Subjects

Abstract

Dopaminergic neurons in the ventral tegmental area (VTA) are well known for mediating the positive reinforcing effects of drugs of abuse. Here we identify in rodents and humans a population of VTA dopaminergic neurons expressing corticotropin-releasing factor (CRF). We provide further evidence in rodents that chronic nicotine exposure upregulates Crh mRNA (encoding CRF) in dopaminergic neurons of the posterior VTA, activates local CRF1 receptors and blocks nicotine-induced activation of transient GABAergic input to dopaminergic neurons. Local downregulation of Crh mRNA and specific pharmacological blockade of CRF1 receptors in the VTA reversed the effect of nicotine on GABAergic input to dopaminergic neurons, prevented the aversive effects of nicotine withdrawal and limited the escalation of nicotine intake. These results link the brain reward and stress systems in the same brain region to signaling of the negative motivational effects of nicotine withdrawal.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , , , & Imaging dopamine's role in drug abuse and addiction. Neuropharmacology 56 (suppl. 1), 3–8 (2009).

  2. 2.

    & Addiction and the brain antireward system. Annu. Rev. Psychol. 59, 29–53 (2008).

  3. 3.

    & Cellular and molecular mechanisms of drug dependence. Science 242, 715–723 (1988).

  4. 4.

    & Neurocircuitry of addiction. Neuropsychopharmacology 35, 217–238 (2010).

  5. 5.

    , & The role of corticotropin-releasing factor in drug addiction. Pharmacol. Rev. 53, 209–243 (2001).

  6. 6.

    & Molecular mechanisms underlying behaviors related to nicotine addiction. Cold Spring Harb. Perspect. Med. 3, a012112 (2013).

  7. 7.

    , , , & Prevention of social stress-escalated cocaine self-administration by CRF-R1 antagonist in the rat VTA. Psychopharmacology (Berl.) 218, 257–269 (2011).

  8. 8.

    , & Chronic cocaine enhances corticotropin-releasing factor-dependent potentiation of excitatory transmission in ventral tegmental area dopamine neurons. J. Neurosci. 29, 6535–6544 (2009).

  9. 9.

    , & CRF acts in the midbrain to attenuate accumbens dopamine release to rewards but not their predictors. Nat. Neurosci. 16, 383–385 (2013).

  10. 10.

    , , & Stress-induced relapse to cocaine seeking: roles for the CRF2 receptor and CRF-binding protein in the ventral tegmental area of the rat. Psychopharmacology (Berl.) 193, 283–294 (2007).

  11. 11.

    & Corticotropin-releasing factor binding protein within the ventral tegmental area is expressed in a subset of dopaminergic neurons. J. Comp. Neurol. 509, 302–318 (2008).

  12. 12.

    et al. Augmented cocaine seeking in response to stress or CRF delivered into the ventral tegmental area following long-access self-administration is mediated by CRF receptor type 1 but not CRF receptor type 2. J. Neurosci. 31, 11396–11403 (2011).

  13. 13.

    , , , & Stress-induced cocaine seeking requires a beta-2 adrenergic receptor-regulated pathway from the ventral bed nucleus of the stria terminalis that regulates CRF actions in the ventral tegmental area. J. Neurosci. 34, 12504–12514 (2014).

  14. 14.

    et al. Dopaminergic signaling mediates the motivational response underlying the opponent motivational process to chronic but not acute nicotine. Neuropsychopharmacology 35, 943–954 (2010).

  15. 15.

    et al. Phasic D1 and tonic D2 dopamine receptor signaling double dissociate the motivational effects of acute nicotine and chronic nicotine withdrawal. Proc. Natl. Acad. Sci. USA 109, 3101–3106 (2012).

  16. 16.

    , , & Organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: an immunohistochemical study. Neuroendocrinology 36, 165–186 (1983).

  17. 17.

    & Synapses between corticotropin-releasing factor-containing axon terminals and dopaminergic neurons in the ventral tegmental area are predominantly glutamatergic. J. Comp. Neurol. 506, 616–626 (2008).

  18. 18.

    et al. The Edinger-Westphal nucleus: a historical, structural, and functional perspective on a dichotomous terminology. J. Comp. Neurol. 519, 1413–1434 (2011).

  19. 19.

    et al. Nicotine-mediated activation of dopaminergic neurons in distinct regions of the ventral tegmental area. Neuropsychopharmacology 36, 1021–1032 (2011).

  20. 20.

    et al. Increase of extracellular corticotropin-releasing factor-like immunoreactivity levels in the amygdala of awake rats during restraint stress and ethanol withdrawal as measured by microdialysis. J. Neurosci. 15, 5439–5447 (1995).

  21. 21.

    , , & Corticotropin-releasing factor within the central nucleus of the amygdala mediates enhanced ethanol self-administration in withdrawn, ethanol-dependent rats. J. Neurosci. 26, 11324–11332 (2006).

  22. 22.

    et al. Co-activation of VTA DA and GABA neurons mediates nicotine reinforcement. Mol. Psychiatry 18, 382–393 (2013).

  23. 23.

    , , & Ventral tegmental area glutamate neurons: electrophysiological properties and projections. J. Neurosci. 32, 15076–15085 (2012).

  24. 24.

    , , & Reversal of inhibition of putative dopaminergic neurons of the ventral tegmental area: interaction of GABA(B) and D2 receptors. Neuroscience 226, 29–39 (2012).

  25. 25.

    et al. Nicotine decreases ethanol-induced dopamine signaling and increases self-administration via stress hormones. Neuron 79, 530–540 (2013).

  26. 26.

    , & Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas. Neuron 33, 905–919 (2002).

  27. 27.

    et al. CRF–CRF1 system activation mediates withdrawal-induced increases in nicotine self-administration in nicotine-dependent rats. Proc. Natl. Acad. Sci. USA 104, 17198–17203 (2007).

  28. 28.

    et al. Extended access to nicotine leads to a CRF1 receptor dependent increase in anxiety-like behavior and hyperalgesia in rats. Addict. Biol. 10.1111/adb.12077 (2013).

  29. 29.

    , & Robust escalation of nicotine intake with extended access to nicotine self-administration and intermittent periods of abstinence. Neuropsychopharmacology 37, 2153–2160 (2012).

  30. 30.

    & Dendritic peptide release and peptide-dependent behaviours. Nat. Rev. Neurosci. 7, 126–136 (2006).

  31. 31.

    et al. Dendritic peptide release mediates interpopulation crosstalk between neurosecretory and preautonomic networks. Neuron 78, 1036–1049 (2013).

  32. 32.

    , , , & Electron microscopic localization of corticotropin-releasing factor (CRF) and CRF receptor in rat and mouse central nucleus of the amygdala. J. Comp. Neurol. 512, 323–335 (2009).

  33. 33.

    et al. Cocaine experience establishes control of midbrain glutamate and dopamine by corticotropin-releasing factor: a role in stress-induced relapse to drug seeking. J. Neurosci. 25, 5389–5396 (2005).

  34. 34.

    et al. Corticotropin-releasing factor within the central nucleus of the amygdala and the nucleus accumbens shell mediates the negative affective state of nicotine withdrawal in rats. Neuropsychopharmacology 34, 1743–1752 (2009).

  35. 35.

    et al. Nicotine dependence produces hyperalgesia: role of corticotropin-releasing factor-1 receptors (CRF1Rs) in the central amygdala (CeA). Neuropharmacology 77, 217–223 (2014).

  36. 36.

    , , , & Behavioral, biochemical, and molecular indices of stress are enhanced in female versus male rats experiencing nicotine withdrawal. Front. Psychiatry 4, 38 (2013).

  37. 37.

    , , & Withdrawal from chronic nicotine exposure alters dopamine signaling dynamics in the nucleus accumbens. Biol. Psychiatry 71, 184–191 (2012).

  38. 38.

    & Acute and chronic corticotropin-releasing factor 1 receptor blockade inhibits cocaine-induced dopamine release: correlation with dopamine neuron activity. J. Pharmacol. Exp. Ther. 314, 201–206 (2005).

  39. 39.

    , , & Excessive cocaine use results from decreased phasic dopamine signaling in the striatum. Nat. Neurosci. 17, 704–709 (2014).

  40. 40.

    , & Neurochemical and behavioral effects of corticotropin-releasing factor in the ventral tegmental area of the rat. J. Pharmacol. Exp. Ther. 242, 757–763 (1987).

  41. 41.

    , , & Activation of VTA GABA neurons disrupts reward consumption. Neuron 73, 1184–1194 (2012).

  42. 42.

    et al. GABA neurons of the VTA drive conditioned place aversion. Neuron 73, 1173–1183 (2012).

  43. 43.

    et al. Corticotropin releasing factor-induced amygdala gamma-aminobutyric acid release plays a key role in alcohol dependence. Biol. Psychiatry 67, 831–839 (2010).

  44. 44.

    & Deprivation state switches the neurobiological substrates mediating opiate reward in the ventral tegmental area. J. Neurosci. 17, 383–390 (1997).

  45. 45.

    et al. Ventral tegmental area BDNF induces an opiate-dependent like reward state in naive rats. Science 324, 1732–1734 (2009).

  46. 46.

    , & Lesions of the tegmental pedunculopontine nucleus block the rewarding effects and reveal the aversive effects of nicotine in the ventral tegmental area. J. Neurosci. 22, 8653–8660 (2002).

  47. 47.

    et al. Contingent and non-contingent effects of heroin on mu-opioid receptor-containing ventral tegmental area GABA neurons. Exp. Neurol. 202, 139–151 (2006).

  48. 48.

    , , , & Dopamine in drug abuse and addiction: results of imaging studies and treatment implications. Arch. Neurol. 64, 1575–1579 (2007).

  49. 49.

    et al. Addiction as a stress surfeit disorder. Neuropharmacology 76 (pt. B), 370–382 (2014).

  50. 50.

    & The Mouse Brain in Stereotaxic Coordinates (Academic, San Diego, 1997).

  51. 51.

    et al. MPZP: a novel small molecule corticotropin-releasing factor type 1 receptor (CRF1) antagonist. Pharmacol. Biochem. Behav. 88, 497–510 (2008).

  52. 52.

    et al. RSK2 signaling in brain habenula contributes to place aversion learning. Learn. Mem. 18, 574–578 (2011).

  53. 53.

    et al. Production and purification of serotype 1, 2, and 5 recombinant adeno-associated viral vectors. Methods 28, 158–167 (2002).

Download references

Acknowledgements

The authors thank M. Brennan, B. Takabe, C. Arias and the University of Toronto Division of Comparative Medicine staff for technical assistance and M. Arends for editorial assistance. The authors would also like to thank R. Nagra and J. Riehl and the UCLA Brain Bank (The Human Brain and Spinal Fluid Resource Center) for providing the human samples. This work was supported by the Canadian Institutes of Health Research, US National Institute on Drug Abuse (DA023597, DA035371 and DA031566), US National Institute on Alcohol Abuse and Alcoholism (AA021491, AA015566, F32 AA020430, AA006420, AA016658, AA021667 and INIA AA013498), Tobacco-Related Disease Research Program (12RT-0099), US National Institute of Diabetes and Digestive and Kidney Diseases (DK026741) and the Clayton Medical Research Foundation.

Author information

Affiliations

  1. Institute of Medical Science and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.

    • Taryn E Grieder
    • , Hector Vargas-Perez
    • , Michal Chwalek
    • , Geith Maal-Bared
    • , Laura Clarke
    •  & Derek van der Kooy
  2. Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California, USA.

    • Melissa A Herman
    • , Candice Contet
    • , Ami Cohen
    • , John Freiling
    • , Joel E Schlosburg
    • , Elena Crawford
    • , Marisa Roberto
    •  & Olivier George
  3. The Salk Institute, La Jolla, California, USA.

    • Laura A Tan
    •  & Paul E Sawchenko
  4. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS / INSERM / Université de Strasbourg, Illkirch, France.

    • Pascale Koebel
    •  & Brigitte L Kieffer
  5. Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, California, USA.

    • Vez Repunte-Canonigo
    •  & Pietro P Sanna
  6. Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

    • Andrew R Tapper
  7. Douglas Hospital Research Center, Department of Psychiatry, McGill University, Montreal, Quebec, Canada.

    • Brigitte L Kieffer
  8. National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland, USA.

    • George F Koob

Authors

  1. Search for Taryn E Grieder in:

  2. Search for Melissa A Herman in:

  3. Search for Candice Contet in:

  4. Search for Laura A Tan in:

  5. Search for Hector Vargas-Perez in:

  6. Search for Ami Cohen in:

  7. Search for Michal Chwalek in:

  8. Search for Geith Maal-Bared in:

  9. Search for John Freiling in:

  10. Search for Joel E Schlosburg in:

  11. Search for Laura Clarke in:

  12. Search for Elena Crawford in:

  13. Search for Pascale Koebel in:

  14. Search for Vez Repunte-Canonigo in:

  15. Search for Pietro P Sanna in:

  16. Search for Andrew R Tapper in:

  17. Search for Marisa Roberto in:

  18. Search for Brigitte L Kieffer in:

  19. Search for Paul E Sawchenko in:

  20. Search for George F Koob in:

  21. Search for Derek van der Kooy in:

  22. Search for Olivier George in:

Contributions

T.E.G. and O.G. designed the experiments. T.E.G., H.V.-P., M.C., J.E.S. and G.M.-B. performed minipump, cannulation and viral vector surgeries. M.R. and M.A.H. performed the electrophysiology experiments. T.E.G. performed place conditioning and open field testing. A.C. performed self-administration experiments. C.C., L.A.T. and P.E.S. performed ISH. C.C. and E.C. performed double ISH and immunohistochemistry. T.E.G., V.R.-C., P.P.S., A.R.T. and L.C. performed molecular studies. J.F. and E.C. performed immunohistochemistry. C.C., P.K. and B.L.K. supplied viral vectors. T.E.G. and O.G. analyzed the data. T.E.G., C.C., G.F.K., D.v.d.K. and O.G. wrote the paper. All of the authors discussed the results and read the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Olivier George.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–8 and Supplementary Table 1

  2. 2.

    Supplementary Methods Checklist

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nn.3872

Further reading