Skip to main content
SpringerLink
Log in

Role of serotonin on cocaine-mediated effects on prodynorphin gene expression in the rat brain

  • Original Article
  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

The effect of the selective serotonin uptake inhibitor fluoxetine was examined on prodynorphin gene expression. Fluoxetine or vehicle was infused continuously for 7 d via osmotic minipumps into male rats. Northern blot analysis showed significant increases in prodynorphin gene expression in the hypothalamus (171% of controls) and significant decreases in the caudate putamen and nucleus accumbens (62% and 70% of controls, respectively). There were no significant changes in the hippocampus. Thus, chronic inhibition of serotonin uptake can regulate prodynorphin gene expression in the hypothalamus, caudate putamen, and nucleus accumbens. Fluoxetine effects were also evaluated in rats treated with p-chloroamphetamine (PCA), a neurotoxin that depletes serotonin. Because we previously reported that continuous infusion of cocaine for 7 d (which inhibits dopamine, serotonin, and norepinephrine uptake), or GBR 12909 (a selective dopamine uptake inhibitor), produced significant decreases in the hypothalamus and cocaine also produced a significant increase in prodynorphin gene expression in caudate putamen, regulation of prodynorphin gene expression by fluoxetine is suggested to be different from that by cocaine. Because neither a selective dopamine uptake inhibitor nor a selective serotonin uptake inhibitor produced the same effect as cocaine in the caudate putamen, this effect is likely regulated by the inhibition of norepinephrine uptake, by a combination of effects on two or three neurotransmitter transporters, or by a mechanism unrelated to transporter inhibition.

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

  • Baker D. A., Tran-Nguyen T. L., Fuchs R. A., and Neisewander J. L. (2001) Influence of individual differences and chronic fluoxetine treatment on cocaine-seeking behavior in rats. Psychopharmacology (Berl.) 155, 18–26.

    Article  CAS  Google Scholar 

  • Bymaster F. P., Zhang W., Carter P. A., Shaw J., Chernet E., Phebus L., et al. (2002) Fluoxetine, but not other selective serotonin uptake inhibitors, increase norepinephrine and dopamine extracellular levels in prefrontal cortex. Psychopharmacology (Berl.) 160, 353–361.

    Article  CAS  Google Scholar 

  • Carroll M. E., Lac S. T., Asencio M., and Kragh R. (1990) Fluoxetine reduces intravenous cocaine self-administration in rats. Pharmacol. Biochem. Behav. 35, 237–244.

    Article  PubMed  CAS  Google Scholar 

  • Chomczynski P. and Sacchi N. (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156–159.

    Article  PubMed  CAS  Google Scholar 

  • Civelli O., Douglass J., Goldstein A., and Herbert E. (1985) Sequence and expression of the rat prodynorphin gene. Proc. Natl. Acad. Sci. USA 82, 4291–4295.

    Article  PubMed  CAS  Google Scholar 

  • Collins S. L., Kunko P. M., Ladenheim B., Cadet J. L., Carroll F. I. and Izenwasser S. (2002) Chronic cocaine increases kappa-opioid receptor density: lack of effect by selective dopamine uptake inhibitors. Synapse 45, 153–158.

    Article  PubMed  CAS  Google Scholar 

  • Daunais J. B. and McGinty J. F. (1995) Cocaine binges differentially alter striatal preprodynorphin and zif/268 mRNAs. Brain Res. Mol. Brain Res. 29, 201–210.

    Article  PubMed  CAS  Google Scholar 

  • Daunais J. B., Hart S. L., Hedgecock-Rowe A., Matasi J. J., Thornley C., Davies H. M. L., and Porrino L. J. (1997) Alterations in behavior and opioid gene expression induced by the novel tropane analog WF-31. Brain Res. Mol. Brain Res. 50, 3293–3304.

    Article  Google Scholar 

  • Daunais J. B., Roberts D. C. S., and McGinty J. E. L. (1993) Cocaine self-administration increases preprodynorphin, but not c-fos, mRNA in rat striatum. NeuroReport 4, 543–546.

    Article  PubMed  CAS  Google Scholar 

  • Gunning P., Ponte P., Okayama H., Engel J., Blau H., and Kedes L. (1983) Isolation and characterization of full-length cDNA clones for human alpha-, beta-, and gamma-actin mRNAs: skeletal but not cytoplasmic actins have an amino-terminal cysteine that is subsequently removed. Mol. Cell Biol. 3, 787–795.

    PubMed  CAS  Google Scholar 

  • Hall F. S., Li X. F., Sora I., Xu F., Caron M., Lesch K. P., et al. (2002) Cocaine mechanisms: enhanced cocaine, fluoxetine and nisoxetine place preferences following monoamine transporter deletions. Neuroscience 115, 153–161.

    Article  PubMed  CAS  Google Scholar 

  • Herve D., Pickel V. M., Joh T. H., and Breaudet A. (1987) Serotonin axon terminals in the ventral tegmental area of the rat fine structure and synaptic input to dopaminergic neurones. Brain Res. 453, 71–83.

    Article  Google Scholar 

  • Hurd Y. L. and Herkenham M. (1992) Influence of a single injection of cocaine, amphetamine or GBR 12909 on mRNA expression of striatal neuropeptides. Mol. Brain Res. 16, 97–104.

    Article  PubMed  CAS  Google Scholar 

  • Izenwasser S., French D., Carroll F. I., and Kunko P. M. (1999) Continuous infusion of selective dopamine uptake inhibitors or cocaine produces time-dependent changes in rat locomotor activity. Behav. Brain Res. 99, 201–208.

    Article  PubMed  CAS  Google Scholar 

  • Izenwasser S., Heller B., and Cox B. M. (1996) Continuous cocaine administration enhances μ- but not σ-opioid receptor-mediated inhibition of adenylyl cyclase activity in nucleus accumbens. Eur. J. Pharmacol. 297, 187–191.

    Article  PubMed  CAS  Google Scholar 

  • Koch S., Perry K. W., Nelson D. L., Conway R. G., Threlkeld P. G., and Bymaster F. P. (2002) R-fluoxetine increases extracellular DA, NE, as well as 5-HT in rat prefrontal cortex and hypothalamus: an in vivo microdialysis and receptor binding study. Neuropsychopharmacology 27, 949–959.

    Article  PubMed  CAS  Google Scholar 

  • Kondo Y., Ogawa N., Asanuma M., Hirata K., Tanaka K., Kawada Y., and Mori, A. (1993) Regional changes in neuropeptide levels after 5,7-dihydroxytryptamine-induced serotonin in the rat brain. J. Neural Transm. Gen. Sect. 92, 151–157.

    Article  PubMed  CAS  Google Scholar 

  • Kunko P. M., Loeloff R. J., and Izenwasser S. (1997) Chronic administration of GBR 12909, but not cocaine, produces marked decreases in dopamine transporter density. Naunyn-Schmiedeberg’s Arch. Pharmacol. 356, 562–569.

    Article  CAS  Google Scholar 

  • Lee K. and Kornetsky C. (1998) Acute and chronic fluoxetine treatment decreases the sensitivity of rats to rewarding brain stimulation. Pharmacol Biochem Behav. 60, 539–544.

    Article  PubMed  CAS  Google Scholar 

  • Lucas J. J., Mellstrom B., Colado M. I., and Naranjo J. R. (1993) Molecular mechanisms of pain: serotonin 1A receptor agonists trigger transactivation by c-fos of the prodynorphin gene in spinal cord neurons. Neuron 10, 599–611.

    Article  PubMed  CAS  Google Scholar 

  • Maniatis T., Fritsch E. F., and Sambrook J., eds. (1982) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY.

    Google Scholar 

  • Mathieu-Kia A. and Besson M., (1998) Repeated administration of cocaine, nicotine and ethanol: effects on preprodynorphin, preprotachykinin A and preproenkephalin mRNA expression in the dorsal and the ventral striatum of the rat. Mol. Brain Res. 54, 141–151.

    Article  PubMed  CAS  Google Scholar 

  • Matsumoto M., Togashi H., Mori K., Veno K., Miyamoto A., and Yoshioka M. (1999) Characterization of endogenous serotonin-mediated regulation of dopamine release in the rat prefrontal cortex. Eur. J. Pharmacol. 383, 39–48.

    Article  PubMed  CAS  Google Scholar 

  • Mcmahon L. R. and Cunningham K. A. (2001) Antagonism of 5-hydroxytryptamine2A receptors attenuates the behavioral effects of cocaine in rats. J. Pharmacol. Exp. Ther. 297, 357–363.

    PubMed  CAS  Google Scholar 

  • Peltier R. and Schenk S. (1993) Effects of serotonergic manipulations on cocaine self-administration in rats. Psychopharmacology (Berl.) 110, 390–394.

    Article  CAS  Google Scholar 

  • Prisco S. and Esposito E. (1995) Differential effects of acute and chronic fluoxetine administration on the spontaneous activity of dopaminergic neurones in the ventral tegmental area. Br. J. Pharmacol. 116, 1923–1931.

    PubMed  CAS  Google Scholar 

  • Richardson N. R. and Roberts D. C. (1991) Fluoxetine pretreatment reduces breaking points on a progressive ratio schedule reinforced by intravenous cocaine self-administration in the rat. Life Sci. 49, 833–840.

    Article  PubMed  CAS  Google Scholar 

  • Rocha B., Fumagalli F., Gainetdinov R., Jones S., Ator R., Giros B., et al. (1998) Cocaine self-administration in dopamine-transporter knockout mice. Nat. Neurosci. 1, 132–137.

    Article  PubMed  CAS  Google Scholar 

  • Romualdi P., D’Addario C., Ferri S., Cox B. M., and Izenwasser S. (2001) Chronic GBR 12909 administration differentially alters prodynorphin gene expression compared to cocaine. Eur. J. Pharmacol. 413, 207–212.

    Article  PubMed  CAS  Google Scholar 

  • Romualdi P., Donatini A., Izenwasser S., Cox B. M., and Ferri S. (1996) Chronic intracerebroventricular cocaine differentially affects prodynorphin gene expression in rat hypothalamus and caudate putamen. Mol. Brain Res. 40, 153–156.

    Article  PubMed  CAS  Google Scholar 

  • Sanders-Bush E., Bushing J. A., and Sulser F. (1975) Long-term effects of p-chloroamphetamine and related drugs on central serotonergic mechanisms. J. Pharmacol. Exp. Ther. 192, 33–41.

    PubMed  CAS  Google Scholar 

  • Smiley P. L., Johnson M., Bush L., Gibb J. W., and Hanson G. R. (1990) Effects of cocaine on extrapyramidal and limbic dynorphin systems. J. Pharmacol. Exp. Ther. 253, 938–943.

    PubMed  CAS  Google Scholar 

  • Spangler R., Unterwald E. M., and Kreek M. J. (1993) ‘Binge’ cocaine administration induces a sustained increase of prodynorphin mRNA in rat caudate-putamen. Mol. Brain Res. 19, 323–327.

    Article  PubMed  CAS  Google Scholar 

  • Spangler R., Zhou Y., Maggos C. E., Schlussman S. D., Ho A., and Kreek M. J. (1997) Prodynorphin, proenkephalin and kappa opioid receptor mRNA responses to acute “binge” cocaine. Brain Res. Mol. Brain Res. 44, 139–142.

    Article  PubMed  CAS  Google Scholar 

  • Spangler R., Zhou Y., Maggos C. E., Zlobin A., Ho A., and Kreek M. J. (1996) Dopamine antagonist and “binge” cocaine effects on rat opioid and dopamine transporter mRNAs. NeuroReport. 7, 2196–2200.

    Article  PubMed  CAS  Google Scholar 

  • Sprague J. E., Johnson M. P., Schmidt C. J., and Nichols D. E. (1996) Studies on the mechanism of p-chloroamphetamine neurotoxicity. Biochem. Pharmacol. 52, 1271–1277

    Article  PubMed  CAS  Google Scholar 

  • Steranka L. R. and Sanders-Bush E. (1978) Long-term reduction of brain serotonin by p-chloroamphetamine: effects of inducers and inhibitors of drug metabolism. J. Pharmacol. Exp. Ther. 206, 460–467.

    PubMed  CAS  Google Scholar 

  • Steinbush H. V. M. Serotonin-immunoreactive neurones and their projections in the CNS, in: Bjorklund A., Hokfelt T., eds. Classical Transmitters Receptors in the CNS. Part II. Handbook of Chemical Neuroanatomy, 3, Elsevier, Amsterdam, 1984, pp. 68–90.

    Google Scholar 

  • Steiner H. and Gerfen C. R. (1993) Cocaine-induced c-fos messenger RNA is inversely related to dynorphin expression in striatum. J. Neurosci. 13, 5066–5081.

    PubMed  CAS  Google Scholar 

  • Tran-Nguyen L. T., Baker D. A., Grote K. A., Solano J., and Neisewander J. L. (1999) Serotonin depletion attenuates cocaine-seeking behavior in rats. Psychopharmacology (Berl.) 146, 60–66.

    Article  CAS  Google Scholar 

  • Tran-Nguyen L. T., Bellew J. G., Grote K. A., and Neisewander J. L. (2001) Serotonin depletion attenuates cocaine seeking but enhances sucrose seeking and the effects of cocaine priming on reinstatement of cocaine seeking in rats. Psychopharmacology (Berl.) 157, 340–348.

    Article  CAS  Google Scholar 

  • Turchan J., Przewlocka B., Lason W., and Przewlocki R. (1998) Effects of repeated psychostimulant administration on the prodynorphin system activity and kappa opioid receptor density in the rat brain. Neuroscience 85, 1051–1059.

    Article  PubMed  CAS  Google Scholar 

  • Turchan J., Przewlocka B., Toth G., Lason W., and Borsodi A. (1999) The effect of repeated administration of morphine, cocaine and ethanol on mu and delta opioid receptor density in the nucleus accumbens and striatum of the rat. Neuroscience 91, 971–977.

    Article  PubMed  CAS  Google Scholar 

  • Uhl G. R., Hall F. S., and Sora I. (2002) Cocaine, reward, movement and monoamine transporters. Mol. Psychiatry 7, 21–26.

    Article  PubMed  CAS  Google Scholar 

  • Unterwald E. M., Horne-King J., and Kreek M. J. (1992) Chronic cocaine alters brain mu opioid receptors. Brain Res. 584, 314–318.

    Article  PubMed  CAS  Google Scholar 

  • Unterwald E. M., Rubenfeld J. M., and Kreek M. J. (1994) Repeated cocaine administration upregulates κ and μ, but not σ, opioid receptors. NeuroReport 5, 1613–1616.

    Article  PubMed  CAS  Google Scholar 

  • Ward R. P. and Dorsa D. M. (1996) Colocalization of serotonin receptor subtypes 5-HT2A, 5-HT2C and 5-HT6 with neuropeptides in rat striatum. J. Comp. Neurol. 370, 405–414.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, University of Bologna, 40126, Bologna, Italy

    Manuela Di Benedetto, Claudio D’Addario, Stephanie Collins, Sari Izenwasser, Sanzio Candeletti & Patrizia Romualdi

  2. Department of Psychiatry and Behavioural Sciences, University of Miami School of Medicine, 33136, Miami, FL

    Sari Izenwasser

Authors
  1. Manuela Di Benedetto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Claudio D’Addario
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephanie Collins
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sari Izenwasser
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sanzio Candeletti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Patrizia Romualdi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Patrizia Romualdi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Di Benedetto, M., D’Addario, C., Collins, S. et al. Role of serotonin on cocaine-mediated effects on prodynorphin gene expression in the rat brain. J Mol Neurosci 22, 213–222 (2004). https://doi.org/10.1385/JMN:22:3:213

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1385/JMN:22:3:213

Index Entries

Search

Navigation