The Orbitofrontal Cortex, Impulsivity, and Addiction: Probing Orbitofrontal Dysfunction at the Neural, Neurochemical, and Molecular Level
Abstract
The association between impulsivity and addiction is currently a topic of intense research interest. Investigations into the neurobiological basis of aspects of impulse control have revealed some striking parallels between the brain circuitry and neurochemical systems implicated in drug dependence and impulsive behavior. Both processes are heavily regulated by limbic corticostriatal circuits including the orbitofrontal cortex (OFC) and nucleus accumbens (NAC), and are modulated by dopamine (DA) and serotonin (5-HT). Hypoactivity within the OFC has been observed in recently abstinent cocaine users, and this is thought to contribute to the cognitive deficits associated with drug abuse, including impairments in impulse control. However, the neurobiological mechanisms underlying these functional and behavioral deficits are unclear. In parallel to observations made in the NAC, recent data indicate that chronic cocaine use also induces the transcription factor DeltaFosB in the OFC and that this plays a role in the cognitive sequelae of chronic cocaine administration. In particular, DeltaFosB appears to be involved in the development of tolerance to the disruptive effects of acute cocaine on impulsivity and motivation observed after repeated cocaine administration. Increased DeltaFosB also contributes to increased impulsivity during withdrawal from the drug. Both effects could be attributed to the up-regulation of local inhibitory processes in the OFC after over-expression of DeltaFosB and chronic cocaine treatment. Through integrating what is known of the interaction between addictive drugs and impulsivity at the neural, neurochemical, and molecular level, novel insight may be obtained into the multi-faceted regulation of the addicted state.
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Reciprocal connections among frontal cortical regions, hippocampal-amygdala limbic areas, and striatal regions regulate goal-directed behavior.
“Reciprocal connections between frontal cortical brain regions, hippocampal-amygdala limbic brain areas and striatal regions regulate goal directed behavior (Winstanley, 2007).”
From Impulsivity, frontal lobes and risk for addiction (2009) · cites this paper as Winstanley, 2007
Cites
Insensitivity to future consequences following damage to human prefrontal cortex
Bechara, A., Damasio, A. R., Damasio, H., & Anderson, S. W. (1994) · Cognition · doi:10.1016/0010-0277(94)90018-3 · Cited by 6,128 · see citing works
Neural systems of reinforcement for drug addiction: from actions to habits to compulsion
Everitt, B. J., & Robbins, T. W. (2005) · Nature Neuroscience · doi:10.1038/nn1579 · Cited by 3,785 · see citing works
Psychiatric Aspects of Impulsivity
Moeller, F. G., Barratt, E. S., Dougherty, D. M., Schmitz, J. M., & Swann, A. C. (2001) · American Journal of Psychiatry · doi:10.1176/appi.ajp.158.11.1783 · Cited by 2,747 · see citing works
A continuous performance test of brain damage
Rosvold, H. E., Mirsky, A. F., Sarason, I., Bransome, E. D., & Beck, L. H. (1956) · Journal of Consulting Psychology · doi:10.1037/h0043220 · Cited by 2,261 · see citing works
Evenden, J. L. (1999) · Psychopharmacology · doi:10.1007/pl00005481 · Cited by 2,044 · see citing works
Different contributions of the human amygdala and ventromedial prefrontal cortex to decision-making
Bechara, A., Damasio, H., Damasio, A. R., & Lee, G. P. (1999) · The Journal of Neuroscience · doi:10.1523/jneurosci.19-13-05473.1999 · Cited by 2,001 · see citing works
Jentsch, J. D., & Taylor, J. R. (1999) · Psychopharmacology · doi:10.1007/pl00005483 · Cited by 1,545 · see citing works
Addiction and the brain: The neurobiology of compulsion and its persistence
Hyman, S. E., & Malenka, R. C. (2001) · Nature reviews. Neuroscience · doi:10.1038/35094560 · Cited by 1,297 · see citing works
Addiction, a disease of compulsion and drive: involvement of the orbitofrontal cortex
Volkow, N. D. (2000) · Cerebral Cortex · doi:10.1093/cercor/10.3.318 · Cited by 1,240 · see citing works
Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement
Dalley, J. W., Fryer, T. D., Brichard, L., Robinson, E. S. J., Theobald, D. E. H., Lääne, K., Peña, Y., Murphy, E. R., Shah, Y., Probst, K., et al. (2007) · Science · doi:10.1126/science.1137073 · Cited by 1,188 · see citing works
Bechara, A., Dolan, S. L., Denburg, N. L., Hindes, A. R., Anderson, S. W., & Nathan, P. E. (2001) · Neuropsychologia · doi:10.1016/s0028-3932(00)00136-6 · Cited by 1,168 · see citing works
Molecular mechanisms of drug addiction
Nestler, E. J. (2004) · Neuropharmacology · doi:10.1016/j.neuropharm.2004.06.031 · Cited by 1,108 · see citing works
Structural plasticity associated with exposure to drugs of abuse
Robinson, T. E., & Kolb, B. E. (2004) · Neuropharmacology · doi:10.1016/j.neuropharm.2004.06.025 · Cited by 1,104 · see citing works
Wise, R. A. (1996) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(96)80079-1 · Cited by 1,072 · see citing works
Impulsive choice induced in rats by lesions of the nucleus accumbens core
Cardinal, R. N., Pennicott, D. R., Lakmali, C., Sugathapala, Robbins, T. W., & Everitt, B. J. (2001) · Science · doi:10.1126/science.1060818 · Cited by 923 · see citing works
Winstanley, C. A., Eagle, D. M., & Robbins, T. W. (2006) · Clinical Psychology Review · doi:10.1016/j.cpr.2006.01.001 · Cited by 848 · see citing works
Self-citationKirby, K., & Petry, N. (2004) · Addiction · doi:10.1111/j.1360-0443.2003.00669.x · Cited by 737 · see citing works
Carli, M., Robbins, T. W., Evenden, J. L., & Everitt, B. J. (1983) · Behavioural Brain Research · doi:10.1016/0166-4328(83)90138-9 · Cited by 736 · see citing works
Contrasting Roles of Basolateral Amygdala and Orbitofrontal Cortex in Impulsive Choice
Winstanley, C. A., Theobald, D. E. H., Cardinal, R. N., & Robbins, T. W. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.5606-03.2004 · Cited by 675 · see citing works
Self-citationExpression of the transcription factor ΔFosB in the brain controls sensitivity to cocaine
Kelz, M. B., Chen, J., Carlezon, W. A., Whisler, K., Gilden, L., Beckmann, A. M., Steffen, C., Zhang, Y.-J., Marotti, L., Self, D. W., et al. (1999) · Nature · doi:10.1038/45790 · Cited by 641 · see citing works
ΔFosB: A sustained molecular switch for addiction
Nestler, E. J., Barrot, M., & Self, D. W. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.191352698 · Cited by 640 · see citing works
Solanto, M. V., Abikoff, H., Sonuga-Barke, E., Schachar, R., Logan, G. D., Wigal, T., Hechtman, L., Hinshaw, S., & Turkel, E. (2001) · Journal of Abnormal Child Psychology · doi:10.1023/a:1010329714819 · Cited by 639 · see citing works
Evenden, J. L., & Ryan, C. N. (1996) · Psychopharmacology · doi:10.1007/s002130050121 · Cited by 636 · see citing works
Volkow, N. D., Fowler, J. S., & Wang, G.-J. (2004) · Neuropharmacology · doi:10.1016/j.neuropharm.2004.07.019 · Cited by 616 · see citing works
Schoenbaum, G., Chiba, A. A., & Gallagher, M. (1999) · The Journal of Neuroscience · doi:10.1523/jneurosci.19-05-01876.1999 · Cited by 579 · see citing works
Cognitive enhancing effects of modafinil in healthy volunteers
Turner, D. C., Robbins, T. W., Clark, L., Aron, A. R., Dowson, J. H., & Sahakian, B. J. (2003) · Psychopharmacology · doi:10.1007/s00213-002-1250-8 · Cited by 518 · see citing works
Volkow, N. (2002) · Neurobiology of Learning and Memory · doi:10.1006/nlme.2002.4099 · Cited by 514 · see citing works
Muir, J. L., Everitt, B. J., & Robbins, T. W. (1996) · Cerebral Cortex · doi:10.1093/cercor/6.3.470 · Cited by 503 · see citing works
Harrison, A. A., Everitt, B. J., & Robbins, T. W. (1997) · Psychopharmacology · doi:10.1007/s002130050410 · Cited by 452 · see citing works
Frontal lobe dysfunction in pathological gambling patients
Cavedini, P., Riboldi, G., Keller, R., D’Annucci, A., & Bellodi, L. (2002) · Biological Psychiatry · doi:10.1016/s0006-3223(01)01227-6 · Cited by 418 · see citing works
A Double-Blind, Placebo-Controlled Trial of Modafinil for Cocaine Dependence
Dackis, C. A., Kampman, K. M., Lynch, K. G., Pettinati, H. M., & O'Brien, C. P. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300600 · Cited by 391 · see citing works
Glutamate systems in cocaine addiction
Kalivas, P. W. (2003) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2003.11.002 · Cited by 349 · see citing works
Drug Addiction: The Yin and Yang of Hedonic Homeostasis
Koob, G. F. (1996) · Neuron · doi:10.1016/s0896-6273(00)80109-9 · Cited by 347 · see citing works
Investigating the neurocognitive deficits associated with chronic drug misuse
Rogers, R. D., & Robbins, T. W. (2001) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(00)00204-x · Cited by 344 · see citing works
Cardinal, R. N., Robbins, T. W., & Everitt, B. J. (2000) · Psychopharmacology · doi:10.1007/s002130000536 · Cited by 339 · see citing works
Critical Involvement of Dopaminergic Neurotransmission in Impulsive Decision Making
van Gaalen, M. M., van Koten, R. C., Schoffelmeer, A. N. M., & Vanderschuren, L. J. M. J. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.06.005 · Cited by 338 · see citing works
Effects of dopaminergic drugs on delayed reward as a measure of impulsive behavior in rats
de Wit, H., Wade, T. R., & Richards, J. B. (2000) · Psychopharmacology · doi:10.1007/s002130000402 · Cited by 333 · see citing works
Winstanley, C. A., Theobald, D. E. H., Dalley, J. W., & Robbins, T. W. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300610 · Cited by 331 · see citing works
Self-citationCole, B. J., & Robbins, T. W. (1989) · Behavioural Brain Research · doi:10.1016/s0166-4328(89)80048-8 · Cited by 316 · see citing works
Kennedy, H. G. (2024) · Cambridge University Press eBooks · doi:10.1017/9781911623809.003 · Cited by 286 · see citing works
Christakou, A., Robbins, T. W., & Everitt, B. J. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.0949-03.2004 · Cited by 281 · see citing works
Winstanley, C. A., Theobald, D. E. H., Dalley, J. W., Cardinal, R. N., & Robbins, T. W. (2005) · Cerebral Cortex · doi:10.1093/cercor/bhi088 · Cited by 279 · see citing works
Self-citationDalley, J. W. (2002) · Neuropsychopharmacology · doi:10.1016/s0893-133x(01)00412-2 · Cited by 271 · see citing works
An essential role for ΔFosB in the nucleus accumbens in morphine action
Zachariou, V., Bolaños, C. A., Selley, D. E., Theobald, D. E. H., Cassidy, M. P., Kelz, M. B., Shaw-Lutchman, T., Berton, O., Sim‐Selley, L. J., Dileone, R., et al. (2006) · Nature Neuroscience · doi:10.1038/nn1636 · Cited by 266 · see citing works
Winstanley, C. A., Dalley, J. W., Theobald, D. E. H., & Robbins, T. W. (2003) · Psychopharmacology · doi:10.1007/s00213-003-1546-3 · Cited by 255 · see citing works
Self-citationA neurodevelopmental view of impulsivity.
Daruna, J. H., & Barnes, P. A. (1993) · American Psychological Association eBooks · doi:10.1037/10500-002 · Cited by 254 · see citing works
Cole, B. J., & Robbins, T. W. (1987) · Psychopharmacology · doi:10.1007/bf00216011 · Cited by 240 · see citing works
Behavioral disinhibition requires dopamine receptor activation
van Gaalen, M. M., Brueggeman, R. J., Bronius, P. F. C., Schoffelmeer, A. N. M., & Vanderschuren, L. J. M. J. (2006) · Psychopharmacology · doi:10.1007/s00213-006-0396-1 · Cited by 236 · see citing works
Striatal Cell Type-Specific Overexpression of ΔFosB Enhances Incentive for Cocaine
Colby, C. R., Whisler, K., Steffen, C., Nestler, E. J., & Self, D. W. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-06-02488.2003 · Cited by 217 · see citing works
Discounting of delayed rewards in substance abusers: relationship to antisocial personality disorder
Petry, N. (2002) · Psychopharmacology · doi:10.1007/s00213-002-1115-1 · Cited by 202 · see citing works
Doucet, J. ‐., Nakabeppu, Y., Bédard, P. J., Hope, B. T., Nestler, E. J., Jasmin, B. J., Chen, J. ‐., ladarola, M. J., St-Jean, M., Wigle, N., et al. (1996) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.1996.tb01220.x · Cited by 185 · see citing works
Robbins, T. W., & Sahakian, B. J. (1979) · Neuropharmacology · doi:10.1016/0028-3908(79)90157-6 · Cited by 170 · see citing works
ΔFosB Induction in Orbitofrontal Cortex Mediates Tolerance to Cocaine-Induced Cognitive Dysfunction
Winstanley, C., LaPlant, Q., Theobald, D., Green, T., Bachtell, R., Perrotti, L., DiLeone, R., Russo, S., Garth, W. J., Self, D., et al. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.2566-07.2007 · Cited by 149 · see citing works
Self-citationDalley, J. W., Lääne, K., Peña, Y., Theobald, D. E. H., Everitt, B. J., & Robbins, T. W. (2005) · Psychopharmacology · doi:10.1007/s00213-005-0107-3 · Cited by 132 · see citing works
Uslaner, J. M., & Robinson, T. E. (2006) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2006.05117.x · Cited by 131 · see citing works
Seeman, P. M., Tallerico, T., & Ko, F. (2003) · Synapse · doi:10.1002/syn.10232 · Cited by 128 · see citing works
Volkow, N. D., Ding, Y., Fowler, J. S., & Wang, G. (1996) · Journal of Addictive Diseases · doi:10.1300/j069v15n04_04 · Cited by 121 · see citing works
Kheramin, S., Body, S., Ho, M.-Y., Vel�zquez-Martinez, D. N., Bradshaw, C. M., Szabadi, E., Deakin, J. F. W., & Anderson, I. M. (2004) · Psychopharmacology · doi:10.1007/s00213-004-1813-y · Cited by 117 · see citing works
P300 Event-Related Potential Amplitude and Impulsivity in Cocaine-Dependent Subjects
Moeller, F. G., Barratt, E. S., Fischer, C. J., Dougherty, D. M., Reilly, E. L., Mathias, C. W., & Swann, A. C. (2004) · Neuropsychobiology · doi:10.1159/000079110 · Cited by 104 · see citing works
Homayoun, H., & Moghaddam, B. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.0842-06.2006 · Cited by 79 · see citing works
Müller, D., & Unterwald, E. M. (2005) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.105.083410 · Cited by 79 · see citing works
Eysenck, S. B. G. (1993) · American Psychological Association eBooks · doi:10.1037/10500-009 · Cited by 74 · see citing works
Limbic Responsiveness to Procaine in Cocaine-Addicted Subjects
Adinoff, B. H., Devous, M. D., Best, S. M., George, M. S., Alexander, D., & Payne, K. (2001) · American Journal of Psychiatry · doi:10.1176/appi.ajp.158.3.390 · Cited by 61 · see citing works
Hutcheson, D. M., & Everitt, B. J. (2003) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1300.038 · Cited by 49 · see citing works
Activation of Group I mGluRs Increases Spontaneous IPSC Frequency in Rat Frontal Cortex
Chu, Z., & Hablitz, J. J. (1998) · Journal of Neurophysiology · doi:10.1152/jn.1998.80.2.621 · Cited by 45 · see citing works
Gomez, R. (2003) · Journal of Attention Disorders · doi:10.1177/108705470300600303 · Cited by 39 · see citing works
Kreek, M. J., Schlussman, S. D., Bart, G. B., LaForge, K. S., & Butelman, E. R. (2004) · Neuropharmacology · doi:10.1016/j.neuropharm.2004.07.024 · Cited by 34 · see citing works
Maubach, K. A., Cody, C., & Jones, R. S. G. (1998) · Neuroscience · doi:10.1016/s0306-4522(97)00469-7 · Cited by 30 · see citing works
Powell, K. J., Binder, T. L., Hori, S. E., Nakabeppu, Y., Weinberger, D. R., Lipska, B. K., & Robertson, G. S. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300883 · Cited by 24 · see citing works
Dunn, E., Fritschy, J., Carter, D. B., & Merchant, K. (1996) · Neuroscience Letters · doi:10.1016/0304-3940(96)12678-1 · Cited by 18 · see citing works
Drug Addiction: To the Cortex…and Beyond!
Kalivas, P. W. (2001) · American Journal of Psychiatry · doi:10.1176/appi.ajp.158.3.349 · Cited by 13 · see citing works
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Crews, F. T., & Boettiger, C. A. (2009) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2009.04.018 · Cited by 679 · see citing works
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Andrews, M. M., Meda, S. A., Thomas, A. D., Potenza, M. N., Krystal, J. H., Worhunsky, P., Stevens, M. C., O'Malley, S., Book, G. A., Reynolds, B., et al. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.09.049 · Cited by 181 · see citing works
Perry, J. L., Joseph, J. E., Jiang, Y., Zimmerman, R. S., Kelly, T. H., Darna, M., Huettl, P., Dwoskin, L. P., & Bardo, M. T. (2011) · Brain Research Reviews · doi:10.1016/j.brainresrev.2010.09.001 · Cited by 180 · see citing works
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- Authors
- WINSTANLEY, C. A.
- Affiliations
- University of British Columbia (CA)
- Corresponding author
- WINSTANLEY, CATHARINE A.
- Venue
- Annals of the New York Academy of Sciences
- Publisher
- Wiley
- Published
- 2007-12
- Volume
- 1121
- Issue
- 1
- Pages
- 639-655
- ISSN
- 0077-8923 (ISSN-L)
- 1749-6632
- OpenAlex
- W2044346852
- Cited by
- 119
- References
- 71
- Citations by year
- 2026: 4 · 2025: 6 · 2023: 2 · 2022: 3 · 2021: 2 · 2020: 7 · 2019: 5 · 2018: 6 · 2017: 4 · 2016: 3 · 2015: 6 · 2014: 11 · 2013: 12 · 2012: 11
- FWCI
- 3.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of the New York Academy of Sciences (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Keywords
- orbitofrontal cortex, impulsivity, addiction, cocaine, ΔFosB, nucleus accumbens, dopamine, serotonin, impulse control, drug addiction, cocaine withdrawal, cognitive impairment, corticostriatal circuits, inhibitory interneurons
- MeSH terms
- Animals, Pharmaceutical Preparations, Frontal Lobe, Humans, Neurons, Behavior, Addictive, Substance-Related Disorders
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