The dopamine-containing projection from the ventral tegmental area of the midbrain to the nucleus accumbens is critically involved in mediating the reinforcing properties of cocaine1,2. Although neurons in this area respond to rewards on a subsecond timescale3,4, neurochemical studies have only addressed the role of dopamine in drug addiction by examining changes in the tonic (minute-to-minute) levels of extracellular dopamine5,6,7,8,9. To investigate the role of phasic (subsecond) dopamine signalling10, we measured dopamine every 100 ms in the nucleus accumbens using electrochemical technology11. Rapid changes in extracellular dopamine concentration were observed at key aspects of drug-taking behaviour in rats. Before lever presses for cocaine, there was an increase in dopamine that coincided with the initiation of drug-seeking behaviours. Notably, these behaviours could be reproduced by electrically evoking dopamine release on this timescale. After lever presses, there were further increases in dopamine concentration at the concurrent presentation of cocaine-related cues. These cues alone also elicited similar, rapid dopamine signalling, but only in animals where they had previously been paired to cocaine delivery. These findings reveal an unprecedented role for dopamine in the regulation of drug taking in real time.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Wise, R. A. Drug-activation of brain reward pathways. Drug Alcohol Depend. 51, 13–22 (1998)
Koob, G. F. & Nestler, E. J. The neurobiology of drug addiction. J. Neuropsychiatry Clin. Neurosci. 9, 482–497 (1997)
Schultz, W. Predictive reward signal of dopamine neurons. J. Neurophysiol. 80, 1–27 (1998)
Hyland, B. I., Reynolds, J. N. J., Hay, J., Perk, C. G. & Miller, R. Firing modes of midbrain dopamine cells in the freely moving rat. Neuroscience 114, 475–492 (2002)
Pettit, H. O. & Justice, J. B. Jr Dopamine in the nucleus accumbens during cocaine self-administration as studied by in vivo microdialysis. Pharmacol. Biochem. Behav. 34, 899–904 (1989)
Wise, R. A. et al. Fluctuations in nucleus accumbens dopamine concentration during intravenous cocaine self-administration in rats. Psychopharmacology 120, 10–20 (1995)
Di Chiara, G. Drug addiction as dopamine-dependent associative learning disorder. Eur. J. Pharmacol. 375, 13–30 (1999)
Bradberry, C. W., Barrett-Larimore, R. L., Jatlow, P. & Rubino, S. R. Impact of self-administered cocaine and cocaine cues on extracellular dopamine in mesolimbic and sensorimotor striatum in rhesus monkeys. J. Neurosci. 20, 3874–3883 (2000)
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. 20, 7489–7495 (2000)
Wightman, R. M. & Robinson, D. L. Transient changes in mesolimbic dopamine and their association with ‘reward’. J. Neurochem. 82, 721–735 (2002)
Stamford, J. A. & Justice, J. B. Jr Probing brain chemistry. Anal. Chem. 68, 359A–363A (1996)
Schultz, W., Dayan, P. & Montague, P. R. A neural substrate of prediction and reward. Science 275, 1593–1599 (1997)
Breiter, H. C. et al. Acute effects of cocaine on human brain activity and emotion. Neuron 19, 591–611 (1997)
Childress, A. R. et al. Limbic activation during cue-induced cocaine craving. Am. J. Psychiatry 156, 11–18 (1999)
Wise, R. A. Neurobiology of addiction. Curr. Opin. Neurobiol. 6, 243–251 (1996)
Grace, A. A. Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience 41, 1–24 (1991)
Einhorn, L. C., Johansen, P. A. & White, F. J. Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: studies in the ventral tegmental area. J. Neurosci. 8, 100–112 (1988)
Lacey, M. G., Mercuri, N. B. & North, R. A. Actions of cocaine on rat dopaminergic neurones in vitro. Br. J. Pharmacol. 99, 731–735 (1990)
Kiyatkin, E. A. & Rebec, G. V. Dopaminergic modulation of glutamate-induced excitations of neurons in the neostriatum and nucleus accumbens of awake, unrestrained rats. J. Neurophysiol. 75, 142–153 (1996)
Pennartz, C. M., Groenewegen, H. J. & Lopes da Silva, F. H. The nucleus accumbens as a complex of functionally distinct neuronal ensembles: an integration of behavioural, electrophysiological and anatomical data. Prog. Neurobiol. 42, 719–761 (1994)
Sesack, S. R. & Pickel, V. M. In the rat medial nucleus accumbens, hippocampal and catecholaminergic terminals converge on spiny neurons and are in apposition to each other. Brain Res. 527, 266–279 (1990)
Sesack, S. R. & Pickel, V. M. Prefrontal cortical efferents in the rat synapse on unlabeled neuronal targets of catecholamine terminals in the nucleus accumbens septi and on dopamine neurons in the ventral tegmental area. J. Comp. Neurol. 320, 145–160 (1992)
Mogenson, G. J. Limbic-motor integration. Prog. Psychobiol. Physiol. Psychol. 12, 117–170 (1987)
Carelli, R. M. The nucleus accumbens and reward: neurophysiological investigations in behaving animals. Behav. Cogn. Neurosci. Rev. 1, 281–296 (2002)
Carelli, R. M., King, V. C., Hampson, R. E. & Deadwyler, S. A. Firing patterns of nucleus accumbens neurons during cocaine self-administration in rats. Brain Res. 626, 14–22 (1993)
Carelli, R. M. Activation of accumbens cell firing by stimuli associated with cocaine delivery during self-administration. Synapse 35, 238–242 (2000)
Carelli, R. M., Ijames, S. G. & Crumling, A. J. Evidence that separate neural circuits in the nucleus accumbens encode cocaine versus ‘natural’ (water and food) reward. J. Neurosci. 20, 4255–4266 (2000)
Garris, P. A., Christensen, J. R. C., Rebec, G. V. & Wightman, R. M. Real-time measurement of electrically evoked extracellular dopamine in the striatum of freely moving rats. J. Neurochem. 68, 152–161 (1997)
Marsden, C. A. et al. In vivo voltammetry—present electrodes and methods. Neuroscience 25, 389–400 (1988)
Millar, J., Stamford, J. A., Kruk, Z. L. & Wightman, R. M. Electrochemical, pharmacological and electrophysiological evidence of rapid dopamine release and removal in the rat caudate nucleus following electrical stimulation of the median forebrain bundle. Eur. J. Pharmacol. 109, 341–348 (1985)
We thank M. Roitman, D. Robinson, R. Gainetdinov, P. Garris and S. Grigson for useful comments, and J. Venton, J. Peterson, C. McKinney, S. Brooks and J. Wondolowski for technical assistance. We also acknowledge the vision of R. Adams who set the foundation for this work. This work was supported by grants from the National Institute on Drug Abuse to R.M.W. and R.M.C.
The authors declare that they have no competing financial interests.
About this article
Cite this article
Phillips, P., Stuber, G., Heien, M. et al. Subsecond dopamine release promotes cocaine seeking. Nature 422, 614–618 (2003). https://doi.org/10.1038/nature01476
Accelerated development of cocaine-associated dopamine transients and cocaine use vulnerability following traumatic stress
Development of CuAlO2-Encapsulated Reduced Graphene Oxide Nanocomposites: An Efficient and Selective Electrocatalyst for Detection of Neurodegenerative Disorders
ACS Applied Bio Materials (2020)
The Projection From Ventral CA1, Not Prefrontal Cortex, to Nucleus Accumbens Core Mediates Recent Memory Retrieval of Cocaine-Conditioned Place Preference
Frontiers in Behavioral Neuroscience (2020)
Choosing the Optimal Brain Target for Neuromodulation Therapies as Alcohol Addiction Progresses—Insights From Pre-Clinical Studies
Current Addiction Reports (2020)
Nature Communications (2020)