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. 1992 Jul 1;89(13):5764–5768. doi: 10.1073/pnas.89.13.5764

Regulation of immediate early gene expression and AP-1 binding in the rat nucleus accumbens by chronic cocaine.

B Hope 1, B Kosofsky 1, S E Hyman 1, E J Nestler 1
PMCID: PMC402098  PMID: 1631058

Abstract

Chronic treatment of rats with cocaine leads to long-term biochemical changes in the nucleus accumbens (NAc), a brain region implicated in mediating the reinforcing effects of cocaine and other drugs of abuse. Immediate early genes (IEGs) and their protein products appear to play an important role in transducing extracellular stimuli into altered patterns of cellular gene expression and, therefore, into long-term changes in cellular functioning. We therefore examined changes in the mRNA levels for the IEGs c-fos, c-jun, fosB, junB, and zif268 in the NAc of rats treated acutely and chronically with cocaine. A single cocaine injection increased the mRNA levels of all of the IEGs examined. Following chronic cocaine treatment, however, IEG expression had returned to control levels and was not significantly increased following a further acute challenge with cocaine, suggesting desensitization in the ability of cocaine to induce these IEGs. Similarly, levels of Fos-like immunoreactivity, which are increased in the NAc by acute cocaine, were reduced to control levels in chronic cocaine-treated rats. Fos, Jun, and a number of related proteins activate or repress transcription of genes by binding to DNA response elements called AP-1 sites. As would be expected from the RNA data and immunohistochemistry, acute cocaine administration increased AP-1 binding activity in the NAc, an effect that reverted completely to control levels within 8-12 hr. In contrast, AP-1 binding activity in the NAc of animals treated chronically with cocaine remained elevated at acute levels 18 hr after the last chronic injection, a time at which c-fos and c-jun mRNA levels and Fos-like immunoreactivity had returned to control values. An additional acute cocaine challenge did not further increase AP-1 binding. The data suggest that chronic cocaine treatment leads to a persistent increase in AP-1 binding activity, which may be involved in some of the physiological and behavioral aspects of cocaine addiction.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Beitner-Johnson D., Nestler E. J. Morphine and cocaine exert common chronic actions on tyrosine hydroxylase in dopaminergic brain reward regions. J Neurochem. 1991 Jul;57(1):344–347. doi: 10.1111/j.1471-4159.1991.tb02133.x. [DOI] [PubMed] [Google Scholar]
  2. Cambi F., Fung B., Chikaraishi D. 5' flanking DNA sequences direct cell-specific expression of rat tyrosine hydroxylase. J Neurochem. 1989 Nov;53(5):1656–1659. doi: 10.1111/j.1471-4159.1989.tb08567.x. [DOI] [PubMed] [Google Scholar]
  3. Campeau S., Hayward M. D., Hope B. T., Rosen J. B., Nestler E. J., Davis M. Induction of the c-fos proto-oncogene in rat amygdala during unconditioned and conditioned fear. Brain Res. 1991 Nov 29;565(2):349–352. doi: 10.1016/0006-8993(91)91669-r. [DOI] [PubMed] [Google Scholar]
  4. Danielson P. E., Forss-Petter S., Brow M. A., Calavetta L., Douglass J., Milner R. J., Sutcliffe J. G. p1B15: a cDNA clone of the rat mRNA encoding cyclophilin. DNA. 1988 May;7(4):261–267. doi: 10.1089/dna.1988.7.261. [DOI] [PubMed] [Google Scholar]
  5. Gawin F. H. Cocaine addiction: psychology and neurophysiology. Science. 1991 Mar 29;251(5001):1580–1586. doi: 10.1126/science.2011738. [DOI] [PubMed] [Google Scholar]
  6. Graybiel A. M., Moratalla R., Robertson H. A. Amphetamine and cocaine induce drug-specific activation of the c-fos gene in striosome-matrix compartments and limbic subdivisions of the striatum. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6912–6916. doi: 10.1073/pnas.87.17.6912. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Henry D. J., White F. J. Repeated cocaine administration causes persistent enhancement of D1 dopamine receptor sensitivity within the rat nucleus accumbens. J Pharmacol Exp Ther. 1991 Sep;258(3):882–890. [PubMed] [Google Scholar]
  8. Hyman S. E., Comb M., Lin Y. S., Pearlberg J., Green M. R., Goodman H. M. A common trans-acting factor is involved in transcriptional regulation of neurotransmitter genes by cyclic AMP. Mol Cell Biol. 1988 Oct;8(10):4225–4233. doi: 10.1128/mcb.8.10.4225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hyman S. E., Comb M., Pearlberg J., Goodman H. M. An AP-2 element acts synergistically with the cyclic AMP- and phorbol ester-inducible enhancer of the human proenkephalin gene. Mol Cell Biol. 1989 Jan;9(1):321–324. doi: 10.1128/mcb.9.1.321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kalivas P. W., Duffy P., DuMars L. A., Skinner C. Behavioral and neurochemical effects of acute and daily cocaine administration in rats. J Pharmacol Exp Ther. 1988 May;245(2):485–492. [PubMed] [Google Scholar]
  11. Koob G. F., Bloom F. E. Cellular and molecular mechanisms of drug dependence. Science. 1988 Nov 4;242(4879):715–723. doi: 10.1126/science.2903550. [DOI] [PubMed] [Google Scholar]
  12. Korner M., Rattner A., Mauxion F., Sen R., Citri Y. A brain-specific transcription activator. Neuron. 1989 Nov;3(5):563–572. doi: 10.1016/0896-6273(89)90266-3. [DOI] [PubMed] [Google Scholar]
  13. Kuhar M. J., Ritz M. C., Boja J. W. The dopamine hypothesis of the reinforcing properties of cocaine. Trends Neurosci. 1991 Jul;14(7):299–302. doi: 10.1016/0166-2236(91)90141-g. [DOI] [PubMed] [Google Scholar]
  14. Lett B. T. Repeated exposures intensify rather than diminish the rewarding effects of amphetamine, morphine, and cocaine. Psychopharmacology (Berl) 1989;98(3):357–362. doi: 10.1007/BF00451687. [DOI] [PubMed] [Google Scholar]
  15. Morgan J. I., Cohen D. R., Hempstead J. L., Curran T. Mapping patterns of c-fos expression in the central nervous system after seizure. Science. 1987 Jul 10;237(4811):192–197. doi: 10.1126/science.3037702. [DOI] [PubMed] [Google Scholar]
  16. Morgan J. I., Curran T. Stimulus-transcription coupling in the nervous system: involvement of the inducible proto-oncogenes fos and jun. Annu Rev Neurosci. 1991;14:421–451. doi: 10.1146/annurev.ne.14.030191.002225. [DOI] [PubMed] [Google Scholar]
  17. Nestler E. J., Terwilliger R. Z., Walker J. R., Sevarino K. A., Duman R. S. Chronic cocaine treatment decreases levels of the G protein subunits Gi alpha and Go alpha in discrete regions of rat brain. J Neurochem. 1990 Sep;55(3):1079–1082. doi: 10.1111/j.1471-4159.1990.tb04602.x. [DOI] [PubMed] [Google Scholar]
  18. Peris J., Boyson S. J., Cass W. A., Curella P., Dwoskin L. P., Larson G., Lin L. H., Yasuda R. P., Zahniser N. R. Persistence of neurochemical changes in dopamine systems after repeated cocaine administration. J Pharmacol Exp Ther. 1990 Apr;253(1):38–44. [PubMed] [Google Scholar]
  19. Post R. M., Rose H. Increasing effects of repetitive cocaine administration in the rat. Nature. 1976 Apr 22;260(5553):731–732. doi: 10.1038/260731a0. [DOI] [PubMed] [Google Scholar]
  20. Sagar S. M., Sharp F. R., Curran T. Expression of c-fos protein in brain: metabolic mapping at the cellular level. Science. 1988 Jun 3;240(4857):1328–1331. doi: 10.1126/science.3131879. [DOI] [PubMed] [Google Scholar]
  21. Sheng M., Greenberg M. E. The regulation and function of c-fos and other immediate early genes in the nervous system. Neuron. 1990 Apr;4(4):477–485. doi: 10.1016/0896-6273(90)90106-p. [DOI] [PubMed] [Google Scholar]
  22. Sonnenberg J. L., Macgregor-Leon P. F., Curran T., Morgan J. I. Dynamic alterations occur in the levels and composition of transcription factor AP-1 complexes after seizure. Neuron. 1989 Sep;3(3):359–365. doi: 10.1016/0896-6273(89)90260-2. [DOI] [PubMed] [Google Scholar]
  23. Terwilliger R. Z., Beitner-Johnson D., Sevarino K. A., Crain S. M., Nestler E. J. 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. 1991 May 10;548(1-2):100–110. doi: 10.1016/0006-8993(91)91111-d. [DOI] [PubMed] [Google Scholar]
  24. Winston S. M., Hayward M. D., Nestler E. J., Duman R. S. Chronic electroconvulsive seizures down-regulate expression of the immediate-early genes c-fos and c-jun in rat cerebral cortex. J Neurochem. 1990 Jun;54(6):1920–1925. doi: 10.1111/j.1471-4159.1990.tb04892.x. [DOI] [PubMed] [Google Scholar]
  25. Wise R. A., Bozarth M. A. A psychomotor stimulant theory of addiction. Psychol Rev. 1987 Oct;94(4):469–492. [PubMed] [Google Scholar]
  26. Young S. T., Porrino L. J., Iadarola M. J. Cocaine induces striatal c-fos-immunoreactive proteins via dopaminergic D1 receptors. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1291–1295. doi: 10.1073/pnas.88.4.1291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Zerial M., Toschi L., Ryseck R. P., Schuermann M., Müller R., Bravo R. The product of a novel growth factor activated gene, fos B, interacts with JUN proteins enhancing their DNA binding activity. EMBO J. 1989 Mar;8(3):805–813. doi: 10.1002/j.1460-2075.1989.tb03441.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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