Discriminative Inhibitory Control of Cocaine Seeking Involves the Prelimbic Prefrontal Cortex

  • Claudia Mihindou
    Université de Bordeaux and the Centre National de la Recherche Scientifique, Institut des Maladies Neurodégénératives, Bordeaux, France
    Search for articles by this author
  • Author Footnotes
    1 Authors KG and SN Contributed equally to this work.
    Karine Guillem
    1 Authors KG and SN Contributed equally to this work.
    Université de Bordeaux and the Centre National de la Recherche Scientifique, Institut des Maladies Neurodégénératives, Bordeaux, France
    Search for articles by this author
  • Author Footnotes
    1 Authors KG and SN Contributed equally to this work.
    Sylvia Navailles
    1 Authors KG and SN Contributed equally to this work.
    Université de Bordeaux and the Centre National de la Recherche Scientifique, Institut des Maladies Neurodégénératives, Bordeaux, France
    Search for articles by this author
  • Caroline Vouillac
    Université de Bordeaux and the Centre National de la Recherche Scientifique, Institut des Maladies Neurodégénératives, Bordeaux, France
    Search for articles by this author
  • Serge H. Ahmed
    Address correspondence to Serge H. Ahmed, Ph.D., Université Bordeaux-Segalen, Institut des Maladies Neurodégénératives/CNRS UMR 5293, 146 rue Léo-Saignat, Bordeaux 33076, France
    Université de Bordeaux and the Centre National de la Recherche Scientifique, Institut des Maladies Neurodégénératives, Bordeaux, France
    Search for articles by this author
  • Author Footnotes
    1 Authors KG and SN Contributed equally to this work.
Published:September 17, 2012DOI:


      Recent neuroimaging studies have shown that people with cocaine addiction retain some degree of control over drug craving that correlates with neural activity in the lateral prefrontal cortex (PFC). Here, we report similar findings in a rat model of inhibitory control of cocaine seeking.


      Rats actively responding for cocaine were trained to stop responding when presented with a discriminative stimulus that signaled lack of reinforcement. Rats were then tested for inhibitory control of cocaine seeking in novel behavioral contexts and in circumstances when cocaine seeking is particularly intense (e.g., following drug priming). The role of neuronal activity in different subregions of the PFC was assessed using local pharmacologic inactivation and c-Fos immunohistochemistry.


      Rats progressively acquired the ability to stop cocaine seeking, even during drug intoxication and after a long history of cocaine self-administration. Inhibitory control of cocaine seeking was flexible, sufficiently strong to block cocaine-primed reinstatement, and selectively depended on increased neuronal activity within the prelimbic PFC, which is considered the rodent functional homolog of the human lateral PFC.


      Parallel evidence in both animal models and humans indicate that recruitment of prefrontal inhibitory control of drug seeking is still functional after prolonged cocaine use. Preclinical investigation of the mechanisms underlying this capacity may contribute to designing new behavioral and/or pharmacologic strategies to promote its use for the prevention of relapse in addiction.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Kober H.
        • Kross E.F.
        • Mischel W.
        • Hart C.L.
        • Ochsner K.N.
        Regulation of craving by cognitive strategies in cigarette smokers.
        Drug Alcohol Depend. 2010; 106: 52-55
        • Kober H.
        • Mende-Siedlecki P.
        • Kross E.F.
        • Weber J.
        • Mischel W.
        • Hart C.L.
        • Ochsner K.N.
        Prefrontal-striatal pathway underlies cognitive regulation of craving.
        Proc Natl Acad Sci U S A. 2010; 107: 14811-14816
        • Volkow N.D.
        • Fowler J.S.
        • Wang G.J.
        • Telang F.
        • Logan J.
        • Jayne M.
        • et al.
        Cognitive control of drug craving inhibits brain reward regions in cocaine abusers.
        Neuroimage. 2010; 49: 2536-2543
        • Hare T.A.
        • Camerer C.F.
        • Rangel A.
        Self-control in decision-making involves modulation of the vmPFC valuation system.
        Science. 2009; 324: 646-648
        • Beauregard M.
        • Levesque J.
        • Bourgouin P.
        Neural correlates of conscious self-regulation of emotion.
        J Neurosci. 2001; 21: RC165
        • Diekhof E.K.
        • Gruber O.
        When desire collides with reason: Functional interactions between anteroventral prefrontal cortex and nucleus accumbens underlie the human ability to resist impulsive desires.
        J Neurosci. 2010; 30: 1488-1493
        • Figner B.
        • Knoch D.
        • Johnson E.J.
        • Krosch A.R.
        • Lisanby S.H.
        • Fehr E.
        • Weber E.U.
        Lateral prefrontal cortex and self-control in intertemporal choice.
        Nat Neurosci. 2010; 13: 538-539
        • Herwig U.
        • Baumgartner T.
        • Kaffenberger T.
        • Bruhl A.
        • Kottlow M.
        • Schreiter-Gasser U.
        • et al.
        Modulation of anticipatory emotion and perception processing by cognitive control.
        Neuroimage. 2007; 37: 652-662
        • Kim S.H.
        • Hamann S.
        Neural correlates of positive and negative emotion regulation.
        J Cogn Neurosci. 2007; 19: 776-798
        • Levesque J.
        • Eugene F.
        • Joanette Y.
        • Paquette V.
        • Mensour B.
        • Beaudoin G.
        • et al.
        Neural circuitry underlying voluntary suppression of sadness.
        Biol Psychiatry. 2003; 53: 502-510
        • Ochsner K.N.
        • Bunge S.A.
        • Gross J.J.
        • Gabrieli J.D.
        Rethinking feelings: An fMRI study of the cognitive regulation of emotion.
        J Cogn Neurosci. 2002; 14: 1215-1229
        • Phan K.L.
        • Fitzgerald D.A.
        • Nathan P.J.
        • Moore G.J.
        • Uhde T.W.
        • Tancer M.E.
        Neural substrates for voluntary suppression of negative affect: A functional magnetic resonance imaging study.
        Biol Psychiatry. 2005; 57: 210-219
        • Siep N.
        • Roefs A.
        • Roebroeck A.
        • Havermans R.
        • Bonte M.
        • Jansen A.
        Fighting food temptations: The modulating effects of short-term cognitive reappraisal, suppression and up-regulation on mesocorticolimbic activity related to appetitive motivation.
        Neuroimage. 2012; 60: 213-220
        • Wager T.D.
        • Davidson M.L.
        • Hughes B.L.
        • Lindquist M.A.
        • Ochsner K.N.
        Prefrontal-subcortical pathways mediating successful emotion regulation.
        Neuron. 2008; 59: 1037-1050
        • Potenza M.N.
        • Sofuoglu M.
        • Carroll K.M.
        • Rounsaville B.J.
        Neuroscience of behavioral and pharmacological treatments for addictions.
        Neuron. 2011; 69: 695-712
        • Bickel W.K.
        • Yi R.
        • Landes R.D.
        • Hill P.F.
        • Baxter C.
        Remember the future: Working memory training decreases delay discounting among stimulant addicts.
        Biol Psychiatry. 2011; 69: 260-265
        • Ahmed S.H.
        The science of making drug-addicted animals.
        Neuroscience. 2012; 211: 107-125
        • Ahmed S.H.
        Validation crisis in animal models of drug addiction: Beyond non-disordered drug use toward drug addiction.
        Neurosci Biobehav Rev. 2010; 35: 172-184
        • Kearns D.N.
        • Weiss S.J.
        • Schindler C.W.
        • Panlilio L.V.
        Conditioned inhibition of cocaine seeking in rats.
        J Exp Psychol Anim Behav Process. 2005; 31: 247-253
        • Kearns D.N.
        • Weiss S.J.
        • Panlilio L.V.
        Conditioned suppression of behavior maintained by cocaine self-administration.
        Drug Alcohol Depend. 2002; 65: 253-261
        • Grove R.N.
        • Schuster C.R.
        Suppression of cocaine self-administration by extinction and punishment.
        Pharmacol Biochem Behav. 1974; 2: 199-208
        • Bouton M.E.
        Context, ambiguity, and unlearning: Sources of relapse after behavioral extinction.
        Biol Psychiatry. 2002; 52: 976-986
        • Ahmed S.H.
        • Koob G.F.
        Transition to drug addiction: A negative reinforcement model based on an allostatic decrease in reward function.
        Psychopharmacology (Berl). 2005; 180: 473-490
        • Mihindou C.
        • Vouillac C.
        • Koob G.F.
        • Ahmed S.H.
        Preclinical validation of a novel cocaine exposure therapy for relapse prevention.
        Biol Psychiatry. 2011; 70: 593-598
        • Ahmed S.H.
        • Cador M.
        Dissociation of psychomotor sensitization from compulsive cocaine consumption.
        Neuropsychopharmacology. 2006; 31: 563-571
        • van Duuren E.
        • van der Plasse G.
        • van der Blom R.
        • Joosten R.N.
        • Mulder A.B.
        • Pennartz C.M.
        • Feenstra M.G.
        Pharmacological manipulation of neuronal ensemble activity by reverse microdialysis in freely moving rats: A comparative study of the effects of tetrodotoxin, lidocaine, and muscimol.
        J Pharmacol Exp Ther. 2007; 323: 61-69
        • Bari A.
        • Mar A.C.
        • Theobald D.E.
        • Elands S.A.
        • Oganya K.C.
        • Eagle D.M.
        • Robbins T.W.
        Prefrontal and monoaminergic contributions to stop-signal task performance in rats.
        J Neurosci. 2011; 31: 9254-9263
        • Chan T.
        • Kyere K.
        • Davis B.R.
        • Shemyakin A.
        • Kabitzke P.A.
        • Shair H.N.
        • et al.
        The role of the medial prefrontal cortex in innate fear regulation in infants, juveniles, and adolescents.
        J Neurosci. 2011; 31: 4991-4999
        • Marquis J.P.
        • Killcross S.
        • Haddon J.E.
        Inactivation of the prelimbic, but not infralimbic, prefrontal cortex impairs the contextual control of response conflict in rats.
        Eur J Neurosci. 2007; 25: 559-566
        • Allen T.A.
        • Narayanan N.S.
        • Kholodar-Smith D.B.
        • Zhao Y.
        • Laubach M.
        • Brown T.H.
        Imaging the spread of reversible brain inactivations using fluorescent muscimol.
        J Neurosci Methods. 2008; 171: 30-38
        • Harris G.C.
        • Aston-Jones G.
        Enhanced morphine preference following prolonged abstinence: Association with increased Fos expression in the extended amygdala.
        Neuropsychopharmacology. 2003; 28: 292-299
        • Neisewander J.L.
        • Baker D.A.
        • Fuchs R.A.
        • Tran-Nguyen L.T.L.
        • Palmer A.
        • Marshall J.F.
        Fos protein expression and cocaine-seeking behavior in rats after exposure to a cocaine self-administration environment.
        J Neurosci. 2000; 20: 798-805
        • Ahmed S.H.
        • Koob G.F.
        Transition from moderate to excessive drug intake: Change in hedonic set point.
        Science. 1998; 282: 298-300
        • Epstein D.H.
        • Preston K.L.
        The reinstatement model and relapse prevention: A clinical perspective.
        Psychopharmacology (Berl). 2003; 168: 31-41
        • Fowler S.C.
        • Covington 3rd, H.E.
        • Miczek K.A.
        Stereotyped and complex motor routines expressed during cocaine self-administration: Results from a 24-h binge of unlimited cocaine access in rats.
        Psychopharmacology (Berl). 2007; 192: 465-478
        • Joyce E.M.
        • Iversen S.D.
        Dissociable effects of 6-OHDA-induced lesions of neostriatum on anorexia, locomotor activity and stereotypy: The role of behavioural competition.
        Psychopharmacology (Berl). 1984; 83: 363-366
        • Kelly P.H.
        • Seviour P.W.
        • Iversen S.D.
        Amphetamine and apomorphine responses in the rat following 6-OHDA lesions of the nucleus accumbens septi and corpus striatum.
        Brain Res. 1975; 94: 507-522
        • Kovacs K.J.
        c-Fos as a transcription factor: A stressful (re)view from a functional map.
        Neurochem Int. 1998; 33: 287-297
        • Frohmader K.S.
        • Wiskerke J.
        • Wise R.A.
        • Lehman M.N.
        • Coolen L.M.
        Methamphetamine acts on subpopulations of neurons regulating sexual behavior in male rats.
        Neuroscience. 2010; 166: 771-784
        • Hamlin A.S.
        • Clemens K.J.
        • McNally G.P.
        Renewal of extinguished cocaine-seeking.
        Neuroscience. 2008; 151: 659-670
        • Marchant N.J.
        • Hamlin A.S.
        • McNally G.P.
        Lateral hypothalamus is required for context-induced reinstatement of extinguished reward seeking.
        J Neurosci. 2009; 29: 1331-1342
        • Xue Y.X.
        • Luo Y.X.
        • Wu P.
        • Shi H.S.
        • Xue L.F.
        • Chen C.
        • et al.
        A memory retrieval-extinction procedure to prevent drug craving and relapse.
        Science. 2012; 336: 241-245
        • Vertes R.P.
        Interactions among the medial prefrontal cortex, hippocampus and midline thalamus in emotional and cognitive processing in the rat.
        Neuroscience. 2006; 142: 1-20
        • Vertes R.P.
        Differential projections of the infralimbic and prelimbic cortex in the rat.
        Synapse. 2004; 51: 32-58
        • Hoover W.B.
        • Vertes R.P.
        Anatomical analysis of afferent projections to the medial prefrontal cortex in the rat.
        Brain Struct Funct. 2007; 212: 149-179
        • Hayton S.J.
        • Lovett-Barron M.
        • Dumont E.C.
        • Olmstead M.C.
        Target-specific encoding of response inhibition: Increased contribution of AMPA to NMDA receptors at excitatory synapses in the prefrontal cortex.
        J Neurosci. 2010; 30: 11493-11500
        • Hayton S.J.
        • Olmstead M.C.
        • Dumont E.C.
        Shift in the intrinsic excitability of medial prefrontal cortex neurons following training in impulse control and cued-responding tasks.
        PLoS One. 2011; 6: e23885
        • Fitzpatrick C.J.
        • Knox D.
        • Liberzon I.
        Inactivation of the prelimbic cortex enhances freezing induced by trimethylthiazoline, a component of fox feces.
        Behav Brain Res. 2011; 221: 320-323
        • Ghazizadeh A.
        • Ambroggi F.
        • Odean N.
        • Fields H.L.
        Prefrontal cortex mediates extinction of responding by two distinct neural mechanisms in accumbens shell.
        J Neurosci. 2012; 32: 726-737
        • Ishikawa A.
        • Ambroggi F.
        • Nicola S.M.
        • Fields H.L.
        Dorsomedial prefrontal cortex contribution to behavioral and nucleus accumbens neuronal responses to incentive cues.
        J Neurosci. 2008; 28: 5088-5098
        • Killcross S.
        • Coutureau E.
        Coordination of actions and habits in the medial prefrontal cortex of rats.
        Cereb Cortex. 2003; 13: 400-408
        • Jinks A.L.
        • McGregor I.S.
        Modulation of anxiety-related behaviours following lesions of the prelimbic or infralimbic cortex in the rat.
        Brain Res. 1997; 772: 181-190
        • Laurent V.
        • Westbrook R.F.
        Inactivation of the infralimbic but not the prelimbic cortex impairs consolidation and retrieval of fear extinction.
        Learn Mem. 2009; 16: 520-529
        • MacLeod J.E.
        • Bucci D.J.
        Contributions of the subregions of the medial prefrontal cortex to negative occasion setting.
        Behav Neurosci. 2010; 124: 321-328
        • Sierra-Mercado D.
        • Padilla-Coreano N.
        • Quirk G.J.
        Dissociable roles of prelimbic and infralimbic cortices, ventral hippocampus, and basolateral amygdala in the expression and extinction of conditioned fear.
        Neuropsychopharmacology. 2011; 36: 529-538
        • Eagle D.M.
        • Baunez C.
        • Hutcheson D.M.
        • Lehmann O.
        • Shah A.P.
        • Robbins T.W.
        Stop-signal reaction-time task performance: Role of prefrontal cortex and subthalamic nucleus.
        Cereb Cortex. 2008; 18: 178-188
        • Rhodes S.E.
        • Killcross A.S.
        Lesions of rat infralimbic cortex result in disrupted retardation but normal summation test performance following training on a Pavlovian conditioned inhibition procedure.
        Eur J Neurosci. 2007; 26: 2654-2660
        • Granon S.
        • Vidal C.
        • Thinus-Blanc C.
        • Changeux J.P.
        • Poucet B.
        Working memory, response selection, and effortful processing in rats with medial prefrontal lesions.
        Behav Neurosci. 1994; 108: 883-891
        • Verbruggen F.
        • Logan G.D.
        Response inhibition in the stop-signal paradigm.
        Trends Cogn Sci. 2008; 12: 418-424
        • Capriles N.
        • Rodaros D.
        • Sorge R.E.
        • Stewart J.
        A role for the prefrontal cortex in stress- and cocaine-induced reinstatement of cocaine seeking in rats.
        Psychopharmacology (Berl). 2003; 168: 66-74
        • Di Pietro N.C.
        • Black Y.D.
        • Kantak K.M.
        Context-dependent prefrontal cortex regulation of cocaine self-administration and reinstatement behaviors in rats.
        Eur J Neurosci. 2006; 24: 3285-3298
        • Mashhoon Y.
        • Wells A.M.
        • Kantak K.M.
        Interaction of the rostral basolateral amygdala and prelimbic prefrontal cortex in regulating reinstatement of cocaine-seeking behavior.
        Pharmacol Biochem Behav. 2010; 96: 347-353
        • McLaughlin J.
        • See R.E.
        Selective inactivation of the dorsomedial prefrontal cortex and the basolateral amygdala attenuates conditioned-cued reinstatement of extinguished cocaine-seeking behavior in rats.
        Psychopharmacology (Berl). 2003; 168: 57-65
        • McFarland K.
        • Lapish C.C.
        • Kalivas P.W.
        Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior.
        J Neurosci. 2003; 23: 3531-3537
        • Fuchs R.A.
        • Evans K.A.
        • Ledford C.C.
        • Parker M.P.
        • Case J.M.
        • Mehta R.H.
        • See R.E.
        The role of the dorsomedial prefrontal cortex, basolateral amygdala, and dorsal hippocampus in contextual reinstatement of cocaine seeking in rats.
        Neuropsychopharmacology. 2005; 30: 296-309
        • Hyman J.M.
        • Ma L.
        • Balaguer-Ballester E.
        • Durstewitz D.
        • Seamans J.K.
        Contextual encoding by ensembles of medial prefrontal cortex neurons.
        Proc Natl Acad Sci U S A. 2012; 109: 5086-5091
        • Chatham C.H.
        • Claus E.D.
        • Kim A.
        • Curran T.
        • Banich M.T.
        • Munakata Y.
        Cognitive control reflects context monitoring, not motoric stopping, in response inhibition.
        PLoS One. 2012; 7: e31546
        • Peters J.
        • LaLumiere R.T.
        • Kalivas P.W.
        Infralimbic prefrontal cortex is responsible for inhibiting cocaine seeking in extinguished rats.
        J Neurosci. 2008; 28: 6046-6053
        • de Wit H.
        • Stewart J.
        Reinstatement of cocaine-reinforced responding in the rat.
        Psychopharmacology (Berl). 1981; 75: 134-143
        • Deroche-Gamonet V.
        • Belin D.
        • Piazza P.V.
        Evidence for addiction-like behavior in the rat.
        Science. 2004; 305: 1014-1017
      1. Paxinos G, Watson C (2007): The Rat Brain in Stereotaxic Coordinates, 6th ed. San Diego, CA: Academic Press.