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Excessive cocaine use results from decreased phasic dopamine signaling in the striatum

Abstract

Drug addiction is a neuropsychiatric disorder marked by escalating drug use. Dopamine neurotransmission in the ventromedial striatum (VMS) mediates acute reinforcing effects of abused drugs, but with protracted use the dorsolateral striatum is thought to assume control over drug seeking. We measured striatal dopamine release during a cocaine self-administration regimen that produced escalation of drug taking in rats. Surprisingly, we found that phasic dopamine decreased in both regions as the rate of cocaine intake increased, with the decrement in dopamine in the VMS significantly correlated with the rate of escalation. Administration of the dopamine precursor L-DOPA at a dose that replenished dopamine signaling in the VMS reversed escalation, thereby demonstrating a causal relationship between diminished dopamine transmission and excessive drug use. Together these data provide mechanistic and therapeutic insight into the excessive drug intake that emerges following protracted use.

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Figure 1: Escalation of drug taking over the course of weeks.
Figure 2: Dopamine signaling in VMS and DLS over the course of weeks.
Figure 3: Individual differences in drug-taking behavior and striatal dopamine signaling.
Figure 4: L-DOPA decreases escalated drug intake by replenishing VMS dopamine release.
Figure 5: L-DOPA prevents and reverses the escalation of drug intake.

References

  1. Everitt, B.J. & Robbins, T.W. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat. Neurosci. 8, 1481–1489 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Di Chiara, G. & Bassareo, V. Reward system and addiction: what dopamine does and doesn't do. Curr. Opin. Pharmacol. 7, 69–76 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Di Chiara, G. Nucleus accumbens shell and core dopamine: differential role in behavior and addiction. Behav. Brain Res. 137, 75–114 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ito, R., Dalley, J.W., Robbins, T.W. & Everitt, B.J. Dopamine release in the dorsal striatum during cocaine-seeking behavior under the control of a drug-associated cue. J. Neurosci. 22, 6247–6253 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Di Chiara, G. & Imperato, A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc. Natl. Acad. Sci. USA 85, 5274–5278 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wise, R.A. & Bozarth, M.A. A psychomotor stimulant theory of addiction. Psychol. Rev. 94, 469–492 (1987).

    Article  CAS  PubMed  Google Scholar 

  8. Wise, R.A. et al. Fluctuations in nucleus accumbens dopamine concentration during intravenous cocaine self-administration in rats. Psychopharmacology (Berl.) 120, 10–20 (1995).

    Article  CAS  Google Scholar 

  9. Phillips, P.E.M., Stuber, G.D., Heien, M.L., Wightman, R.M. & Carelli, R.M. Subsecond dopamine release promotes cocaine seeking. Nature 422, 614–618 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Stuber, G.D., Roitman, M.F., Phillips, P.E.M., Carelli, R.M. & Wightman, R.M. Rapid dopamine signaling in the nucleus accumbens during contingent and noncontingent cocaine administration. Neuropsychopharmacology 30, 853–863 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Stuber, G.D., Wightman, R.M. & Carelli, R.M. Extinction of cocaine self-administration reveals functionally and temporally distinct dopaminergic signals in the nucleus accumbens. Neuron 46, 661–669 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Owesson-White, C.A. et al. Neural encoding of cocaine-seeking behavior is coincident with phasic dopamine release in the accumbens core and shell. Eur. J. Neurosci. 30, 1117–1127 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Willuhn, I., Burgeno, L.M., Everitt, B.J. & Phillips, P.E.M. Hierarchical recruitment of phasic dopamine signaling in the striatum during the progression of cocaine use. Proc. Natl. Acad. Sci. USA 109, 20703–20708 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. White, N.M. Addictive drugs as reinforcers: multiple partial actions on memory systems. Addiction 91, 921–949, discussion 951–965 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. Robbins, T.W. & Everitt, B.J. Drug addiction: bad habits add up. Nature 398, 567–570 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Berke, J.D. & Hyman, S.E. Addiction, dopamine, and the molecular mechanisms of memory. Neuron 25, 515–532 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Kalivas, P.W. & Volkow, N.D. The neural basis of addiction: a pathology of motivation and choice. Am. J. Psychiatry 162, 1403–1413 (2005).

    Article  PubMed  Google Scholar 

  18. Porrino, L.J., Smith, H.R., Nader, M.A. & Beveridge, T.J. The effects of cocaine: a shifting target over the course of addiction. Prog. Neuropsychopharmacol. Biol. Psychiatry 31, 1593–1600 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Deroche-Gamonet, V., Belin, D. & Piazza, P.V. Evidence for addiction-like behavior in the rat. Science 305, 1014–1017 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Vanderschuren, L.J. & Everitt, B.J. Drug seeking becomes compulsive after prolonged cocaine self-administration. Science 305, 1017–1019 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Ahmed, S.H. & Koob, G.F. Transition from moderate to excessive drug intake: change in hedonic set point. Science 282, 298–300 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Jonkman, S., Pelloux, Y. & Everitt, B.J. Drug intake is sufficient, but conditioning is not necessary for the emergence of compulsive cocaine seeking after extended self-administration. Neuropsychopharmacology 37, 1612–1619 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 4th edn. text revision (American Psychiatric Association, 2000).

  24. Zernig, G. et al. Explaining the escalation of drug use in substance dependence: models and appropriate animal laboratory tests. Pharmacology 80, 65–119 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Clark, J.J. et al. Chronic microsensors for longitudinal, subsecond dopamine detection in behaving animals. Nat. Methods 7, 126–129 (2010).

    Article  CAS  PubMed  Google Scholar 

  26. Pan, H.T., Menacherry, S. & Justice, J.B. Jr. Differences in the pharmacokinetics of cocaine in naive and cocaine-experienced rats. J. Neurochem. 56, 1299–1306 (1991).

    Article  CAS  PubMed  Google Scholar 

  27. Ahmed, S.H., Lin, D., Koob, G.F. & Parsons, L.H. Escalation of cocaine self-administration does not depend on altered cocaine-induced nucleus accumbens dopamine levels. J. Neurochem. 86, 102–113 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. De Wit, H. & Wise, R.A. Blockade of cocaine reinforcement in rats with the dopamine receptor blocker pimozide, but not with the noradrenergic blockers phentolamine or phenoxybenzamine. Can. J. Psychol. 31, 195–203 (1977).

    Article  CAS  PubMed  Google Scholar 

  29. Ettenberg, A., Pettit, H.O., Bloom, F.E. & Koob, G.F. Heroin and cocaine intravenous self-administration in rats: mediation by separate neural systems. Psychopharmacology (Berl.) 78, 204–209 (1982).

    Article  CAS  Google Scholar 

  30. Robledo, P., Maldonado-Lopez, R. & Koob, G.F. Role of dopamine receptors in the nucleus accumbens in the rewarding properties of cocaine. Ann. NY Acad. Sci. 654, 509–512 (1992).

    Article  CAS  PubMed  Google Scholar 

  31. Wightman, R.M. et al. Real-time characterization of dopamine overflow and uptake in the rat striatum. Neuroscience 25, 513–523 (1988).

    Article  CAS  PubMed  Google Scholar 

  32. Bradberry, C.W. Acute and chronic dopamine dynamics in a nonhuman primate model of recreational cocaine use. J. Neurosci. 20, 7109–7115 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kirkland Henry, P., Davis, M. & Howell, L.L. Effects of cocaine self-administration history under limited and extended access conditions on in vivo striatal dopamine neurochemistry and acoustic startle in rhesus monkeys. Psychopharmacology (Berl.) 205, 237–247 (2009).

    Article  CAS  Google Scholar 

  34. Mateo, Y., Lack, C.M., Morgan, D., Roberts, D.C. & Jones, S.R. Reduced dopamine terminal function and insensitivity to cocaine following cocaine binge self-administration and deprivation. Neuropsychopharmacology 30, 1455–1463 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Ferris, M.J. et al. Cocaine self-administration produces pharmacodynamic tolerance: differential effects on the potency of dopamine transporter blockers, releasers, and methylphenidate. Neuropsychopharmacology 37, 1708–1716 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Calipari, E.S. et al. Methylphenidate and cocaine self-administration produce distinct dopamine terminal alterations. Addict. Biol. 19, 145–155 (2014).

    Article  CAS  PubMed  Google Scholar 

  37. Calipari, E.S., Ferris, M.J., Zimmer, B.A., Roberts, D.C. & Jones, S.R. Temporal pattern of cocaine intake determines tolerance vs sensitization of cocaine effects at the dopamine transporter. Neuropsychopharmacology 38, 2385–2392 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Schultz, W., Dayan, P. & Montague, P.R. A neural substrate of prediction and reward. Science 275, 1593–1599 (1997).

    Article  CAS  PubMed  Google Scholar 

  39. Clark, J.J., Collins, A.L., Sanford, C.A. & Phillips, P.E.M. Dopamine encoding of Pavlovian incentive stimuli diminishes with extended training. J. Neurosci. 33, 3526–3532 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Robinson, T.E. & Berridge, K.C. The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res. Brain Res. Rev. 18, 247–291 (1993).

    Article  CAS  PubMed  Google Scholar 

  41. Ferrario, C.R. et al. Neural and behavioral plasticity associated with the transition from controlled to escalated cocaine use. Biol. Psychiatry 58, 751–759 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Redish, A.D. Addiction as a computational process gone awry. Science 306, 1944–1947 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Keramati, M. & Gutkin, B. Imbalanced decision hierarchy in addicts emerging from drug-hijacked dopamine spiraling circuit. PLoS ONE 8, e61489 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Dackis, C.A. & Gold, M.S. New concepts in cocaine addiction: the dopamine depletion hypothesis. Neurosci. Biobehav. Rev. 9, 469–477 (1985).

    Article  CAS  PubMed  Google Scholar 

  45. Lynch, W.J. et al. A paradigm to investigate the regulation of cocaine self-administration in human cocaine users: a randomized trial. Psychopharmacology (Berl.) 185, 306–314 (2006).

    Article  CAS  Google Scholar 

  46. Pickens, R. & Thompson, T. Cocaine-reinforced behavior in rats: effects of reinforcement magnitude and fixed-ratio size. J. Pharmacol. Exp. Ther. 161, 122–129 (1968).

    CAS  PubMed  Google Scholar 

  47. Mariani, J.J. & Levin, F.R. Psychostimulant treatment of cocaine dependence. Psychiatr. Clin. North Am. 35, 425–439 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Paxinos, G. & Watson, C. The Rat Brain in Stereotaxic Coordinates (Academic, 1998).

  49. Phillips, P.E.M. & Wightman, R.M. Critical guidelines for validation of the selectivity of in-vivo chemical microsensors. Trends Analyt. Chem. 22, 509–514 (2003).

    Article  CAS  Google Scholar 

  50. Wright, S.P. Adjusted P-Values for simultaneous inference. Biometrics 48, 1005–1013 (1992).

    Article  Google Scholar 

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Acknowledgements

We thank S. Ng-Evans, C. Akers Sanford, C. Zietz, N. Murray and D. Hadidi for technical support and M. Arnold and J. Clark for feedback. This work was supported by German Research Foundation (Deutsche Forschungsgemeinschaft) grant WI 3643/1-1 (I.W.), awards from the Alcohol and Drug Institute (P.E.M.P.) and the provost of the University of Washington (P.E.M.P.), and US National Institutes of Health grants T32-DA027858 (L.M.B.), F32-DA033004 (P.A.G.), P01-DA015916 (P.E.M.P.), R21-DA021793 (P.E.M.P.) and R01-DA027858 (P.E.M.P.).

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I.W. and P.E.M.P. designed research, I.W., L.M.B. and P.A.G. performed research, and I.W. analyzed data; I.W. and P.E.M.P. wrote the paper.

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Correspondence to Ingo Willuhn.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Histological verification of recording sites in VMS and DLS (first experiment).

VMS recording sites (blue circles) were confirmed to be within the nucleus accumbens core, and DLS recording sites (red circles) were in the lateral half of the dorsal striatum. The numbers on each plate indicate distance in millimeters anterior from bregma48.

Supplementary Figure 2 Escalated animals display increased motivation to obtain cocaine.

Subsequent to FI20 cocaine self-administration, a subset of LgA rats (n = 19) underwent progressive-ratio testing. Progressive-ratio sessions were identical to FI20 sessions except that animals were required to perform an increasing number of operant responses for successive infusions of cocaine. The break point was operationally defined as the maximum number of responses. Average break point values are depicted (mean + SEM). Escalated rats (purple bar) displayed significantly more responses (and earned more infusions) than non-escalated animals (orange bar). *P<0.05.

Supplementary Figure 3 Examples of phasic dopamine release in VMS and DLS associated with an individual nose poke (single trial) into the active port for animals with escalated cocaine intake.

a, Pseudocolor plots (top panel), dopamine traces (bottom panel), and cyclic voltammograms (inset in bottom panel) for representative current fluctuations recorded in VMS for the period 10 seconds before an operant response (dashed line), during the subsequent 20-second presentation of the CS (yellow box; includes cocaine infusion), and 10 seconds after the offset of the CS during the first (Left), second (Middle), and third (Right) weeks of LgA cocaine self-administration (first hour). b, Pseudocolor plots (top panel), dopamine traces (bottom panel), and cyclic voltammograms (inset in bottom panel) for representative current fluctuations recorded in DLS during the first (Left), second (Middle), and third (Right) weeks of LgA cocaine self-administration. The color plots show current changes across the applied voltages (Eapp; y-axis) over time (x-axis).

Supplementary Figure 4 Examples of phasic dopamine release in VMS and DLS associated with an individual nose poke (single trial) into the active port for animals with non-escalated, stable cocaine intake.

a, Pseudocolor plots (top panel), dopamine traces (bottom panel), and cyclic voltammograms (inset in bottom panel) for representative current fluctuations recorded in VMS for the period 10 seconds before an operant response (dashed line), during the subsequent 20-second presentation of the CS (yellow box; includes cocaine infusion), and 10 seconds after the offset of the CS during the first (Left), second (Middle), and third (Right) weeks of LgA cocaine self-administration (first hour). b, Pseudocolor plots (top panel), dopamine traces (bottom panel), and cyclic voltammograms (inset in bottom panel) for representative current fluctuations recorded in DLS during the first (Left), second (Middle), and third (Right) weeks of LgA cocaine self-administration. The color plots show current changes across the applied voltages (Eapp; y-axis) over time (x-axis).

Supplementary Figure 5 Effects of cocaine (pharmacological) and responding for cocaine delivery (behavioral) vary with access regimen (ShA/LgA) and intake pattern (Esc/Non-esc).

a, Average increases in extracellular concentration of dopamine in the VMS over a thirty-second period following a non-contingent (response-independent; no CS) intravenous infusion of cocaine (0.5 mg/kg) are depicted for non-escalated (closed bars) and escalated (open bars) animals (mean + SEM) given ShA (left) or LgA (right). Cocaine-induced dopamine release in the VMS was significantly decreased in rats given LgA compared to ShA, but release did not differ significantly between non-escalated and escalated rats (P>0.05). b, Phasic dopamine in the VMS of non-escalated animals (n = 6/16) in the third week of LgA was not different to that of non-escalated ShA rats (n = 10/16). Escalated ShA animals (n = 6/16) displayed a non-significant trend for decreased VMS dopamine compared to non-escalating ShA rats (n = 10/16); #P = 0.094). Escalated LgA animals exhibited less dopamine release than escalated ShA animals. Data are mean+SEM. *P<0.05, **P<0.01.

Supplementary Figure 6 Intake pattern, but not access regimen, affects motivation to obtain cocaine.

Subsequent to FI20 cocaine self-administration, a subset of ShA and LgA rats (n = 32) underwent progressive-ratio testing. Progressive-ratio sessions were identical to FI20 sessions except that animals were required to perform an increasing number of operant responses for successive infusions of cocaine. The break point was operationally defined as the maximum number of responses. Average break point values are depicted (mean + SEM). a, Escalated rats (purple bar; ShA and LgA pooled) displayed significantly more responses (and earned more infusions) than non-escalated animals (orange bar; ShA and LgA). b, Access regimen (ShA in orange and LgA in purple) had no significant effect on the number of responses rats performed to receive an infusion of cocaine (P>0.05). *P<0.05.

Supplementary Figure 7 Histological verification of recording sites in VMS (second experiment).

VMS recording sites (blue circles) were confirmed to be within the nucleus accumbens core. The numbers on each plate indicate distance in millimeters anterior from bregma48.

Supplementary Figure 8 Slow changes in dopamine release in the VMS following a cocaine infusion induced by an active nose-poke response.

Increases in peak concentration of extracellular dopamine in the VMS measured during LgA cocaine self-administration sessions. Measurements were conducted over 90 seconds following an infusion of cocaine induced by a nose poke into the active hole (that occurred without additional operant responses within 90 seconds following this infusion) prior to escalation (pre-esc), after escalation (esc), and after escalation with L-DOPA treatment (L-DOPA). Average changes in such “tonic” dopamine concentration did not differ significantly from each other (ns, not significant; P >0.05). Data are mean+SEM.

Supplementary Figure 9 Histological verification of infusion sites in VMS (third experiment).

VMS infusion sites (blue circles) were confirmed to be within the nucleus accumbens core. The numbers on each plate indicate distance in millimeters anterior from bregma48.

Supplementary Figure 10 Escalation of cocaine intake and effects of L-DOPA during LgA over 6 h of cocaine self-administration.

a, LgA animals showed a significantly increasing number of active nose pokes during six hours of cocaine self-administration across weeks (n = 24). b, Non-escalated animals (n = 10) showed no significant increase in cocaine intake during six hours of self-administration over the course of LgA (closed circles), whereas escalated rats (n = 14) increased their intake significantly (open circles). c, A single i.v. injection of L-DOPA (30 mg/kg) and Benserazide (2 mg/kg) prior to session start decreased the escalated number of active nose poke responses (purple bar) to a number (open purple bar) comparable to the pre-escalation stage (orange bar; n = 5). d, Repeated i.v. administration of L-DOPA (30 mg/kg) and Benserazide (2 mg/kg) on five consecutive days reliably reduced the escalated number of active nose poke responses (purple bar) and maintain the responses at a rate (open purple bar) comparable to the pre-escalation stage (orange bar; n = 5). Data are mean + SEM. *P<0.05. **P<0.01.

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Willuhn, I., Burgeno, L., Groblewski, P. et al. Excessive cocaine use results from decreased phasic dopamine signaling in the striatum. Nat Neurosci 17, 704–709 (2014). https://doi.org/10.1038/nn.3694

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