, Volume 232, Issue 24, pp 4481–4491 | Cite as

Inactivation of the prelimbic or infralimbic cortex impairs decision-making in the rat gambling task

  • Fiona D. ZeebEmail author
  • P. J. J. Baarendse
  • L. J. M. J. Vanderschuren
  • Catharine A. WinstanleyEmail author
Original Investigation



Studies employing the Iowa Gambling Task (IGT) demonstrated that areas of the frontal cortex, including the ventromedial prefrontal cortex, orbitofrontal cortex (OFC), dorsolateral prefrontal cortex, and anterior cingulate cortex (ACC), are involved in the decision-making process. However, the precise role of these regions in maintaining optimal choice is not clear.


We used the rat gambling task (rGT), a rodent analogue of the IGT, to determine whether inactivation of or altered dopamine signalling within discrete cortical sub-regions disrupts decision-making.


Following training on the rGT, animals were implanted with guide cannulae aimed at the prelimbic (PrL) or infralimbic (IL) cortices, the OFC, or the ACC. Prior to testing, rats received an infusion of saline or a combination of baclofen and muscimol (0.125 μg of each/side) to inactivate the region and an infusion of a dopamine D2 receptor antagonist (0, 0.1, 0.3, and 1.0 μg/side).


Rats tended to increase their choice of a disadvantageous option and decrease their choice of the optimal option following inactivation of either the IL or PrL cortex. In contrast, OFC or ACC inactivation did not affect decision-making. Infusion of a dopamine D2 receptor antagonist into any sub-region did not alter choice preference.


Online activity of the IL or PrL cortex is important for maintaining an optimal decision-making strategy, but optimal performance on the rGT does not require frontal cortex dopamine D2 receptor activation. Additionally, these results demonstrate that the roles of different cortical regions in cost-benefit decision-making may be dissociated using the rGT.


Anterior cingulate cortex Decision-making Dopamine receptor Infralimbic cortex Orbitofrontal cortex Prelimbic cortex Rat gambling task Reward Punishment Probability 



This work was supported by an operating grant awarded to CAW from the Canadian Institutes for Health Research (CIHR) and by National Institute on Drug Abuse Grant R01 DA022628 (LJMJV). CAW also receives salary support through the Michael Smith Foundation for Health Research and the CIHR New Investigator Award program. FDZ currently receives salary support through the CIHR Postdoctoral Fellowship. We thank Suzanne Lemstra and Ruth Damsteegt for practical assistance. CAW has previously consulted for Shire, and FDZ has previously consulted for Intervivo Solutions, Inc, both on unrelated matters. The authors declare no competing financial interests.


  1. Baarendse PJJ, Vanderschuren LJMJ (2012) Dissociable effects of monoamine reuptake inhibitors on distinct forms of impulsive behavior in rats. Psychopharmacology (Berl) 219:313–326. doi: 10.1007/s00213-011-2576-x CrossRefGoogle Scholar
  2. Baarendse PJJ, Winstanley CA, Vanderschuren LJMJ (2013) Simultaneous blockade of dopamine and noradrenaline reuptake promotes disadvantageous decision making in a rat gambling task. Psychopharmacology (Berl) 225:719–731. doi: 10.1007/s00213-012-2857-z CrossRefGoogle Scholar
  3. Barch DM, Braver TS, Akbudak E et al (2001) Anterior cingulate cortex and response conflict: effects of response modality and processing domain. Cereb Cortex 11:837–848CrossRefPubMedGoogle Scholar
  4. Bechara A, Damasio AR, Damasio H, Anderson SW (1994) Insensitivity to future consequences following damage to human prefrontal cortex. Cognition 50:7–15CrossRefPubMedGoogle Scholar
  5. Bechara A, Tranel D, Damasio H, Damasio AR (1996) Failure to respond autonomically to anticipated future outcomes following damage to prefrontal cortex. Cereb Cortex 6:215–225. doi: 10.1093/cercor/6.2.215 CrossRefPubMedGoogle Scholar
  6. Bechara A, Damasio H, Damasio AR, Lee GP (1999) Different contributions of the human amygdala and ventromedial prefrontal cortex to decision-making. J Neurosci 19:5473–5481PubMedGoogle Scholar
  7. Bechara A, Tranel D, Damasio H (2000) Characterization of the decision-making deficit of patients with ventromedial prefrontal cortex lesions. Brain 123(Pt 11):2189–2202CrossRefPubMedGoogle Scholar
  8. Bechara A, Dolan S, Denburg N et al (2001) Decision-making deficits, linked to a dysfunctional ventromedial prefrontal cortex, revealed in alcohol and stimulant abusers. Neuropsychologia 39:376–389CrossRefPubMedGoogle Scholar
  9. Behrens TEJ, Woolrich MW, Walton ME, Rushworth MFS (2007) Learning the value of information in an uncertain world. Nat Neurosci 10:1214–1221. doi: 10.1038/nn1954 CrossRefPubMedGoogle Scholar
  10. Bolla KI, Eldreth DA, London ED et al (2003) Orbitofrontal cortex dysfunction in abstinent cocaine abusers performing a decision-making task. Neuroimage 19:1085–1094PubMedCentralCrossRefPubMedGoogle Scholar
  11. Botvinick M, Nystrom LE, Fissell K et al (1999) Conflict monitoring versus selection-for-action in anterior cingulate cortex. Nature 402:179–181. doi: 10.1038/46035 CrossRefPubMedGoogle Scholar
  12. Boulougouris V, Dalley JW, Robbins TW (2007) Effects of orbitofrontal, infralimbic and prelimbic cortical lesions on serial spatial reversal learning in the rat. Behav Brain Res 179:219–228. doi: 10.1016/j.bbr.2007.02.005 CrossRefPubMedGoogle Scholar
  13. Cardinal RN (2006) Neural systems implicated in delayed and probabilistic reinforcement. Neural Netw Off J Int Neural Netw Soc 19:1277–1301. doi: 10.1016/j.neunet.2006.03.004 CrossRefGoogle Scholar
  14. Cardinal RN, Pennicott DR, Sugathapala CL et al (2001) Impulsive choice induced in rats by lesions of the nucleus accumbens core. Science 292:2499–2501. doi: 10.1126/science.1060818 CrossRefPubMedGoogle Scholar
  15. Cella M, Dymond S, Cooper A (2010) Impaired flexible decision-making in major depressive disorder. J Affect Disord 124:207–210. doi: 10.1016/j.jad.2009.11.013 CrossRefPubMedGoogle Scholar
  16. Chudasama Y, Passetti F, Rhodes SE, Lopian D, Desai A, Robbins TW (2003) Dissociable aspects of performance on the 5-choice serial reaction time task following lesions of the dorsal anterior cingulate, infralimbic and orbitofrontal cortex in the rat: differential effects on selectivity, impulsivity and compulsivity. Behav Brain Res 146(1–2):105–19Google Scholar
  17. Clark L, Manes F, Antoun N et al (2003) The contributions of lesion laterality and lesion volume to decision-making impairment following frontal lobe damage. Neuropsychologia 41:1474–1483CrossRefPubMedGoogle Scholar
  18. Connolly NP, Kim JS, Tunstall BJ, Kearns DN (2015) A test of stress, cues, and re-exposure to large wins as potential reinstaters of suboptimal decision making in rats. Front Psychol 6:394. doi: 10.3389/fpsyg.2015.00394
  19. Dalley JW, Cardinal RN, Robbins TW (2004) Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates. Neurosci Biobehav Rev 28:771–784. doi: 10.1016/j.neubiorev.2004.09.006 CrossRefPubMedGoogle Scholar
  20. Eagle DM, Baunez C, Hutcheson DM, Lehmann O, Shah AP, Robbins TW (2008) Stop-signal reaction-time task performance: role of prefrontal cortex and subthalamic nucleus. Cereb Cortex 18(1):178–188Google Scholar
  21. Ernst M, Bolla K, Mouratidis M et al (2002) Decision-making in a risk-taking task: a PET study. Neuropsychopharmacology 26:682–691. doi: 10.1016/S0893-133X(01)00414-6 CrossRefPubMedGoogle Scholar
  22. Fellows LK, Farah MJ (2005) Different underlying impairments in decision-making following ventromedial and dorsolateral frontal lobe damage in humans. Cereb Cortex 15:58–63. doi: 10.1093/cercor/bhh108 CrossRefPubMedGoogle Scholar
  23. Fitoussi A, Le Moine C, De Deurwaerdère P et al (2014) Prefronto-subcortical imbalance characterizes poor decision-making: neurochemical and neural functional evidences in rats. Brain Struct Funct. doi: 10.1007/s00429-014-0868-8 PubMedGoogle Scholar
  24. Floresco SB, Ghods-Sharifi S (2007) Amygdala-prefrontal cortical circuitry regulates effort-based decision making. Cereb Cortex 17:251–260. doi: 10.1093/cercor/bhj143 CrossRefPubMedGoogle Scholar
  25. Floresco SB, Magyar O (2006) Mesocortical dopamine modulation of executive functions: beyond working memory. Psychopharmacology (Berl) 188:567–585. doi: 10.1007/s00213-006-0404-5 CrossRefGoogle Scholar
  26. Goudriaan AE, Oosterlaan J, de Beurs E, van den Brink W (2005) Decision making in pathological gambling: a comparison between pathological gamblers, alcohol dependents, persons with Tourette syndrome, and normal controls. Brain Res Cogn Brain Res 23:137–151. doi: 10.1016/j.cogbrainres.2005.01.017 CrossRefPubMedGoogle Scholar
  27. Hewig J, Straube T, Trippe RH et al (2009) Decision-making under risk: an fMRI study. J Cogn Neurosci 21:1642–1652. doi: 10.1162/jocn.2009.21112 CrossRefPubMedGoogle Scholar
  28. Hillman KL, Bilkey DK (2010) Neurons in the rat anterior cingulate cortex dynamically encode cost-benefit in a spatial decision-making task. J Neurosci 30:7705–7713. doi: 10.1523/JNEUROSCI.1273-10.2010 CrossRefPubMedGoogle Scholar
  29. Holec V, Pirot HL, Euston DR (2014) Not all effort is equal: the role of the anterior cingulate cortex in different forms of effort-reward decisions. Front Behav Neurosci 8:12. doi: 10.3389/fnbeh.2014.00012 PubMedCentralCrossRefPubMedGoogle Scholar
  30. Hoover WB, Vertes RP (2007) Anatomical analysis of afferent projections to the medial prefrontal cortex in the rat. Brain Struct Funct 212:149–179. doi: 10.1007/s00429-007-0150-4 CrossRefPubMedGoogle Scholar
  31. Lapish CC, Durstewitz D, Chandler LJ, Seamans JK (2008) Successful choice behavior is associated with distinct and coherent network states in anterior cingulate cortex. Proc Natl Acad Sci U S A 105:11963–11968. doi: 10.1073/pnas.0804045105 PubMedCentralCrossRefPubMedGoogle Scholar
  32. Lawrence NS, Jollant F, O’Daly O et al (2009) Distinct roles of prefrontal cortical subregions in the Iowa Gambling Task. Cereb Cortex 19:1134–1143. doi: 10.1093/cercor/bhn154 CrossRefPubMedGoogle Scholar
  33. Li X, Lu Z-L, D’Argembeau A et al (2010) The Iowa Gambling Task in fMRI images. Hum Brain Mapp 31:410–423. doi: 10.1002/hbm.20875 PubMedCentralPubMedGoogle Scholar
  34. Manes F, Sahakian B, Clark L et al (2002) Decision-making processes following damage to the prefrontal cortex. Brain 125:624–639CrossRefPubMedGoogle Scholar
  35. McDonald J (2009) Handbook of biological statistics, 2nd edn. Sparky House Publishing, BaltimoreGoogle Scholar
  36. Muir JL, Everitt BJ, Robbins TW (1996) The cerebral cortex of the rat and visual attentional function: dissociable effects of mediofrontal, cingulate, anterior dorsolateral, and parietal cortex lesions on a fivechoice serial reaction time task. Cerebral Cortex 6(3):470–481Google Scholar
  37. Murphy ER, Fernando AB, Urcelay GP, Robinson ES, Mar AC, Theobald DE, Dalley JW, Robbins TW (2012) Impulsive behaviour induced by both NMDA receptor antagonism and GABAA receptor activation in rat ventromedial prefrontal cortex. Psychopharmacology (Berl). 219(2):401–410Google Scholar
  38. Naccache L, Dehaene S, Cohen L et al (2005) Effortless control: executive attention and conscious feeling of mental effort are dissociable. Neuropsychologia 43:1318–1328. doi: 10.1016/j.neuropsychologia.2004.11.024 CrossRefPubMedGoogle Scholar
  39. Njomboro P, Deb S, Humphreys GW (2012) Apathy and executive functions: insights from brain damage involving the anterior cingulate cortex. BMJ Case Rep. doi: 10.1136/bcr-02-2012-5934 PubMedCentralPubMedGoogle Scholar
  40. Paine TA, Asinof SK, Diehl GW et al (2013) Medial prefrontal cortex lesions impair decision-making on a rodent gambling task: reversal by D1 receptor antagonist administration. Behav Brain Res 243:247–254. doi: 10.1016/j.bbr.2013.01.018 PubMedCentralCrossRefPubMedGoogle Scholar
  41. Paine TA, O’Hara A, Plaut B, Lowes DC (2014) Effects of disrupting medial prefrontal cortex GABA transmission on decision-making in a rodent gambling task. Psychopharmacology (Berl). doi: 10.1007/s00213-014-3816-7 Google Scholar
  42. Pattij T, Vanderschuren LJMJ (2008) The neuropharmacology of impulsive behaviour. Trends Pharmacol Sci 29:192–199. doi: 10.1016/ CrossRefPubMedGoogle Scholar
  43. Paxinos G, Watson C (1998) The rat brain in stereotaxic co-ordinates. Academic, SydneyGoogle Scholar
  44. Ragozzino ME (2007) The contribution of the medial prefrontal cortex, orbitofrontal cortex, and dorsomedial striatum to behavioral flexibility. Ann N Y Acad Sci 1121:355–375. doi: 10.1196/annals.1401.013 CrossRefPubMedGoogle Scholar
  45. Rivalan M, Coutureau E, Fitoussi A, Dellu-Hagedorn F (2011) Inter-individual decision-making differences in the effects of cingulate, orbitofrontal, and prelimbic cortex lesions in a rat gambling task. Front Behav Neurosci 5:22. doi: 10.3389/fnbeh.2011.00022 PubMedCentralCrossRefPubMedGoogle Scholar
  46. Robbins TW (2002) The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry. Psychopharmacology (Berl) 163:362–380. doi: 10.1007/s00213-002-1154-7 CrossRefGoogle Scholar
  47. Rogers RD, Owen AM, Middleton HC et al (1999) Choosing between small, likely rewards and large, unlikely rewards activates inferior and orbital prefrontal cortex. J Neurosci 19:9029–9038PubMedGoogle Scholar
  48. Rogers RD, Ramnani N, Mackay C et al (2004) Distinct portions of anterior cingulate cortex and medial prefrontal cortex are activated by reward processing in separable phases of decision-making cognition. Biol Psychiatry 55:594–602. doi: 10.1016/j.biopsych.2003.11.012 CrossRefPubMedGoogle Scholar
  49. Rudebeck PH, Walton ME, Smyth AN et al (2006) Separate neural pathways process different decision costs. Nat Neurosci 9:1161–1168. doi: 10.1038/nn1756 CrossRefPubMedGoogle Scholar
  50. Schweimer J, Hauber W (2005) Involvement of the rat anterior cingulate cortex in control of instrumental responses guided by reward expectancy. Learn Mem 12:334–342. doi: 10.1101/lm.90605 PubMedCentralCrossRefPubMedGoogle Scholar
  51. Seamans JK, Yang CR (2004) The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog Neurobiol 74:1–58. doi: 10.1016/j.pneurobio.2004.05.006 CrossRefPubMedGoogle Scholar
  52. Seamans JK, Gorelova N, Durstewitz D, Yang CR (2001) Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons. J Neurosci 21:3628–3638PubMedGoogle Scholar
  53. Seamans JK, Lapish CC, Durstewitz D (2008) Comparing the prefrontal cortex of rats and primates: insights from electrophysiology. Neurotox Res 14:249–262. doi: 10.1007/BF03033814 CrossRefPubMedGoogle Scholar
  54. Shurman B, Horan WP, Nuechterlein KH (2005) Schizophrenia patients demonstrate a distinctive pattern of decision-making impairment on the Iowa Gambling Task. Schizophr Res 72:215–224. doi: 10.1016/j.schres.2004.03.020 CrossRefPubMedGoogle Scholar
  55. Smoski MJ, Lynch TR, Rosenthal MZ et al (2008) Decision-making and risk aversion among depressive adults. J Behav Ther Exp Psychiatry 39:567–576. doi: 10.1016/j.jbtep.2008.01.004 PubMedCentralCrossRefPubMedGoogle Scholar
  56. St Onge JR, Floresco SB (2009) Dopaminergic modulation of risk-based decision making. Neuropsychopharmacology 34:681–697. doi: 10.1038/npp.2008.121 CrossRefPubMedGoogle Scholar
  57. St Onge JR, Floresco SB (2010) Prefrontal cortical contribution to risk-based decision making. Cereb Cortex 20:1816–1828. doi: 10.1093/cercor/bhp250 CrossRefPubMedGoogle Scholar
  58. Trantham-Davidson H, Neely LC, Lavin A, Seamans JK (2004) Mechanisms underlying differential D1 versus D2 dopamine receptor regulation of inhibition in prefrontal cortex. J Neurosci 24:10652–10659. doi: 10.1523/JNEUROSCI.3179-04.2004 CrossRefPubMedGoogle Scholar
  59. Tsutsui-Kimura I, Yoshida T, Ohmura Y, Izumi T, Yoshioka M (2014) Milnacipran remediates impulsive deficits in rats with lesions of the ventromedial prefrontal cortex. Int J Neuropsychopharmacol 8(5). doi: 10.1093/ijnp/pyu083
  60. Uylings HBM, Groenewegen HJ, Kolb B (2003) Do rats have a prefrontal cortex? Behav Brain Res 146:3–17CrossRefPubMedGoogle Scholar
  61. Veeneman MMJ, Broekhoven MH, Damsteegt R, Vanderschuren LJMJ (2012) Distinct contributions of dopamine in the dorsolateral striatum and nucleus accumbens shell to the reinforcing properties of cocaine. Neuropsychopharmacology 37:487–498. doi: 10.1038/npp.2011.209 PubMedCentralCrossRefPubMedGoogle Scholar
  62. Vertes RP (2004) Differential projections of the infralimbic and prelimbic cortex in the rat. Synapse 51:32–58. doi: 10.1002/syn.10279 CrossRefPubMedGoogle Scholar
  63. Walton ME, Bannerman DM, Alterescu K, Rushworth MFS (2003) Functional specialization within medial frontal cortex of the anterior cingulate for evaluating effort-related decisions. J Neurosci 23:6475–6479PubMedGoogle Scholar
  64. Walton ME, Groves J, Jennings KA et al (2009) Comparing the role of the anterior cingulate cortex and 6-hydroxydopamine nucleus accumbens lesions on operant effort-based decision making. Eur J Neurosci 29:1678–1691. doi: 10.1111/j.1460-9568.2009.06726.x PubMedCentralCrossRefPubMedGoogle Scholar
  65. Windmann S, Kirsch P, Mier D et al (2006) On framing effects in decision making: linking lateral versus medial orbitofrontal cortex activation to choice outcome processing. J Cogn Neurosci 18:1198–1211. doi: 10.1162/jocn.2006.18.7.1198 CrossRefPubMedGoogle Scholar
  66. Zeeb FD, Winstanley CA (2011) Lesions of the basolateral amygdala and orbitofrontal cortex differentially affect acquisition and performance of a rodent gambling task. J Neurosci 31(6):2197–2204. doi: 10.1523/JNEUROSCI.5597-10.2011
  67. Zeeb FD, Winstanley CA (2013) Functional disconnection of the orbitofrontal cortex and basolateral amygdala impairs acquisition of a rat gambling task and disrupts animals’ ability to alter decision-making behavior after reinforcer devaluation. J Neurosci 33:6434–6443. doi: 10.1523/JNEUROSCI.3971-12.2013 CrossRefPubMedGoogle Scholar
  68. Zeeb FD, Robbins TW, Winstanley CA (2009) Serotonergic and dopaminergic modulation of gambling behavior as assessed using a novel rat gambling task. Neuropsychopharmacology 34:2329–2343. doi: 10.1038/npp.2009.62 CrossRefPubMedGoogle Scholar
  69. Zeeb FD, Floresco SB, Winstanley CA (2010) Contributions of the orbitofrontal cortex to impulsive choice: interactions with basal levels of impulsivity, dopamine signalling, and reward-related cues. Psychopharmacology (Berl) 211(1):87–98. doi: 10.1007/s00213-010-1871-2 CrossRefGoogle Scholar
  70. Zeeb FD, Wong AC, Winstanley CA (2013) Differential effects of environmental enrichment, social-housing, and isolation-rearing on a rat gambling task: dissociations between impulsive action and risky decision-making. Psychopharmacology (Berl) 225:381–395. doi: 10.1007/s00213-012-2822-x CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Fiona D. Zeeb
    • 1
    • 4
    Email author
  • P. J. J. Baarendse
    • 2
  • L. J. M. J. Vanderschuren
    • 2
    • 3
  • Catharine A. Winstanley
    • 1
    Email author
  1. 1.Department of PsychologyUniversity of British ColumbiaVancouverCanada
  2. 2.Department of Translational Neuroscience, Brain Center Rudolf MagnusUniversity Medical Center UtrechtUtrechtThe Netherlands
  3. 3.Department of Animals in Science and Society, Division of Behavioural Neuroscience, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
  4. 4.Centre for Addiction and Mental Health, Section of BiopsychologyCampbell Family Mental Health Research InstituteTorontoCanada

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