Skip to main content
SpringerLink
Log in

Second messenger and protein phosphorylation mechanisms underlying opiate addiction: Studies in the rat locus coeruleus

  • Original Articles
  • Mini-Review
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

We have studied the role of second messenger and protein phosphorylation pathways in mediating changes in neuronal function associated with opiate addiction in the rat locus coeruleus. We have found that chronic opiates increase levels of the G-protein subunits Giα and Goα, adenylate cyclase, cyclic AMP-dependent protein kinase, and a number of phosphoproteins (including tyrosine hydroxylase) in this brain region. Electrophysiological data have provided direct support for the view that this up-regulation of the cyclic AMP system contributes to opiate tolerance, dependence, and withdrawal exhibited by these neurons. As the adaptations in G-proteins and the cyclic AMP system appear to occur at least in part at the level of gene expression, current efforts are aimed at identifying the mechanisms, at the molecular level, by which opiates regulate the expression of these intracellular messenger proteins in the locus coeruleus. These studies will lead to an improved understanding of the biochemical basis of opiate addiction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Aghajanian, G. K., and Wang, Y. Y. 1986. Pertussis toxin blocks the outward currents evoked by opiate and α2-agonists in locus coeruleus neurons. Brain Res. 371:390–394.

    Google Scholar 

  2. Aghajanian, G. K., and Wang, Y. Y. 1987. Common alpha-2 and opiate effector mechanisms in the locus coeruleus: intracellular studies in brain slices. Neuropharmacol. 26:789–800.

    Google Scholar 

  3. Aghajanian, G. K. 1978. Tolerance of locus coeruleus neurons to morphine and suppression of withdrawal, response by clonidine. Nature. 267:186–188.

    Google Scholar 

  4. Alreja, M., and Aghajanian, G. K. 1991. pacemaker activity of locus coeruleus neurons: whole-cell recordings in brain slices show dependence on cAMP and protein kinase A. Brain Res. 556:339–343.

    Google Scholar 

  5. Andrade, R., VanderMaelen, C. P., and Aghajanian, G. K. 1983. Morphine tolerance and dependence in the locus coeruleus: single cell studies in brain slices. Eur. J. Pharmacol. 91:161–169.

    Google Scholar 

  6. Attali, B., and Vogel, Z. 1989. Long-term opiate exposure leads to reduction of the αi-1 subunit of GTP-binding proteins. J. Neurochem. 53:1636–1639.

    Google Scholar 

  7. Beitner, D., Duman, R. S., and Nestler, E. J. 1989. A novel action of morphine in the rat locus coeruleus: persistent decrease in adenylate cyclase. Mol. Pharmacol. 35:559–564.

    Google Scholar 

  8. Beitner-Johnson, D. and Nestler, E. J. 1991. Morphine and cocaine exert common chronic actions on tyrosine hydroxylase in dopaminergic brain reward regions. J. Neurochem. 57:344–347.

    Google Scholar 

  9. Beitner-Johnson, D., Guitart, X., and Nestler, E. J. 1992. Neurofilaments and the mesolimbic dopamine system. Common regulation by chronic morphine and chronic cocaine in the rat ventral tegmental area. J. Neurosci., 12:2165–2176.

    Google Scholar 

  10. Christie, M. J., Williams, J. T., and North, R. A. 1987. Cellular mechanisms of opioid tolerance: studies in single brain neurons. Mol. Pharmacol. 32:634–638.

    Google Scholar 

  11. Childers, S. 1991. Opioid receptor-coupled second messenger systems. Life Sci. 48:1991–2003.

    Google Scholar 

  12. Collier, H. O. J., Cuthbert, N. J., Francis, D. L. 1981. Character and meaning of quasimorphine withdrawal phenomena elicited by methylxanthines. Fed. Proc. 40:1513–1518.

    Google Scholar 

  13. Duman, R. S., Tallman, J. F., and Nestler, E. J. 1988. Acute and chronic opiate-regulation, of adenylate cyclase in brain: specific effects in locus coeruleus. J. Pharmacol. Exp. Ther. 246:1033–1039.

    Google Scholar 

  14. Ennis, M., and Aston-Jones, G. 1988. Activation, of locus coeruleus from nucleus paragigantocellularis: A new excitatory amino acid pathway in brain. J. Neurosci. 8:3644–3657.

    Google Scholar 

  15. Foote, S. L., Bloom, F. E., and Aston-Jones, G. 1983. Nucleus locus coeruleus: new evidence of anatomical and physiological specificity. Physiol. Rev. 63:844–914.

    Google Scholar 

  16. Gilman, A. G. 1987. G-proteins: transducers of receptor-generated signals. Ann. Rev. Biochem. 56:615–650.

    Google Scholar 

  17. Grant, S. J., and Redmond, E. E., Jr. 1982. Methylxanthine activation of noradrenergic unit activity and reversal by clonidine. Eur. J. Pharmacol. 85:105–109.

    Google Scholar 

  18. Grant, S. J., Huang, Y. H., and Redmond, D. E., Jr. 1988. Behavior of monkeys during opiate withdrawal and locus coeruleus stimulation. Pharmacol. Biochem. Behav. 30:13–19.

    Google Scholar 

  19. Guitart, X. and Nestler, E. J. 1989. Identification of morphine- and cyclic AMP-regulated phosphoproteins (MARPPs) in the locus coeruleus and other regions of the rat brain: regulation by acute and chronic morphine. J. Neurosci. 9:4371–4387.

    Google Scholar 

  20. Guitart, X., and Nestler, E. J. 1990. Identification of MARPP-14-20, morphine- and cyclic AMP-regulated phosphoproteins of 14–20 kD, as myelin basic proteins: evidence for their acute and chronic regulation by morphine in rat brain. Brain Res. 516:57–65.

    Google Scholar 

  21. Guitart, X., Hayward, M., Nisenbaum, L. K., Beitner-Johnson, D., Haycock, J. W., and Nestler, E. J. 1990. Identification of MARPP-58 a morphine- and cyclic AMP-regulated phosphoprotein of 58 kDa, as tyrosine hydroxylase: evidence for regulation of its expression by chronic morphine in the rat locus coeruleus. J. Neurosci. 10:2649–2659.

    Google Scholar 

  22. Guitart, X. Greenberg, M. E., and Nestler, E. J. 1992. Regulation of CREB phosphorylation by acute and chronic morphine in the rat locus coeruleus. J. Neurochem., 58:1168–1171.

    Google Scholar 

  23. Harris, G. C., and Williams, J. T. 1991. Transcient homologous μ-ipioid receptor desensitization in rat locus coeruleus neurons. J. Neurosci. 11:2574–2581.

    Google Scholar 

  24. Hayward, M. D., Duman, R. S., and Nestler, E. J. 1990. Induction of the c-fos protooncogene during opiate withdrawal, in the locus coeruleus and other regions of rat brain. Brain Res. 525:256–266.

    Google Scholar 

  25. Holtzman, S. G. 1989. Phosphodiesterase inhibitors potentiate opiate-antagonist discrimination by morphine-dependent rats. Pharmacol. Biochem. Behav. 33:875–879.

    Google Scholar 

  26. Hyman, S. E., and Nestler, E. J. 1993. The Molecular Foundations of Psychiatry. American Psychiatric Press, Washington, DC.

    Google Scholar 

  27. Johnson, S. M., and Fleming, W. W. 1989. Mechanisms of cellular adaptive sensitivity changes: applications to opioid tolerance and dependence. Pharmacol. Rev. 41:435–488.

    Google Scholar 

  28. Kogan, J. H., Nestler, E. J., and Aghajanian, G. K. 1992. Elevated basal firing rates and enhanced responses to 8-Br-cAMP in locus coeruleus neurons in brain slices from opiate-dependent rats. Eur. J. Pharmacol., 211:47–53.

    Google Scholar 

  29. Koob, G. F. and Bloom, F. E. 1988. Cellular and molecular mechanisms of drug dependence. Science. 242:715–723.

    Google Scholar 

  30. Loh, H. H., Tao, P. L., and Smith, A. P. 1988. Invited review: role of receptor regulation in opioid tolerance mechanisms. Synapse 2:457–462.

    Google Scholar 

  31. Makman, M. H., Dvorkin, B., and Crain, S. M. 1988. Modulation of adenylate cyclase activity of mouse spinal cord-ganglion explants by opioids, serotonin and pertussis toxin. Brain Res. 445:303–313.

    Google Scholar 

  32. Maldonado, R., Stinus, L., Gold, L. H., and Koob, G. F. 1992. Role of different brain structures in the expression of the physical morphine withdrawal syndrome. J. Pharmacol. Exp. Ther., in press.

  33. Montminy, M. R., Gonzalez, G. A., and Yamamoto, K. K. 1990. Regulation of cAMP-inducible genes by CREB. Trends Neurosci. 13:184–188.

    Google Scholar 

  34. Nestler, E. J. 1992. Molecular mechanisms of drug addiction. J. Neurosci. 12:2439–2450.

    Google Scholar 

  35. Nestler, E. J., and Greengard, P. 1984. Protein Phosphorylation in the Nervous System. Wiley, New York.

    Google Scholar 

  36. Nestler, E. J., and Greengard, P. 1989. Protein phosphorylation and the regulation of neuronal function. Pages 373–398,in Siegel, G. J., Agranoff, B., Albers, R. W., Molinoff, P. (eds.) Basic neurochemistry: Molecular, Cellular, and Medical Aspects, 4th ed., Raven, New York.

    Google Scholar 

  37. Nestler, E. J., and Tallman, J. F. 1988. Chronic morphine treatment increases cyclic-AMP-dependent protein kinase activity in the rat locus coeruleus. Mol. Pharmacol. 33:127–132.

    Google Scholar 

  38. Nestler, E. J., Erdos, J. J., Terwilliger, R., Duman, R. S., and Tallman, J. F. 1989. Regulation of G-proteins by chronic morphine treatment in the rat locus coeruleus. Brain Res. 476:230–239.

    Google Scholar 

  39. Nestler, E. J., Terwilliger, R. Z., Walker, J. R., Sevarino, K. A., and Duman, R. S. 1990. Chronic cocaine treatment decreases levels of the G protein subunits Giα and Goα in discrete regions of rat brain. J. Neurochem. 55:1079–1082.

    Google Scholar 

  40. Nestler, E. J., Guitart, X., and Beitner-Johnson, D. 1992. Second messenger and protein phosphorylation mechanisms underlying opiate and cocaine addiction.in Barchas, J. D., and Korenman, S. G., (eds.), UCLA/NIDA Symposium on Substance Abuse, in press, New York.

  41. North, R. A., Williams, J. T., Suprenant, A., and Christie, M. J. 1987. Mu and delta receptors belong to a family of receptors that are coupled to potassium channels. Proc. Natl. Acad. Sci. USA 84:5487–5491.

    Google Scholar 

  42. Rasmussen, K. and Aghajanian, G. K. 1989. Withdrawal-induced activation of locus coeruleus neurons in opiate-dependent rats: Attenuation by lesions of the nucleus paragigantocellularis. Brain Res. 505:346–350.

    Google Scholar 

  43. Rasmussen, K., Beitner-Johnson, D., Krystal, J. H., Aghajanian, G. K., and Nestler, E. J. 1990. Opiate withdrawal and the rat locus coeruleus: behavioral, electrophysiological, and biochemical correlates. J. Neurosci. 10:2308–2317.

    Google Scholar 

  44. Redmond, D. E. Jr. and Krystal, J. H. 1984. Multiple mechanisms of withdrawal from opioid drugs. Annu. Rev. Neurosci. 7:443–478.

    Google Scholar 

  45. Sharma, S. K., Klee, W. A., Nirenberg M. 1975. Dual regulation of adenylate cyclase accounts for narcotic dependence and tolerance. Proc. Natl. Acad. Sci. USA. 72:3092–3096.

    Google Scholar 

  46. Sheng, M., Thompson, M. A., and Greenberg, m. E. 1991. CREB: A Ca2+-regulated transcription factor phosphorylated by calmodulin-dependent kinases. Science. 252:1427–1430.

    Google Scholar 

  47. Terwilliger R. Z., Beitner-Johnson, D., Sevarino, K. A., Crain, S. M., and Nestler, E. J. 1991. A general role for adaptations in G-proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function. Brain Res. 548:100–110.

    Google Scholar 

  48. Wang, Y. and Aghajanian, G. K. 1987. Excitation of locus coeruleus neurons by an adenosine 3′, 5′-cyclic monophosphate-activated inward current: Extracellular and intracellular studies in rat brain slices. Synapse. 1:481–487.

    Google Scholar 

  49. Wang, Y. Y., and Aghajanian, G. K. 1990. Excitation of locus coeruleus neurons by vasoactive intestinal peptide: role of cAMP and protein kinase. A. J. Neurosci. 10:3335–3343.

    Google Scholar 

  50. Wise, R. A., and Bozarth, M. E. 1987. A psychomotor stimulant theory of addiction. Psychol. Rev. 94:469–492.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Molecular Psychiatry, Departments of Psychiatry and Pharmacology, Yale University School of Medicine and Connecticut Mental Health Center, 34 Park Street, 06508, New Haven, CT

    Xavier Guitart & Eric J. Nestler

Authors
  1. Xavier Guitart
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eric J. Nestler
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Special issue dedicated to Dr. Paul Greengard

Rights and permissions

Reprints and permissions

About this article

Cite this article

Guitart, X., Nestler, E.J. Second messenger and protein phosphorylation mechanisms underlying opiate addiction: Studies in the rat locus coeruleus. Neurochem Res 18, 5–13 (1993). https://doi.org/10.1007/BF00966918

Download citation

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00966918

Key Words

Search

Navigation