NEURONAL SUBSTRATES OF RELAPSE TO COCAINE-SEEKING BEHAVIOR: ROLE OF PREFRONTAL CORTEX
Corresponding Author
George V. Rebec
INDIANA UNIVERSITY
Indiana University, 1101 E. Tenth Street., Bloomington, Indiana 47405-7007 (e-mail: [email protected]).Search for more papers by this authorCorresponding Author
George V. Rebec
INDIANA UNIVERSITY
Indiana University, 1101 E. Tenth Street., Bloomington, Indiana 47405-7007 (e-mail: [email protected]).Search for more papers by this authorAbstract
The return to drug seeking, even after prolonged periods of abstinence, is a defining feature of cocaine addiction. The neural circuitry underlying relapse has been identified in neuropharmacological studies of experimental animals, typically rats, and supported in brain imaging studies of human addicts. Although the nucleus accumbens (NAcc), which has long been implicated in goal-directed behavior, plays a critical role in this circuit, the prefrontal cortex (PFC) appears to process the events that directly trigger relapse: exposure to acute stress, cues previously associated with the drug, and the drug itself. In this paper, we review animal models of relapse and what they have revealed about the mechanisms underlying the involvement of the NAcc and PFC in cocaine-seeking behavior. We also present electrophysiological data from PFC illustrating how the hedonic, motor, motivational, and reinforcing effects of cocaine can be analyzed at the neuronal level. Our preliminary findings suggest a role for PFC in processing information related to cocaine seeking but not the hedonic effects of the drug. Further use of this recording technology can help dissect the functions of PFC and other components of the neural circuitry underlying relapse.
REFERENCES
- Anderson, S. M., Bari, A. A., & Pierce, R. C. (2003). Administration of the D1-like dopamine receptor antagonist SCH-23390 into the medial nucleus accumbens shell attenuates cocaine priming-induced reinstatement of drug-seeking behavior in rats. Psychopharmacology (Berl), 168, 132–138.
- Apicella, P., Ljungberg, T., Scarnati, E., & Schultz, W. (1991). Responses to reward in monkey dorsal and ventral striatum. Experimental Brain Research, 85, 491–500.
- Baker, D. A., McFarland, K., Lake, R. W., Shen, H., Tang, X. C., Toda, S., & Kalivas, P. W. (2003). Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse. Nature Neuroscience, 6, 743–749.
-
Bergman, J., &
Katz, J. L. (1998). Behavioral pharmacology of cocaine and the determinants of abuse liability. In S. T. Higgins &
J. L. Katz (Eds.), Cocaine abuse: Behavior, pharmacology, and clinical applications (pp. 51–79). San Diego: Academic Press.
10.1016/B978-012347360-8/50005-7 Google Scholar
- Bowers, M. S., Lake, R. W., McFarland, K., Peterson, Y. K., Lanier, S. M., Lapish, C. C., & Kalivas, P. W. (2003). AGS3: A G-Protein regulator of addiction-associated behaviors. Annals of the New York Academy of Science, 1003, 356–357.
- Bowers, M. S., McFarland, K., Lake, R. W., Peterson, Y. K., Lapish, C. C., Gregory, M. L., Lanier, S. M., & Kalivas, P. W. (2004). Activator of G protein signaling 3: A gatekeeper of cocaine sensitization and drug seeking. Neuron, 42, 269–281.
- Breiter, H. C., Gollub, R. L., Weisskoff, R. M., Kennedy, D. N., Makris, N., Berke, J. D., Goodman, J. M., Kantor, H. L., Gastfriend, D. R., Riorden, J. P., Mathew, R. T., Rosen, B. R., & Hyman, S. E. (1997). Acute effects of cocaine on human brain activity and emotion. Neuron, 19, 591–611.
- Brog, J. S., Salyapongse, A., Deutch, A. Y., & Zahm, D. S. (1993). The patterns of afferent innervation of the core and shell in the accumbens part of the rat ventral striatum—immunohistochemical detection of retrogradely transported fluoro-gold. Journal of Comparative Neurology, 338, 255–278.
- Brown, V. J., & Bowman, E. M. (2002). Rodent models of prefrontal cortical function. Trends in Neuroscience, 25, 340–343.
- Capriles, N., Rodaros, D., Sorge, R. E., & Stewart, J. (2003). A role for the prefrontal cortex in stress- and cocaine-induced reinstatement of cocaine seeking in rats. Psychopharmacology, 168, 66–74.
- Cardinal, R. N., Parkinson, J. A., Hall, J., & Everitt, B. J. (2002). Emotion and motivation: The role of the amygdala, ventral striatum, and prefrontal cortex. Neuroscience and Biobehavioral Reviews, 26, 321–352.
- Carelli, R. M. (2002). Nucleus accumbens cell firing during goal-directed behaviors for cocaine vs. ‘natural’ reinforcement. Physiology and Behavior, 76, 379–87.
- Carelli, R. M., & Deadwyler, S. A. (1994). Comparison of nucleus accumbens neuronal firing patterns during cocaine self-administration and water reinforcement in rats. Journal of Neuroscience, 14, 7735–7746.
- Carelli, R. M., & Deadwyler, S. A. (1996). Dose-dependent transitions in nucleus accumbens cell firing and behavioral responding during cocaine self-administration sessions in rats. Journal of Pharmacological and Experimental Therapy, 277, 385–393.
- Carelli, R. M., & Ijames, S. G. (2000). Nucleus accumbens cell firing during maintenance, extinction, and reinstatement of cocaine self-administration behavior in rats. Brain Research, 866, 44–54.
- Carelli, R. M., Ijames, S. G., & Crumling, A. J. (2000). Evidence that separate neural circuits in the nucleus accumbens encode cocaine versus “natural” (water and food) reward. Journal of Neuroscience, 20, 4255–4266.
- Carelli, R. M., King, V. C., Hampson, R. E., & Deadwyler, S. (1993). Firing patterns of nucleus accumbens neurons during cocaine self-administration in rats. Brain Research, 626, 14–22.
- Chang, J. Y., Janak, P. H., & Woodward, D. J. (2000). Neuronal and behavioral correlations in the medial prefrontal cortex and nucleus accumbens during cocaine self-administration by rats. Neuroscience, 99, 433–443.
- Chang, J. Y., Sawyer, S. F., Lee, R. S., & Woodward, D. J. (1994). Electrophysiological and pharmacological evidence for the role of the nucleus accumbens in cocaine self-administration in freely moving rats. Journal of Neuroscience, 14, 1224–1244.
-
Chang, J. Y.,
Sawyer, S. F.,
Paris, J. M.,
Kirillov, A., &
Woodward, D. J. (1997). Single neuronal responses in medial prefrontal cortex during cocaine self-administration in freely moving rats.
Synapse, 26, 22–35.
10.1002/(SICI)1098-2396(199705)26:1<22::AID-SYN3>3.0.CO;2-G CAS PubMed Web of Science® Google Scholar
- Childress, A. R., Mozley, P. D., McElgin, W., Fitzgerald, J., Reivich, M., & O'Brien, C. P. (1999). Limbic activation during cue-induced cocaine craving. American Journal of Psychiatry, 156, 11–18.
- Ciccocioppo, R., Sanna, P. O., & Weiss, F. (2001). Cocaine-predictive stimulus induces drug-seeking behavior and neural activation in limbic brain regions after multiple months of abstinence: referal by D1 antagonists. Proceedings of the National Academy of Sciences, 98, 1976–1981.
- Comoli, E., Coizet, V., Boyes, J., Bolam, J. P., Canteras, N. S., Quirk, R. H., Overton, P. G., & Redgrave, P. (2003). A direct projection from superior colliculus to substantia nigra for detecting salient visual events. Nature Neuroscience, 6, 974–980.
- Cornish, J. L., Duffy, P., & Kalivas, P. W. (1999). A role for nucleus accumbens glutamate transmission in the relapse to cocaine-seeking behavior. Neuroscience, 93, 1359–1367.
- Cornish, J. L., & Kalivas, P. W. (2000). Glutamate transmission in the nucleus accumbens mediates relapse in cocaine addiction. Journal of Neuroscience, 20, U11–U15.
- Davis, W. M., & Smith, S. G. (1976). Role of conditioned reinforcers in the initiation, maintenance and extinction of drug-seeking behavior. Pavlovian Journal of Biological Science, 11, 222–236.
- de Wit, H., & Stewart, J. (1981). Reinstatement of cocaine-reinforced responding in the rat. Psychopharmacology (Berl), 75, 134–143.
- Di Chiara, G. (1998). A motivational learning hypothesis of the role of mesolimbic dopamine in compulsive drug use. Journal of Psychopharmacology, 12, 54–67.
- Di Ciano, P., & Everitt, B. J. (2001). Dissociable effects of antagonism of NMDA and AMPA/KA receptors in the nucleus accumbens core and shell on cocaine-seeking behavior. Neuropsychopharmacology, 25, 341–360.
- Durstewitz, D., & Seamans, J. K. (2002). The computational role of dopamine D1 receptors in working memory. Neural Networks, 15, 561–572.
- Epstein, D. H., & Preston, K. L. (2003). The reinstatement model and relapse prevention: A clinical perspective. Psychopharmacology, 168, 31–41.
- Ettenberg, A. (1990). Haloperidol prevents the reinstatement of amphetamine-rewarded runway responding in rats. Pharmacology, Biochemistry, and Behavior, 36, 635–638.
- Everitt, B. J., & Robbins, T. W. (2000). Second-order schedules of drug reinforcement in rats and monkeys: Measurement of reinforcing efficacy and drug-seeking behaviour. Psychopharmacology, 153, 17–30.
- Ghitza, U. E., Fabbricatore, A. T., Prokopenko, V., Pawlak, A. P., & West, M. O. (2003). Persistent cue-evoked activity of accumbens neurons after prolonged abstinence from self-administered cocaine. Journal of Neuroscience, 23, 7239–7245.
- Gonzalez-Islas, C., & Hablitz, J. J. (2003). Dopamine enhances EPSCs in layer II-III pyramidal neurons in rat prefrontal cortex. Journal of Neuroscience, 23, 867–875.
- Grant, S., London, E. D., Newlin, D. B., Villemagne, V. L., Liu, X., Contoreggi, C., Phillips, R. L., Kimes, A. S., & Margolin, A. (1996). Activation of memory circuits during cue-elicited cocaine craving. Proceedings of the National Academy of Sciences of the United States of America, 93, 12040–12045.
- Grimm, J. W., & See, R. E. (2000). Chronic haloperidol-induced alterations in pallidal GABA and striatal D-1-mediated dopamine turnover as measured by dual probe microdialysis in rats. Neuroscience, 100, 507–514.
- Groenewegen, H. J., Wright, C. I., Beijer, A. V., & Voorn, P. (1999). Convergence and segregation of ventral striatal inputs and outputs. Annals of the New York Academy of Sciences, 877, 49–63.
- Gulley, J. M., Kosobud, A. E. K., & Rebec, G. V. (2002). Behavior-related modulation of substantia nigra pars reticulata neurons in rats performing a conditioned reinforcement task. Neuroscience, 111, 337–349.
- Heimer, L., Alheid, G. F., & Zahm, D. S. (1993). Basal forebrain organization: An anatomical framework for motor aspects of drive and motivation. In P. W. Kalivas & C. D. Barnes (Eds.), Limbic motor circuits and neuropsychiatry (pp. 1–32). Boca Raton: CRC Press.
- Hemby, S. E., Co, C., Koves, T. R., Smith, J. E., & Dworkin, S. I. (1997). Differences in extracellular dopamine concentrations in the nucleus accumbens during response-dependent and response-independent cocaine administration in the rat. Psychopharmacology, 133, 7–16.
- Horvitz, J. C. (2000). Mesolimbocortical and nigrostriatal dopamine responses to salient non-reward events. Neuroscience, 96, 651–656.
- Ikemoto, S., & Panksepp, J. (1999). The role of nucleus accumbens dopamine in motivated behavior: A unifying interpretation with special reference to reward-seeking. Brain Research Reviews, 31, 6–41.
- Jentsch, J. D., & Taylor, J. R. (1999). Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli. Psychopharmacology, 146, 373–390.
- Kalivas, P. W., & McFarland, K. (2003). Brain circuitry and the reinstatement of cocaine-seeking behavior. Psychopharmacology, 168, 44–56.
- Kalivas, P. W., & Nakamura, M. (1999). Neural systems for behavioral activation and reward. Current Opinion in Neurobiology, 9, 223–227.
- Katz, J. L., & Higgins, S. T. (2003). The validity of the reinstatement model of craving and relapse to drug use. Psychopharmacology, 168, 21–30.
- Kolb, B., & Tees, R. C. (1990). Cerebral cortex of the rat. Cambridge, MA: MIT Press.
- Lavin, A., & Grace, A. A. (2001). Stimulation of D1-type dopamine receptors enhances excitability in prefrontal cortical pyramidal neurons in a state-dependent manner. Neuroscience, 104, 335–346.
- Lee, J. H., Telang, F. W., Springer, C. S., Jr., & Volkow, N. D. (2003). Abnormal brain activation to visual stimulation in cocaine abusers. Life Science, 73, 1953–1961.
- Lee, R. S., Koob, G. F., & Henriksen, S. J. (1998). Electrophysiological responses of nucleus neurons to novelty stimuli and exploratory behavior in the awake, unrestrained rat. Brain Research, 799, 317–322.
- LeMoal, M., & Simon, H. (1991). Mesocorticolimbic dopaminergic network: Functional and regulatory roles. Physiological Reviews, 7, 155–234.
- LeMoal, M. (1995). Mesocorticolimbic dopaminergic neurons: Functional and regulatory roles. In F. E. Bloom & D. J. Kupfer (Eds.), Psychopharmacology: The fourth generation of progress (pp. 283–294). New York: Raven Press.
- Lewis, B. L., & O'Donnell, P. (2000). Ventral tegmental area afferents to the prefrontal cortex maintain membrane potential ‘up’ states in pyramidal neurons via D(1) dopamine receptors. Cerebral Cortex, 10, 1168–1175.
- Lu, L., Shepard, J. D., Hall, F. S., & Shaham, Y. (2003). Effect of environmental stressors on opiate and psychostimulant reinforcement, reinstatement and discrimination in rats: A review. Neuroscience and Biobehavioral Reviews, 27, 457–491.
- Marlatt, A. G. (1996). Models of relapse and relapse prevention: A commentary. Experimental and Clinical Psychopharmacology, 4, 55–60.
- McFarland, K., & Kalivas, P. W. (2001). The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior. Journal of Neuroscience, 21, 8655–8663.
- McFarland, K., Lapish, C. C., & Kalivas, P. W. (2003). Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. Journal of Neuroscience, 23, 3531–3537.
- McLaughlin, J., & See, R. E. (2003). Selective inactivation of the dorsomedial prefrontal cortex and the basolateral amygdala attenuates conditioned—cued reinstatement of extinguished cocaine-seeking behavior in rats. Psychopharmacologia, 168, 57–65.
- Mogenson, G. J., Jones, D. L., & Yim, C. Y. (1980). From motivation to action: Functional interface between the limbic system and the motor system. Progress in Neurobiology, 14, 69–97.
- Mueller, D., & Stewart, J. (2000). Cocaine-induced conditioned place preference: Reinstatement by priming injections of cocaine after extinction. Behavioural Brain Research, 115, 39–47.
- Neisewander, J. L., Baker, D. A., Fuchs, R. A., Tran-Nguyen, L. T., Palmer, A., & Marshall, J. F. (2000). Fos protein expression and cocaine-seeking behavior in rats after exposure to a cocaine self-administration environment. Journal of Neuroscience, 20, 798–805.
- Nicola, S. M., & Deadwyler, S. A. (2000). Firing rate of nucleus accumbens neurons is dopamine-dependent and reflects the timing of cocaine-seeking behavior in rats on a progressive ratio schedule of reinforcement. Journal of Neuroscience, 20, 5526–5537.
- Park, W.-K., Bari, A. A., Jey, A. R., Anderson, S. M., Spealman, R. D., Rowlett, J. K., & Pierce, R. C. (2002). Cocaine administered into the medial prefrontal cortex reinstates cocaine-seeking behavior by increasing AMPA receptor-mediated glutamate transmission in the nucleus accumbens. Journal of Neuroscience, 22, 2916–2925.
- Paxinos, G., & Watson, C. (1998). The rat brain in stereotaxic coordinates. ( 4th ed.). San Diego, CA: Academic Press.
- Peoples, L. L., & West, M. O. (1996). Phasic firing of single neurons in the rat nucleus accumbens correlated with the timing of intravenous cocaine self-administration. Journal of Neuroscience, 16, 3459–3473.
- Peoples, L. L., Uzwiak, A. J., Gee, F., & West, M. O. (1997). Operant behavior during sessions of intravenous cocaine infusion is necessary and sufficient for phasic filing of single nucleus accumbens neurons. Brain Research, 757, 280–284.
- Peters, Y. M., Lewis, B. L., & O'Donnell, P. (2000). Synchronous activity in the ventral tegmental area and prefrontal cortex. Annals of the New York Academy of Sciences, 909, 267–269.
- Peters, Y., Barnhardt, N. E., & O'Donnell, P. (2004). Prefrontal cortical up states are synchronized with ventral tegmental area activity. Synapse, 52, 143–152.
- Porrino, L. J., & Lyons, D. (2000). Orbital and medial prefrontal cortex and psychostimulant abuse: Studies in animal models. Cerebral Cortex, 10, 326–333.
- Robinson, T. E., & Berridge, K. C. (2000). Animal models in craving research—The psychology and neurobiology of addiction: An incentive-sensitization view. Addiction, 95, S91–S117.
- Roop, R. G., Hollander, J. A., & Carelli, R. M. (2002). Accumbens activity during a multiple schedule for water and sucrose reinforcement in rats. Synapse, 43, 223–226.
- Salamone, J. D. (1996). The behavioral neurochemistry of motivation: Methodological and conceptual issues in studies of the dynamic activity of nucleus accumbens dopamine. Journal of Neuroscience Methods, 64, 137–149.
- Schultz, W. (1998). Predictive reward signal of dopamine neurons. Journal of Neurophysiology, 80, 1–27.
- Schultz, W. (2000). Multiple reward signals in the brain. Nature Review Neuroscience, 1, 199–207.
- Schultz, W., Apicella, P., Scarnati, E., & Ljungberg, T. (1992). Neuronal activity in monkey ventral striatum related to the expectation of reward. Journal of Neuroscience, 12, 4595–4610.
- Self, D. W., Genova, L. M., Hope, B. T., Barnhart, W. J., Spencer, J. J., & Nestler, E. J. (1998). Involvement of cAMP-dependent protein kinase in the nucleus accumbens in cocaine self-administration and relapse of cocaine-seeking behavior. Journal of Neuroscience, 18, 1848–1859.
- Shalev, U., Grimm, J. W., & Shaham, Y. (2002). Neurobiology of relapse to heroin and cocaine seeking: A review. Pharmacological Reviews, 54, 1–42.
- Shidara, M., & Richmond, B. J. (May 31 2002). Anterior cingulate: Single neuronal signals related to degree of reward expectancy. Science, 296, 1709–1711.
- Sun, W., Akins, C. K., Mattingly, A. E., & Rebec, G. V. (in press). Ionotropic glutamate receptors in the ventral tegmental area regulate cocaine-seeking behavior in rats. Neuropsychopharmacology. (Available online at http:www.nature.comnppjournalvaopncurrentabs1300744a.html;jsessionid1510EDA1D0752B3-D80A5B182C58CA9A4).
- Sun, W. L., & Rebec, G. V. (2003). Lidocaine inactivation of ventral subiculum attenuates cocaine-seeking behavior in rats. Journal of Neuroscience, 23, 10258–10264.
- Sun, W. L., & Rebec, G. V. (2005). The role of prefrontal cortex D1-like and D2-like receptors in cocaine-seeking behavior in rats. Psychopharmacology, 177, 315–323.
- Sutton, M. A., Schmidt, E. F., Chol, K. H., Schad, C. A., Whisler, K., Simmons, D., Karanlan, D. A., Monteggla, L. M., Neve, R. L., & Self, D. W. (2003). Extinction-induced upregulation in AMPA receptors reduces cocaine-seeking behaviour. Nature, 421, 70–75.
- Thomas, K. L., & Everitt, B. J. (2001). Limbic—cortical—ventral striatal activation during retrieval of a discrete cocaine-associated stimulus: A cellular imaging study with gamma protein kinase C expression. Journal of Neuroscience, 21, 2526–2535.
- Tran-Nguyen, L. T. L., Fuchs, R. A., Coffey, G. P., Baker, D. A., Odell, L. E., & Neisewander, J. L. (1998). Time-dependent changes in cocaine-seeking behavior and extracellular dopamine levels in the amygdala during cocaine withdrawal. Neuropsychopharmacology, 19, 48–59.
- Uylings, H. B. M., Groenewegen, H. J., & Kolb, B. (2003). Do rats have a prefrontal cortex? Behavioral Brain Research, 146, 3–17.
- Uzwiak, A. J., Guyette, F. X., West, M. O., & Peoples, L. L. (1997). Neurons in accumbens subterritories of the rat: Phasic firing time-locked within seconds of intravenous cocaine self-infusion. Brain Research, 767, 363–369.
- Volkow, N. D., Wang, G. J., Fowler, J. S., Gatley, S. J., Logan, J., Ding, Y. S., Dewey, S. L., Hitzemann, R., Gifford, A. N., & Pappas, N. R. (1999). Blockade of striatal dopamine transporters by intravenous methylphenidate is not sufficient to induce self-reports of “high.” Journal of Pharmacology and Experimental Therapeutics, 288, 14–20.
- Volkow, N. D., Wang, G. J., Ma, Y., Fowler, J. S., Wong, C., Ding, Y. S., Mitzemann, R., Swanson, J. M., & Kalivas, P. (2005). Activation of orbital and medial prefrontal cortex by methylphenidate in cocaine-addicted subjects but not in controls: Relevance to addiction. Journal of Neuroscience, 25, 3932–3939.
- Wang, J. Q., & McGinty, J. F. (1999). Glutamate-dopamine interactions mediate the effects of psychostimulant drugs. Addiction Biology, 4, 141–150.
- White, F. J., & Kalivas, P. W. (1998). Neuroadaptations involved in amphetamine and cocaine addiction. Drug and Alcohol Dependence, 51, 141–153.
- Wise, R. A. (1998). Drug-activation of brain reward pathways. Drug and Alcohol Dependence, 51, 13–22.
- Woodward, D. J., Chang, J. Y., Janak, P., Azarov, A., & Anstrom, K. (2000). Activity patterns in mesolimbic regions in rats during operant tasks for reward. Progress in Brain Research, 126, 303–322.
- Zahm, D. S. (1999). Functional-anatomical implications of the nucleus accumbens core and shell subterritories. Annals of the New York Academy of Sciences, 877, 113–128.
- Zahm, D. S., & Brog, J. S. (1992). On the significance of subterritories in the “accumbens” part of the rat ventral striatum. Neuroscience, 50, 751–767.
- Zahm, D. S., & Heimer, L. (1993). Specificity in the efferent projections of the nucleus accumbens in the rat—comparison of the rostral pole projection patterns with those of the core and shell. Journal of Comparative Neurology, 327, 220–232.