Dynamics of Neuronal Circuits in Addiction: Reward, Antireward, and Emotional Memory

Abstract

Drug addiction is conceptualized as chronic, relapsing compulsive use of drugs with significant dysregulation of brain hedonic systems. Compulsive drug use is accompanied by decreased function of brain substrates for drug positive reinforcement and recruitment of brain substrates mediating the negative reinforcement of motivational withdrawal. The neural substrates for motivational withdrawal (“dark side” of addiction) involve recruitment of elements of the extended amygdala and the brain stress systems, including corticotropin-releasing factor and norepinephrine. These changes, combined with decreased reward function, are hypothesized to persist in the form of an allostatic state that forms a powerful motivational background for relapse. Relapse also involves a key role for the basolateral amygdala in mediating the motivational effects of stimuli previously paired with drug seeking and drug motivational withdrawal. The basolateral amygdala has a key role in mediating emotional memories in general. The hypothesis argued here is that brain stress systems activated by the motivational consequences of drug withdrawal can not only form the basis for negative reinforcement that drives drug seeking, but also potentiate associative mechanisms that perpetuate the emotional state and help drive the allostatic state of addiction.

References

• 1 Ahmed SH, Kenny PJ, Koob GF. et al . Neurobiological evidence for hedonic allostasis associated with escalating cocaine use.  Nat Neurosci. 2002;  5 625-626
• 2 Alheid GF, De Olmos JS, Beltramino CA. Amygdala and extended amygdala. In: Paxinos G, ed. The rat nervous system. San Diego: Academic Press 1995: 495-578
• 3 Alling C, Balldin J, Bokstrom K. et al . Studies on duration of a late recovery period after chronic abuse of ethanol: a cross-sectional study of biochemical and psychiatric indicators.  Acta Psychiatr Scand. 1982;  66 384-397
• 4 American Psychiatric Association .Diagnostic and statistical manual of mental disorders, 4th edition, text revision. Washington DC: American Psychiatric Press 2000
• 5 Baldwin HA, Rassnick S, Rivier J. et al . CRF antagonist reverses the “anxiogenic” response to ethanol withdrawal in the rat.  Psychopharmacology. 1991;  103 227-232
• 6 Becker HC. Positive relationship between the number of prior ethanol withdrawal episodes and the severity of subsequent withdrawal seizures.  Psychopharmacology. 1994;  116 26-32
• 7 Bester H, Menendez L, Besson JM. et al . Spino (trigemino) parabrachiohypothalamic pathway: electrophysiological evidence for an involvement in pain processes.  J Neurophysiol. 1995;  73 568-585
• 8 Breese GR, Overstreet DH, Knapp DJ. et al . Prior multiple ethanol withdrawals enhance stress-induced anxiety-like behavior: inhibition by CRF₁- and benzodiazepine-receptor antagonists and a 5-HT_1a-receptor agonist.  Neuropsychopharmacology. 2005;  30 1662-1669
• 9 Cahill L, Haier RJ, Fallon J. et al . Amygdala activity at encoding correlated with long-term, free recall of emotional information.  Proc Natl Acad Sci USA. 1996;  93 8016-8021
• 10 Carr GD, Fibiger HC, Phillips AG. Conditioned place preference as a measure of drug reward. In: Liebman JM, Cooper SJ, eds. The neuropharmacological basis of reward (series title: Topics in experimental psychopharmacology, vol 1. New York: Oxford University Press 1989: 264-319
• 11 Conway MA. Flashbulb memories. Hillsdale NJ: Lawrence Erlbaum 1995
• 12 Davis WM, Smith SG. Role of conditioned reinforcers in the initiation, maintenance and extinction of drug-seeking behavior.  Pavlovian J Biol Sci. 1976;  11 222-236
• 13 Davis WM, Smith SG. Conditioned reinforcement as a measure of the rewarding properties of drugs. In: Bozarth MA, ed. Methods of assessing the reinforcing properties of abused drugs. New York: Springer-Verlag 1987: 199-210
• 14 Di Chiara G, Bassareo V, Fenu S. et al . Dopamine and drug addiction: the nucleus accumbens shell connection.  Neuropharmacology. 2004;  47 ((Suppl 1)) 227-241
• 15 Doyon WM, York JL, Diaz LM. et al . Dopamine activity in the nucleus accumbens during consummatory phases of oral ethanol self-administration.  Alcohol Clin Exp Res. 2003;  27 1573-1582
• 16 Dworkin SI, Guerin GF, Co C. et al . Lack of an effect of 6-hydroxydopamine lesions of the nucleus accumbens on intravenous morphine self-administration.  Pharmacol Biochem Behav. 1988;  30 1051-1057
• 17 Everitt BJ, Wolf ME. Psychomotor stimulant addiction: a neural systems perspective.  J Neurosci. 2002;  22 3312-3320 , [erratum: 22(16): 1a]
• 18 Ferry B, Roozendaal B, MacGaugh JL. Involvement of alpha1-adrenoceptors in the basolateral amygdala in modulation of memory storage.  Eur J Pharmacol. 1999;  372 9-16
• 19 Funk CK, O’Dell LE, Crawford EF. et al . Corticotropin-releasing factor within the central nucleus of the amygdala mediates enhanced ethanol self-administration in withdrawn, ethanol-dependent rats.  J Neurosci. 2006;  26 11324-11332
• 20 Gallagher M, Kapp BS, Musty RE. et al . Memory formation: evidence for a specific neurochemical system in the amygdala.  Science. 1977;  198 423-425
• 21 George O, Ghozland S, Azar MR. et al . CRF-CRF1 system activation mediates withdrawal-induced increases in nicotine self-administration in nicotine-dependent rats.  Proc Natl Acad Sci USA. 2007;  104 17198-17203
• 22 Goldberg SR, Gardner ML. Second-order schedules: extended sequences of behavior controlled by brief environmental stimuli associated with drug self-administration. In: Thompson T, Johanson CE, eds. Behavioral pharmacology of human drug dependence (series title: NIDA research monograph, vol 37). Rockville MD: National Institute on Drug Abuse 1981: 241-270
• 23 Goldberg SR, Kelleher RT. Behavior controlled by scheduled injections of cocaine in squirrel and rhesus monkeys.  J Exp Anal Behav. 1976;  25 93-104
• 24 Greenwell TN, Funk CK, Cottone P. et al . Corticotropin-releasing factor-1 receptor antagonists decrease heroin self-administration in long-, but not short-access rats.  Addict Biol. 2009;  14 130-143
• 25 Grobin AC, Matthews DB, Devaud LL. et al . The role of GABA_A receptors in the acute and chronic effects of ethanol.  Psychopharmacology. 1998;  139 2-19
• 26 Hatfield T, MacGaugh JL. Norepinephrine infused into the basolateral amygdala posttraining enhances retention in a spatial water maze task.  Neurobiol Learn Mem. 1999;  71 232-239
• 27 Hernandez G, Hamdani S, Rajabi H. et al . Prolonged rewarding stimulation of the rat medial forebrain bundle: neurochemical and behavioral consequences.  Behav Neurosci. 2006;  120 888-904
• 28 Heyser CJ, Roberts AJ, Schulteis G. et al . Central administration of an opiate antagonist decreases oral ethanol self-administration in rats.  Alcohol Clin Exp Res. 1999;  23 1468-1476
• 29 Kalivas PW, MacFarland K, Bowers S. et al .Glutamate transmission and addiction to cocaine. In: Moghaddam B, Wolf ME, eds. Glutamate and disorders of cognition and motivation (series title: Annals of the New York Academy of Sciences, vol 1003). New York: New York Academy of Sciences 2003: 169-175
• 30 Kalivas PW, O’Brien C. Drug addiction as a pathology of staged neuroplasticity.  Neuropsychopharmacology. 2008;  33 166-180
• 31 Kenny PJ, Chen SA, Kitamura O. et al . Conditioned withdrawal drives heroin consumption and decreases reward sensitivity.  J Neurosci. 2006;  26 5894-5900
• 32 Koob GF. Drugs of abuse: anatomy, pharmacology, and function of reward pathways.  Trends Pharmacol Sci. 1992;  13 177-184
• 33 Koob GF. Corticotropin-releasing factor, norepinephrine and stress.  Biol Psychiatry. 1999;  46 1167-1180
• 34 Koob GF. Allostatic view of motivation: implications for psychopathology. In: Bevins RA, Bardo MT, eds. Motivational factors in the etiology of drug abuse (series title: Nebraska Symposium on Motivation, vol 50). Lincoln NE: University of Nebraska Press 2004: 1-18
• 35 Koob GF. The neurobiology of addiction: a neuroadaptational view relevant for diagnosis.  Addiction. 2006;  101 ((Suppl 1)) 23-30
• 36 Koob GF. A role for brain stress systems in addiction.  Neuron. 2008;  59 11-34
• 37 Koob GF. Neurobiological substrates for the dark side of compulsivity in addiction.  Neuropharmacology. 2009;  56 ((Suppl 1)) 18-31
• 38 Koob GF, Bloom FE. Cellular and molecular mechanisms of drug dependence.  Science. 1988;  242 715-723
• 39 Koob GF, Everitt BJ, Robbins TW. Reward, motivation, and addiction. In: Squire LG, Berg D, Bloom FE, Du Lac S, Ghosh A, Spitzer N, eds. Fundamental neuroscience, 3rd edn. Amsterdam: Academic Press 2008: 987-1016
• 40 Koob GF, Heinrichs SC. A role for corticotropin-releasing factor and urocortin in behavioral responses to stressors.  Brain Res. 1999;  848 141-152
• 41 Koob GF, Le Moal M. Drug abuse: Hedonic homeostatic dysregulation.  Science. 1997;  278 52-58
• 42 Koob GF, Le Moal M. Drug addiction, dysregulation of reward, and allostasis.  Neuropsychopharmacology. 2001;  24 97-129
• 43 Koob GF, Le Moal M. Plasticity of reward neurocircuitry and the ‘dark side’ of drug addiction.  Nat Neurosci. 2005;  8 1442-1444
• 44 Koob GF, Le Moal M. Neurobiological mechanisms for opponent motivational processes in addiction.  Phil Trans Royal Society B Biol Sci. 2008a;  363 3113-3123
• 45 Koob GF, Le Moal M. Addiction and the brain antireward system.  Ann Rev Psychol. 2008b;  59 29-53
• 46 Koob GF, Zorrilla EP. Corticotropin-releasing factor-1 antagonists.  Drug Discov Today Ther Strat. 2009;  , submitted
• 47 Kornetsky C, Esposito RU. Euphorigenic drugs: Effects on the reward pathways of the brain.  Fed Proc. 1979;  38 2473-2476
• 48 Kreek MJ, Koob GF. Drug dependence: Stress and dysregulation of brain reward pathways.  Drug Alcohol Depend. 1998;  51 23-47
• 49 LaLumiere RT, Buen TV, MacGaugh JL. Post-training intra-basolateral amygdala infusions of norepinephrine enhance consolidation of memory for contextual fear conditioning.  J Neurosci. 2003;  23 6754-6758
• 50 Le Doux JE, Iwata J, Cicchetti P. et al . Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear.  J Neurosci. 1988;  8 2517-2529
• 51 Markou A, Koob GF. Intracranial self-stimulation thresholds as a measure of reward. In: Sahgal A, ed. Behavioural neuroscience: a practical approach, vol 2. Oxford: IRL Press 1993: 93-115
• 52 Markou A, Weiss F, Gold LH. et al . Animal models of drug craving.  Psychopharmacology. 1993;  112 163-182
• 53 Mason BJ, Light JM, Escher T. et al . Effect of positive and negative affective stimuli and beverage cues on measures of craving in non treatment-seeking alcoholics.  Psychopharmacology. 2008;  200 141-150
• 54 MacEwen BS. Allostasis and allostatic load: Implications for neuropsychopharmacology.  Neuropsychopharmacology. 2000;  22 108-124
• 55 MacGaugh JL. Memory consolidation and the amygdala: a systems perspective.  Trends Neurosci. 2002;  25 456
• 56 MacGaugh JL. The amygdala modulates the consolidation of memories of emotionally arousing experiences.  Ann Rev Neurosci. 2004;  27 1-28
• 57 Merchenthaler I, Vigh S, Petrusz P. et al . Immunocytochemical localization of corticotropin-releasing factor (CRF) in the rat brain.  Am J Anat. 1982;  165 385-396
• 58 Merlo-Pich E, Lorang M, Yeganeh M. et al . 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 5439-5447
• 59 Miranda MI, LaLumiere RT, Buen TV. et al . Blockade of noradrenergic receptors in the basolateral amygdala impairs taste memory.  Eur J Neurosci. 2003;  18 2605-2610
• 60 Myers RD. Anatomical “circuitry” in the brain mediating alcohol drinking revealed by THP-reactive sites in the limbic system.  Alcohol. 1990;  7 449-459
• 61 Nestler EJ. Is there a common molecular pathway for addiction?.  Nat Neurosci. 2005;  8 1445-1449
• 62 O’Brien CP. Experimental analysis of conditioning factors in human narcotic addiction.  Pharmacol Rev. 1975;  27 533-543
• 63 O’Brien CP, Testa J, O’Brien TJ. et al . Conditioned narcotic withdrawal in humans.  Science. 1977;  195 1000-1002
• 64 Olds J, Milner P. Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain.  J Comp Physiol Psychol. 1954;  47 419-427
• 65 Olive MF, Koenig HN, Nannini MA. et al . Elevated extracellular CRF levels in the bed nucleus of the stria terminalis during ethanol withdrawal and reduction by subsequent ethanol intake.  Pharmacol Biochem Behav. 2002;  72 213-220
• 66 Pettit HO, Ettenberg A, Bloom FE. et al . Destruction of dopamine in the nucleus accumbens selectively attenuates cocaine but not heroin self-administration in rats.  Psychopharmacology. 1984;  84 167-173
• 67 Price DD. Central neural mechanisms that interrelate sensory and affective dimensions of pain.  Mol Interv. 2002;  2 392-403
• 68 Rassnick S, Heinrichs SC, Britton KT. et al . Microinjection of a corticotropin-releasing factor antagonist into the central nucleus of the amygdala reverses anxiogenic-like effects of ethanol withdrawal.  Brain Res. 1993a;  605 25-32
• 69 Rassnick S, Stinus L, Koob GF. The effects of 6-hydroxydopamine lesions of the nucleus accumbens and the mesolimbic dopamine system on oral self-administration of ethanol in the rat.  Brain Res. 1993b;  623 16-24
• 70 Rimondini R, Arlinde C, Sommer W. et al . Long-lasting increase in voluntary ethanol consumption and transcriptional regulation in the rat brain after intermittent exposure to alcohol.  FASEB J. 2002;  16 27-35
• 71 Roberto M, Madamba SG, Stouffer DG. et al . Increased GABA release in the central amygdala of ethanol-dependent rats.  J Neurosci. 2004;  24 10159-10166
• 72 Roberts AJ, Heyser CJ, Cole M. et al . Excessive ethanol drinking following a history of dependence: animal model of allostasis.  Neuropsychopharmacology. 2000;  22 581-594
• 73 Roelofs SM. Hyperventilation, anxiety, craving for alcohol: a subacute alcohol withdrawal syndrome.  Alcohol. 1985;  2 501-505
• 74 Roozendaal B, Castello NA, Vedana G. et al . Noradrenergic activation of the basolateral amygdala modulates consolidation of object recognition memory.  Neurobiol Learn Mem. 2008a;  90 576-579
• 75 Roozendaal B, Quirarte GL, MacGaugh JL. Glucocorticoids interact with the basolateral amygdala β-adrenoceptor-cAMP/cAMP/PKA system in influencing memory consolidation.  Eur J Neurosci. 2002;  15 553-560
• 76 Roozendaal B, Schelling G, MacGaugh JL. Corticotropin-releasing factor in the basolateral amygdala enhances memory consolidation via an interaction with the β-adrenoceptor-cAMP pathway: dependence on glucocorticoid receptor activation.  J Neurosci. 2008b;  28 6642-6651
• 77 Roy A, Pandey SC. The decreased cellular expression of neuropeptide Y protein in rat brain structures during ethanol withdrawal after chronic ethanol exposure.  Alcohol Clin Exp Res. 2002;  26 796-803
• 78 Russell MAH. What is dependence?. In: Edwards G, ed. Drugs and drug dependence. Lexington MA: Lexington Books 1976: 182-187
• 79 Schindler CW, Panlilio LV, Goldberg SR. Second-order schedules of drug self-administration in animals.  Psychopharmacology. 2002;  163 327-344
• 80 Schulteis G, Ahmed SH, Morse AC. et al . Conditioning and opiate withdrawal: The amygdala links neutral stimuli with the agony of overcoming drug addiction.  Nature. 2000;  405 1013-1014
• 81 Schuster CR, Thompson T. Self administration and behavioral dependence on drugs.  Ann Rev Pharmacol Toxicol. 1969;  9 483-502
• 82 Schuster CR, Woods JH. The conditioned reinforcing effects of stimuli associated with morphine reinforcement.  Int J Addict. 1968;  3 223-230
• 83 See RE, Fuchs RA, Ledford CC. et al .Drug addiction, relapse, and the amygdala. In: Shinnick-Gallagher P, Pitkanen A, Shekhar A, Cahill L, eds. The amygdala in brain function: basic and clinical approaches (series title: Annals of the New York Academy of Sciences, vol 985). New York: New York Academy of Sciences 2003: 294-307
• 84 Shaw-Lutchman TZ, Barrot M, Wallace T. et al . Regional and cellular mapping of cAMP response element-mediated transcription during naltrexone-precipitated morphine withdrawal.  J Neurosci. 2002;  22 3663-3672
• 85 Specio SE, Wee S, O’Dell LE. et al . CRF₁ receptor antagonists attenuate escalated cocaine self-administration in rats.  Psychopharmacology. 2008;  196 473-482
• 86 Sterling P, Eyer J. Allostasis: a new paradigm to explain arousal pathology. In: Fisher S, Reason J, eds. Handbook of life stress, cognition and health. Chichester: John Wiley 1988: 629-649
• 87 Stewart J. Conditioned stimulus control of the expression of sensitization of the behavioral activating effects of opiate and stimulant drugs. In: Gormezano I, Wasserman EA, eds. Learning and memory: the behavioral and biological substrates. Hillsdale NJ: Lawrence Erlbaum 1992: 129-151
• 88 Stewart J, de Wit H. Reinstatement of drug-taking behavior as a method of assessing incentive motivational properties of drugs. In: Bozarth MA, ed. Methods of assessing the reinforcing properties of abused drugs. New York: Springer-Verlag 1987: 211-227
• 89 Stewart J, Eikelboom R. Conditioned drug effects. In: Iversen LI, Iversen SD, Snyder SH, eds. New directions in behavioral pharmacology (series title: Handbook of psychopharmacology, vol 19. New York: Plenum Press 1987: 1-57
• 90 Swerdlow NR, Gilbert D, Koob GF. Conditioned drug effects on spatial preference: critical evaluation. In: Boulton AA, Baker GB, Greenshaw AJ, eds. Psychopharmacology (series title: Neuromethods, vol 13). Clifton NJ: Humana Press 1989: 399-446
• 91 Ungless MA, Whistler JL, Malenka RC. et al . Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons.  Nature. 2001;  411 583-387
• 92 Vaccarino FJ, Bloom FE, Koob GF. Blockade of nucleus accumbens opiate receptors attenuates intravenous heroin reward in the rat.  Psychopharmacology. 1985;  86 37-42
• 93 Valdez GR, Koob GF. Allostasis and dysregulation of corticotropin-releasing factor and neuropeptide Y systems: implications for the development of alcoholism.  Pharmacol Biochem Behav. 2004;  79 671-689
• 94 van der Kooy D. Place conditioning: a simple and effective method for assessing the motivational properties of drugs. In: Bozarth MA, ed. Methods of assessing the reinforcing properties of abused drugs. New York: Springer-Verlag 1987: 229-240
• 95 Volkow ND, Fowler JS, Wang GJ. The addicted human brain: insights from imaging studies.  J Clin Invest. 2003;  111 1444-1451
• 96 Vorel SR, Ashby Jr CR, Paul M. et al . Dopamine D3 receptor antagonism inhibits cocaine-seeking and cocaine-enhanced brain reward in rats.  J Neurosci. 2002;  22 9595-9603
• 97 Weiss F, Markou A, Lorang MT. et al . Basal extracellular dopamine levels in the nucleus accumbens are decreased during cocaine withdrawal after unlimited-access self-administration.  Brain Res. 1992;  593 314-318
• 98 Zimmerman JM, Rabinak CA, MacLachlan IG. et al . The central nucleus of the amygdala is essential for acquiring and expressing conditional fear after overtraining.  Learn Mem. 2007;  14 634-644
• 99 Zorrilla EP, Koob GF. The therapeutic potential of CRF₁ antagonists for anxiety.  Expert Opin Investig Drugs. 2004;  13 799-828

Correspondence