Archival Report| Volume 69, ISSUE 11, P1067-1074, June 01, 2011

Cocaine Cues Drive Opposing Context-Dependent Shifts in Reward Processing and Emotional State


      Prominent neurobiological theories of addiction posit a central role for aberrant mesolimbic dopamine release but disagree as to whether repeated drug experience blunts or enhances this system. Although drug withdrawal diminishes dopamine release, drug sensitization augments mesolimbic function, and both processes have been linked to drug seeking. One possibility is that the dopamine system can rapidly switch from dampened to enhanced release depending on the specific drug-predictive environment. To test this, we examined dopamine release when cues signaled delayed cocaine delivery versus imminent cocaine self-administration.


      Fast-scan cyclic voltammetry was used to examine real-time dopamine release while simultaneously monitoring behavioral indexes of aversion as rats experienced a sweet taste cue that predicted delayed cocaine availability and during self-administration. Furthermore, the impact of cues signaling delayed drug availability on intracranial self-stimulation, a broad measure of reward function, was assessed.


      We observed decreased mesolimbic dopamine concentrations, decreased reward sensitivity, and negative affect in response to the cocaine-predictive taste cue that signaled delayed cocaine availability. Importantly, dopamine concentration rapidly switched to elevated levels to cues signaling imminent cocaine delivery in the subsequent self-administration session.


      These findings show rapid, bivalent contextual control over brain reward processing, affect, and motivated behavior and have implications for mechanisms mediating substance abuse.

      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


        • Hyman S.E.
        • Malenka R.C.
        • Nestler E.J.
        Neural mechanisms of addiction: The role of reward-related learning and memory.
        Annu Rev Neurosci. 2006; 29: 565-598
        • Everitt B.J.
        • Robbins T.W.
        Neural systems of reinforcement for drug addiction: From actions to habits to compulsion.
        Nat Neurosci. 2005; 8: 1481-1489
        • Kelley A.E.
        Memory and addiction: Shared neural circuitry and molecular mechanisms.
        Neuron. 2004; 44: 161-179
        • Robinson T.E.
        • Berridge K.C.
        The neural basis of drug craving: An incentive-sensitization theory of addiction.
        Brain Res Brain Res Rev. 1993; 18: 247-291
        • Di Chiara G.
        • Tanda G.
        • Bassareo V.
        • Pontieri F.
        • Acquas E.
        • Fenu S.
        • et al.
        Drug addiction as a disorder of associative learning.
        Ann N Y Acad Sci. 1999; 877: 461-485
        • Wise R.A.
        Neurobiology of addiction.
        Curr Opin Neurobiol. 1996; 6: 243-251
        • Koob G.F.
        • Le Moal M.
        Drug abuse: Hedonic homeostatic dysregulation.
        Science. 1997; 278: 52-58
        • Solomon R.L.
        • Corbit J.D.
        An opponent-process theory of motivation.
        Psychol Rev. 1974; 81: 119-145
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders. 4th ed.
        American Psychiatric Publishing, Washington, DC1993
        • Baker T.B.
        • Piper M.E.
        • McCarthy D.E.
        • Majeskie M.R.
        • Fiore M.C.
        Addiction motivation reformulated: An affective processing model of negative reinforcement.
        Psychol Rev. 2004; 111: 33-51
        • Gawin F.H.
        Cocaine addiction: Psychology and neurophysiology.
        Science. 1991; 251: 1580-1586
        • Stewart J.
        • de Wit H.
        • Eikelboom R.
        Role of unconditioned and conditioned drug effects in the self-administration of opiates and stimulants.
        Psychol Rev. 1984; 91: 251-268
        • Wheeler R.A.
        • Twining R.C.
        • Jones J.L.
        • Slater J.M.
        • Grigson P.S.
        • Carelli R.M.
        • et al.
        Behavioral and electrophysiological indices of negative affect predict cocaine self-administration.
        Neuron. 2008; 57: 774-785
        • Wise R.A.
        • Yokel R.A.
        • DeWit H.
        Both positive reinforcement and conditioned aversion from amphetamine and from apomorphine in rats.
        Science. 1976; 191: 1273-1275
        • Grigson P.S.
        • Twining R.C.
        Cocaine-induced suppression of saccharin intake: A model of drug-induced devaluation of natural rewards.
        Behav Neurosci. 2002; 116: 321-333
        • Parker L.A.
        Rewarding drugs produce taste avoidance, but not taste aversion.
        Neurosci Biobehav Rev. 1995; 19: 143-157
        • Berridge K.C.
        Measuring hedonic impact in animals and infants: Microstructure of affective taste reactivity patterns.
        Neurosci Biobehav Rev. 2000; 24: 173-198
        • Wise R.A.
        Dopamine, learning and motivation.
        Nat Rev Neurosci. 2004; 5: 483-494
        • Berridge K.C.
        • Robinson T.E.
        Parsing reward.
        Trends Neurosci. 2003; 26: 507-513
        • Mirenowicz J.
        • Schultz W.
        Preferential activation of midbrain dopamine neurons by appetitive rather than aversive stimuli.
        Nature. 1996; 379: 449-451
        • Roitman M.F.
        • Wheeler R.A.
        • Wightman R.M.
        • Carelli R.M.
        Real-time chemical responses in the nucleus accumbens differentiate rewarding and aversive stimuli.
        Nat Neurosci. 2008; 11: 1376-1377
        • Ungless M.A.
        • Magill P.J.
        • Bolam J.P.
        Uniform inhibition of dopamine neurons in the ventral tegmental area by aversive stimuli.
        Science. 2004; 303: 2040-2042
        • Belin D.
        • Everitt B.J.
        Cocaine seeking habits depend upon dopamine-dependent serial connectivity linking the ventral with the dorsal striatum.
        Neuron. 2008; 57: 432-441
      1. Koob GF, Volkow ND: Neurocircuitry of addiction. Neuropsychopharmacology 35:217-238.

        • Volkow N.D.
        • Wang G.J.
        • Telang F.
        • Fowler J.S.
        • Logan J.
        • Childress A.R.
        • et al.
        Cocaine cues and dopamine in dorsal striatum: Mechanism of craving in cocaine addiction.
        J Neurosci. 2006; 26: 6583-6588
        • Tomasiewicz H.C.
        • Todtenkopf M.S.
        • Chartoff E.H.
        • Cohen B.M.
        • Carlezon Jr, W.A.
        The kappa-opioid agonist U69,593 blocks cocaine-induced enhancement of brain stimulation reward.
        Biol Psychiatry. 2008; 64: 982-988
        • Paxinos G.
        • Watson C.
        The Rat Brain in Stereotaxic Coordinates. 5th ed.
        Elsevier Academic, Burlington, MA2005
        • Heien M.L.
        • Khan A.S.
        • Ariansen J.L.
        • Cheer J.F.
        • Phillips P.E.
        • Wassum K.M.
        • et al.
        Real-time measurement of dopamine fluctuations after cocaine in the brain of behaving rats.
        Proc Natl Acad Sci U S A. 2005; 102: 10023-10028
        • Grill H.J.
        • Norgren R.
        The taste reactivity test.
        Brain Res. 1978; 143: 263-279
        • Aragona B.J.
        • Day J.J.
        • Roitman M.F.
        • Cleaveland N.A.
        • Mark Wightman R.
        • Carelli R.M.
        Regional specificity in the real-time development of phasic dopamine transmission patterns during acquisition of a cue-cocaine association in rats.
        Eur J Neurosci. 2009;
        • Pontieri F.E.
        • Tanda G.
        • Di Chiara G.
        Intravenous cocaine, morphine, and amphetamine preferentially increase extracellular dopamine in the “shell” as compared with the “core” of the rat nucleus accumbens.
        Proc Natl Acad Sci U S A. 1995; 92: 12304-12308
        • Kelley A.E.
        Functional specificity of ventral striatal compartments in appetitive behaviors.
        Ann N Y Acad Sci. 1999; 877: 71-90
        • Wightman R.M.
        Detection technologies.
        Science. 2006; 311: 1570-1574
        • Brischoux F.
        • Chakraborty S.
        • Brierley D.I.
        • Ungless M.A.
        Phasic excitation of dopamine neurons in ventral VTA by noxious stimuli.
        Proc Natl Acad Sci U S A. 2009; 106: 4894-4899
        • Ito R.
        • Dalley J.W.
        • Howes S.R.
        • Robbins T.W.
        • Everitt B.J.
        Dissociation in conditioned dopamine release in the nucleus accumbens core and shell in response to cocaine cues and during cocaine-seeking behavior in rats.
        J Neurosci. 2000; 20: 7489-7495
        • Phillips P.E.
        • Stuber G.D.
        • Heien M.L.
        • Wightman R.M.
        • Carelli R.M.
        Subsecond dopamine release promotes cocaine seeking.
        Nature. 2003; 422: 614-618
        • Weiss F.
        • Maldonado-Vlaar C.S.
        • Parsons L.H.
        • Kerr T.M.
        • Smith D.L.
        • Ben-Shahar O.
        • et al.
        Control of cocaine-seeking behavior by drug-associated stimuli in rats: Effects on recovery of extinguished operant-responding and extracellular dopamine levels in amygdala and nucleus accumbens.
        Proc Natl Acad Sci U S A. 2000; 97: 4321-4326
        • Garcia J.
        • Koelling R.A.
        Relation of cue to consequence in avoidance learning.
        Psychon Sci. 1966; 4: 123-124
        • Parkinson J.A.
        • Olmstead M.C.
        • Burns L.H.
        • Robbins T.W.
        • Everitt B.J.
        Dissociation in effects of lesions of the nucleus accumbens core and shell on appetitive Pavlovian approach behavior and the potentiation of conditioned reinforcement and locomotor activity by D-amphetamine.
        J Neurosci. 1999; 19: 2401-2411
        • Aragona B.J.
        • Cleaveland N.A.
        • Stuber G.D.
        • Day J.J.
        • Carelli R.M.
        • Wightman R.M.
        • et al.
        Preferential enhancement of dopamine transmission within the nucleus accumbens shell by cocaine is attributable to a direct increase in phasic dopamine release events.
        J Neurosci. 2008; 28: 8821-8831
        • Pierce R.C.
        • Kalivas P.W.
        Amphetamine produces sensitized increases in locomotion and extracellular dopamine preferentially in the nucleus accumbens shell of rats administered repeated cocaine.
        J Pharmacol Exp Ther. 1995; 275: 1019-1029
        • Ikemoto S.
        • Qin M.
        • Liu Z.H.
        The functional divide for primary reinforcement of D-amphetamine lies between the medial and lateral ventral striatum: Is the division of the accumbens core, shell, and olfactory tubercle valid?.
        J Neurosci. 2005; 25: 5061-5065
        • Carlezon Jr, W.A.
        • Wise R.A.
        Microinjections of phencyclidine (PCP) and related drugs into nucleus accumbens shell potentiate medial forebrain bundle brain stimulation reward.
        Psychopharmacol Berl. 1996; 128: 413-420
        • Kelley A.E.
        • Bakshi V.P.
        • Haber S.N.
        • Steininger T.L.
        • Will M.J.
        • Zhang M.
        • et al.
        Opioid modulation of taste hedonics within the ventral striatum.
        Physiol Behav. 2002; 76: 365-377
        • Mahler S.V.
        • Smith K.S.
        • Berridge K.C.
        Endocannabinoid hedonic hotspot for sensory pleasure: Anandamide in nucleus accumbens shell enhances “liking” of a sweet reward.
        Neuropsychopharmacology. 2007; 32: 2267-2278
        • Reynolds S.M.
        • Berridge K.C.
        Positive and negative motivation in nucleus accumbens shell: Bivalent rostrocaudal gradients for GABA-elicited eating, taste “liking”/“disliking” reactions, place preference/avoidance, and fear.
        J Neurosci. 2002; 22: 7308-7320
        • Reynolds S.M.
        • Berridge K.C.
        Emotional environments retune the valence of appetitive versus fearful functions in nucleus accumbens.
        Nat Neurosci. 2008; 11: 423-425
        • Robbins S.J.
        • Ehrman R.N.
        • Childress A.R.
        • Cornish J.W.
        • O'Brien C.P.
        Mood state and recent cocaine use are not associated with levels of cocaine cue reactivity.
        Drug Alcohol Depend. 2000; 59: 33-42
        • Childress A.
        • Ehrman R.
        • McLellan A.T.
        • O'Brien C.
        Conditioned craving and arousal in cocaine addiction: A preliminary report.
        NIDA Res Monogr. 1988; 81: 74-80
        • Siegel S.
        • Hinson R.E.
        • Krank M.D.
        • McCully J.
        Heroin “overdose” death: Contribution of drug-associated environmental cues.
        Science. 1982; 216: 436-437