alcohol. Clin. Exp. Res. 24, tems (mediating natural rewards) and increased 3. Martin, W.R. in The Addictive States (ed. Wikler, A.) 1836–1849 (2000). 206–225 (Williams and Wilkins, Baltimore, 1968). 17. Valdez, G.R. et al. Alcohol. Clin. Exp. Res. 26, 1494– anti-reward systems (recruited as an opponent 4. Shippenberg, T.S. & Koob, G.F. in 1501 (2002). process to excessive activation of the brain Neuropsychopharmacology: The Fifth Generation of 18. Kreek, M.J. & Koob, G.F. Drug Alcohol Depend. 51, reward system)22. It is the deficit state for nor- Progress (eds. Davis, K.L., Charney, D., Coyle, J.T. & 23–47 (1998). Nemeroff, C.) 1381–1397 (Lippincott Williams and 19. Deroche-Gamonet, V., Belin, D. & Piazza, P.V. Science mal reward, produced by excessive drug taking, Wilkins, Philadelphia, 2002). 305, 1014–1017 (2004). that provides the core element of the motivation 5. Koob, G.F. & Le Moal, M. Neuropsychopharmacology 20. Vanderschuren, L.J. & Everitt, B.J. Science 305, 1017– 24, 97–129 (2001). 1019 (2004). to seek drugs, not a hyperactive or sensitized 6. Ahmed, S.H., Kenny, P.J., Koob, G.F. & Markou, A. Nat. 21. World Health Organization. International Statistical reward state for drugs per se. In our view, under- Neurosci. 5, 625–626 (2002). Classification of Diseases and Related Health Problems, standing the neuroplasticity of the dark side of 7. Volkow, N.D., Fowler, J.S. & Wang, G.J. J. Clin. Invest. 10th revision (World Health Organization, Geneva, 111, 1444–1451 (2003). 1992). this circuitry will be the key to understanding 8. Koob, G.F. Alcohol. Clin. Exp. Res. 27, 232–243 22. Solomon, R.L. & Corbit, J.D. Psychol. Rev. 81, 119– individual vulnerability to addiction. (2003). 145 (1974). http://www.nature.com/natureneuroscience 2005 Nature Publishing Group Group 2005 Nature Publishing ©

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