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Neural substrates of cognitive flexibility in cocaine and gambling addictions

  • Antonio Verdejo-Garcia (a1), Luke Clark (a2), Juan Verdejo-Román (a3), Natalia Albein-Urios (a3), José M. Martinez-Gonzalez (a3), Blanca Gutierrez (a4) and Carles Soriano-Mas (a5)...



Individuals with cocaine and gambling addictions exhibit cognitive flexibility deficits that may underlie persistence of harmful behaviours.


We investigated the neural substrates of cognitive inflexibility in cocaine users v. pathological gamblers, aiming to disambiguate common mechanisms v. cocaine effects.


Eighteen cocaine users, 18 pathological gamblers and 18 controls performed a probabilistic reversal learning task during functional magnetic resonance imaging, and were genotyped for the DRD2/ANKK Taq1A polymorphism.


Cocaine users and pathological gamblers exhibited reduced ventrolateral prefrontal cortex (PFC) signal during reversal shifting. Cocaine users further showed increased dorsomedial PFC (dmPFC) activation relative to pathological gamblers during perseveration, and decreased dorsolateral PFC activation relative to pathological gamblers and controls during shifting. Preliminary genetic findings indicated that cocaine users carrying the DRD2/ANKK Taq1A1+ genotype may derive unique stimulatory effects on shifting-related ventrolateral PFC signal.


Reduced ventrolateral PFC activation during shifting may constitute a common neural marker across gambling and cocaine addictions. Additional cocaine-related effects relate to a wider pattern of task-related dysregulation, reflected in signal abnormalities in dorsolateral and dmPFC.

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Corresponding author

Antonio Verdejo-Garcia, School of Psychology and Psychiatry, Monash University, 3800 Wellington Rd. Clayton Campus, Melbourne, Australia. Email address:


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Declaration of interest

L.C.: The Centre for Gambling Research at UBC is funded by support from the Province of British Columbia and the British Columbia Lottery Corporation. The other authors declare no conflicts of interest concerning this study.



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1 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. American Psychiatric, 2013.
2 Lucantonio, F, Stalnaker, TA, Shaham, Y, Niv, Y, Schoenbaum, G. The impact of orbitofrontal dysfunction on cocaine addiction. Nat Neurosci 2012; 15: 358–66.
3 Turner, TH, LaRowe, S, Horner, MD, Herron, J, Malcolm, R. Measures of cognitive functioning as predictors of treatment outcome for cocaine dependence. J Subst Abuse Treat 2009; 37: 328–34.
4 Clark, L, Cools, R, Robbins, TW. The neuropsychology of ventral prefrontal cortex: decision-making and reversal learning. Brain Cogn 2004; 55: 4153.
5 Izquierdo, A, Jentsch, JD. Reversal learning as a measure of impulsive and compulsive behavior in addictions. Psychopharmacology 2012; 219: 607–20.
6 Leeman, RF, Potenza, MN. Similarities and differences between pathological gambling and substance use disorders: a focus on impulsivity and compulsivity. Psychopharmacology 2012; 219: 469–90.
7 Fernández-Serrano, MJ, Perales, JC, Moreno-López, L, Pérez-García, M, Verdejo-García, A. Neuropsychological profiling of impulsivity and compulsivity in cocaine dependent individuals. Psychopharmacology 2012; 219: 673–83.
8 Ersche, KD, Roiser, JP, Robbins, TW, Sahakian, BJ. Chronic cocaine but not chronic amphetamine use is associated with perseverative responding in humans. Psychopharmacology 2008; 197: 421–31.
9 Vonmoos, M, Hulka, LM, Preller, KH, Jenni, D, Baumgartner, MR, Stohler, R, et al. Cognitive dysfunctions in recreational and dependent cocaine users: role of attention-deficit hyperactivity disorder, craving and early age at onset. Br J Psychiatry 2013; 203: 3543.
10 Vanes, LD, van Holst, RJ, Jansen, JM, van den Brink, W, Oosterlaan, J, Goudriaan, AE. Contingency learning in alcohol dependence and pathological gambling: learning and unlearning reward contingencies. Alcohol Clin Exp Res 2014 (doi:10.1111/acer.12393).
11 Cools, R, Clark, L, Owen, AM, Robbins, TW. Defining the neural mechanisms of probabilistic reversal learning using event-related functional magnetic resonance imaging. J Neurosci 2002; 22: 4563–7.
12 Camchong, J, MacDonald, AV III, Nelson, B, Bell, C, Mueller, BA, Specker, S, et al. Frontal hyperconnecivity related to discounting and reversal learning in cocaine subjects. Biol Psychiatry 2011; 69: 1117–23.
13 Ersche, KD, Roiser, JP, Abbott, S, Craig, KJ, Muller, U, Suckling, J, et al. Response perseveration in stimulant dependence is associated with striatal dysfunction and can be ameliorated by a D(2/3) receptor agonist. Biol Psychiatry 2011; 70: 754–62.
14 de Ruiter, MB, Veltman, DJ, Goudriaan, AE, Oosterlaan, J, Sjoerds, Z, van den Brink, W. Response perseveration and ventral prefrontal sensitivity to reward and punishment in male problem gamblers and smokers. Neuropsychopharmacology 2009; 34: 1027–38.
15 Jocham, G, Klein, TA, Neumann, J, von Cramon, DY, Reuter, M, Ullsperger, M. Dopamine DRD2 polymorphism alters reversal learning and associated neural activity. J Neurosci 2009; 29: 3695–704.
16 Noble, EP. Addiction and its reward process through polymorphisms of the D2 dopamine receptor gene: a review. Eur Psychiatry 2000; 15: 7989.
17 Madhavan, A, Argilli, E, Bonci, A, Whistler, JL. Loss of D2 dopamine receptor function modulates cocaine-induced glutamatergic synaptic potentiation in the ventral tegmental area. J Neurosci 2013; 33: 12329–36.
18 Volkow, ND, Fowler, JS, Wang, GJ, Hitzemann, R, Logan, J, Schlyer, DJ, et al. Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse 1993; 14: 169–77.
19 Volkow, ND, Chang, L, Wang, GL, Fowler, JS, Ding, YS, Sedler, M, et al. Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex. Am J Psychiatry 2011; 158: 2015–21.
20 Porter, JN, Olsen, AS, Gurnsey, K, Dugan, BP, Jedema, HP, Bradberry, CW. Chronic cocaine self-administration in rhesus monkeys: impact on associative learning, cognitive control, and working memory. J Neurosci 2011; 31: 4926–34.
21 Lee, B, Groman, S, London, ED, Jentsch, JD. Dopamine D2/D3 receptors play a specific role in the reversal of a learned visual discrimination in monkeys. Neuropsychopharmacology 2007; 32: 2125–34.
22 Fernandez-Serrano, MJ, Perez-Garcia, M, Schmidt Rio-Valle, J, Verdejo-Garcia, A. Neuropsychological consequences of alcohol and drug abuse on different components of executive functions. J Psychopharmacol 2010; 24: 1317–32.
23 Woicik, PA, Urban, C, Alia-Klein, N, Henry, A, Maloney, T, Telang, F, et al. A pattern of perseveration in cocaine addiction may reveal neurocognitive processes implicit in the Wisconsin Card Sorting Test. Neuropsychologia 2011; 49: 1660–9.
24 van Holst, RJ, de Ruiter, MB, van den Brink, W, Veltman, DJ, Goudriaan, AE. A voxel-based morphometry study comparing problem gamblers, alcohol abusers, and healthy controls. Drug Alcohol Depend 2012; 124: 142–8.
25 Clark, L, Limbrick-Oldfield, EH. Disordered gambling: a behavioral addiction. Curr Opin Neurobiol 2013; 23: 655–9.
26 Limbrick-Oldfield, EH, van Holst, RJ, Clark, L. Fronto-striatal dysregulation in drug addiction and pathological gambling: consistent inconsistencies? NeuroImage Clin 2013; 2: 385–93.
27 Kaufman, JC, Kaufman, AS. Time for the changing of the guard: a farewell to short forms of intelligence tests. J Psychoeducational Assess 2001; 19: 245–67.
28 Verdejo-Garcia, AJ, Lopez-Torrecillas, F, Aguilar de Arcos, F, Perez-Garcia, M. Differential effects of MDMA, cocaine, and cannabis use severity on distinctive components of the executive functions in polysubstance users: a multiple regression analysis. Addict Behav 2005; 30: 89101.
29 Lobo, A, Perez-Echeverria, MJ, Artal, J. Validity of the scaled version of the General Health Questionnaire (GHQ-28) in a Spanish population. Psychol Med 1986; 16: 135–40.
30 López-Castromán, J, Vaquero-Lorenzo, C, Perez-Rodriguez, MM, Diaz-Hernandez, M, Fernandez-Piqueras, J, Saiz-Ruiz, J, et al. Gender effect on association between DRD2 polymorphism and substance dependence in a Spanish sample. Drug Alcohol Depend 2009; 101: 210–2.
31 Perez de los Cobos, J, Baiget, M, Trujols, J, Sinol, N, Volpini, V, Banuls, E, et al. Allelic and genotypic associations of DRD2 TaqI A polymorphism with heroin dependence in Spanish subjects: a case control study. Behav Brain Funct 2007; 3: 25.
32 First, MB, Spitzer, RL, Gibbon, M, Williams, JBW. Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). American Psychiatric Press, 1997.
33 Loranger, AW, Sartorius, N, Andreoli, A, Berger, P, Buchheim, P, Channabasavanna, SM, et al. The International Personality Disorder Examination. The World Health Organization/Alcohol, Drug Abuse, and Mental Health Administration international pilot study of personality disorders. Arch Gen Psychiatry 1994; 51: 215–24.
34 Conners, CK. Clinical use of rating scales in diagnosis and treatment of attention-deficit/hyperactivity disorder. Pediatr Clin North Am 1999; 46: 857–70.
35 Ritchie, T, Noble, EP. Association of seven polymorphisms of the D2 dopamine receptor gene with brain receptor-binding characteristics. Neurochem Res 2003; 28: 7382.
36 Ward, BD. AlphaSim Program Documentation for AFNI, Simultaneous Inference for fMRI Data. Medical College of Wisconsin, Milwaukee. 2000 (
37 Song, XW, Dong, ZY, Long, XY, Li, SF, Zuo, XN, Zhu, CZ, et al. REST: a toolkit for resting-state functional magnetic resonance imaging data processing. PLoS ONE 2011; 6: e25031.
38 Mitchell, DG, Luo, Q, Avny, SB, Kasprzycki, T, Gupta, K, Chen, G, et al. Adapting to dynamic stimulus-response values: differential contributions of inferior frontal, dorsomedial, and dorsolateral regions of prefrontal cortex to decision making. J Neurosci 2009; 29: 10827–34.
39 Tabibnia, G, Monterosso, JR, Baicy, K, Aron, AR, Poldrack, RA, Chakrapani, S, et al. Different forms of self-control share a neurocognitive substrate. J Neurosci 2011; 31: 4805–10.
40 Glaser, YG, Zubieta, JK, Hsu, DT, Villafuerte, S, Mickey, BJ, Trucco, EM, et al. Indirect effect of corticotropin-releasing hormone receptor 1 gene variation on negative emotionality and alcohol use via right ventrolateral prefrontal cortex. J Neurosci 2014; 34: 4099–107.
41 Smith, DG, Jones, PS, Bullmore, ET, Robbins, TW, Ersche, KD. Cognitive control dysfunction and abnormal frontal cortex activation in stimulant drug users and their biological siblings. Transl Psychiatry 2013; 3: e257.
42 Kroener, S, Chandler, LJ, Phillips, PE, Seamans, JK. Dopamine modulates persistent synaptic activity and enhances the signal-to-noise ratio in the prefrontal cortex. PLoS ONE 2009; 4: e6507.
43 Cohen, MX, Krohn-Grimberghe, A, Elger, CE, Weber, B. Dopamine gene predicts the brain's response to dopaminergic drug. Eur J Neurosci 2007; 26: 3652–60.
44 Ashare, RL, Wileyto, EP, Ruparel, K, Goelz, PM, Hopson, RD, Valdez, JN, et al. Effects of tolcapone on working memory and brain activity in abstinent smokers: a proof-of-concept study. Drug Alcohol Depend 2013; 133: 852–6.
45 Clark, CR, Egan, GF, McFarlane, AC, Morris, P, Weber, D, Sonkkilla, C, et al. Updating working memory for words: a PET activation study. Hum Brain Mapp 2000; 9: 4254.
46 Wager, TD, Jonides, J, Reading, S. Neuroimaging studies of shifting attention: a meta-analysis. NeuroImage 2004; 22: 1679–93.
47 Hearing, M, Kotecki, L, Marron Fernandez de Velasco, E, Fajardo-Serrano, A, Chung, HJ, Lujan, R, et al. Repeated cocaine weakens GABA(B)-Girk signaling in layer 5/6 pyramidal neurons in the prelimbic cortex. Neuron 2013; 80: 159–70.
48 Kasanetz, F, Lafourcade, M, Deroche-Gamonet, V, Revest, JM, Berson, N, Balado, E, et al. Prefrontal synaptic markers of cocaine addiction-like behavior in rats. Mol Psychiatry 2013; 18: 729–37.
49 Mihindou, C, Guillem, K, Navailles, S, Vouillac, C, Ahmed, SH. Discriminative inhibitory control of cocaine seeking involves the prelimbic prefrontal cortex. Biol Psychiatry 2013; 73: 271–9.
50 Barros-Loscertales, A, Garavan, H, Bustamante, JC, Ventura-Campos, N, Llopis, JJ, Belloch, V, et al. Reduced striatal volume in cocaine-dependent patients. Neuroimage 2011; 56: 1021–6.
51 Dombrovski, AY, Clark, L, Siegle, GJ, Butters, MA, Ichikawa, N, Sahakian, BJ, et al. Reward/punishment reversal learning in older suicide attempters. Am J Psychiatry 2010; 167: 699707.
52 Albein-Urios, N, Martinez-González, JM, Lozano, O, Clark, L, Verdejo-García, A. Comparison of impulsivity and working memory in cocaine addiction and pathological gambling: implications for cocaine-induced neurotoxicity. Drug Alcohol Depend 2012; 126: 16.
53 Wesley, MJ, Bickel, WK. Remember the future II: meta-analyses and functional overlap of working memory and delay discounting. Biol Psychiatry 2014; 75: 435–48. doi:10.1016/j.biopsych.2013.08.008.
54 Kuentzel, JG, Henderson, MJ, Melville, CL. The impact of social desirability biases on self-report among college student and problem gamblers. J Gambl Stud 2008; 24: 307–19.
55 Toce-Gerstein, M, Gerstein, DR, Volberg, RA. A hierarchy of gambling disorders in the community. Addiction 2003; 98: 1661–72.

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Neural substrates of cognitive flexibility in cocaine and gambling addictions

  • Antonio Verdejo-Garcia (a1), Luke Clark (a2), Juan Verdejo-Román (a3), Natalia Albein-Urios (a3), José M. Martinez-Gonzalez (a3), Blanca Gutierrez (a4) and Carles Soriano-Mas (a5)...


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Neural substrates of cognitive flexibility in cocaine and gambling addictions

  • Antonio Verdejo-Garcia (a1), Luke Clark (a2), Juan Verdejo-Román (a3), Natalia Albein-Urios (a3), José M. Martinez-Gonzalez (a3), Blanca Gutierrez (a4) and Carles Soriano-Mas (a5)...
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