, Volume 96, Issue 1, pp 121–134 | Cite as

Clonidine infusions into the locus coeruleus attenuate behavioral and neurochemical changes associated with naloxone-precipitated withdrawal

  • J. R. Taylor
  • J. D. Elsworth
  • E. J. Garcia
  • S. J. Grant
  • R. H. Roth
  • D. E. RedmondJr
Original Investigations


Clonidine, an alpha-2-adrenergic agonist, suppresses signs of opiate withdrawal in animals and in man. Electrical or chemical stimulation of the nucleus locus coeruleus (LC) increases noradrenergic activity and brain concentration of the noradrenergic metabolite MHPG, and produces many signs of opiate withdrawal. Thus, clonidine's ability to attenuate withdrawal might be due to the reduction of noradrenergic neuronal activity originating in the LC, but additional alpha-2-adrenergic receptors throughout the body and other mechanisms may also play a role. The present study explored the neuroanatomical and pharmacological selectivity of alpha-2-adrenergic receptors of the LC in the anti-withdrawal action of clonidine. Experiment 1 tested the hypothesis that behavioral and biochemical measures of naloxone-precipitated withdrawal from morphine would be blocked by infusions of clonidine (0.6 or 2.4 μg/μl) into the LC. Significant reductions were observed in the occurrence of diarrhea, ptosis, weight loss and wet-dog shakes. Clonidine also reversed the naloxone-precipitated increase in hippocampus MHPG concentration. In experiment 2 subjects received an LC infusion or IP injection of a non-lipophilic alpha-2-agonist (ST-91), which does not penetrate the blood-brain barrier, or of clonidine into the dorsal parabrachial nucleus (DPB) to test the selectivity of the effects of clonidine infusions into the LC. ST-91 infusions into the LC reduced several of the observed withdrawal signs and increased others (e.g., jumping). Although peripheral injections of ST-91 attenuated some of the checked signs associated with naloxone-precipitated withdrawal, the frequency of wet-dog shakes was not reduced. ST-91 infusions into the LC, but not systemic ST-91 administration, prevented the withdrawal-induced increase in hippocampus MHPG concentration. Clonidine infused lateral to the LC into the DPB did not significantly attenuate withdrawal or reduce hippocampus MHPG levels. These results provide behavioral and biochemical evidence to support the suggestion that clonidine significantly attenuates naloxone-precipitated withdrawal through an interaction with noradrenergic neurons located in the vicinity of the LC.

Key words

Clonidine Locus coeruleus Intracerebral infusion Withdrawal Naloxone Morphine 3-Methoxy-4-hydroxyphenylglycol (MHPG) Rat 


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  1. Abercrombie ED, Jacobs BL (1987) Microinjected clonidine inhibitis noradrenergic neurons of the locus coeruleus in freely moving cats. Neurosci Lett 76:203–208PubMedCrossRefGoogle Scholar
  2. Aghajanian GK (1978) Tolerance of locus coeruleus neurons to morphine and suppression of withdrawal response by clonidine. Nature 276:186–188PubMedCrossRefGoogle Scholar
  3. Aston-Jones G, Ennis M, Pieribone VA, Nickell WT, Shipley MT (1986) The brain nucleus locus coeruleus: restricted afferent control of a broad efferent network. Science 234:734–737PubMedGoogle Scholar
  4. Bird SJ, Kuhar MJ (1977) Iontophoretic applications of opiates to the locus coeruleus. Brain Res 122:523–533PubMedCrossRefGoogle Scholar
  5. Blasig J, Reinhold HK, Zieglgansberger S (1973) Development of physical dependence on morphine in respect to time and dosage and quantification of the precipitated withdrawal syndrome in rats. Psychopharmacologia 33:19–38PubMedCrossRefGoogle Scholar
  6. Britton KT, Svensson T, Schwartz J, Bloom FE, Koob GF (1984) Dorsal noradrenergic bundle lesions fail to alter opiate withdrawal or suppression of opiate withdrawal by clonidine. Life Sci 34:133–139PubMedCrossRefGoogle Scholar
  7. Calvino B, Lagowska J, Ben-Ari Y (1979) Morphine withdrawal syndrome: differential participation of structures located within the amygdaloid complex and striatum of the rat. Brain Res 177:19–34PubMedCrossRefGoogle Scholar
  8. Cedarbaum JM, Aghajanian GK (1976) Noradrenergic neurons of the locus coeruleus: inhibition by epinephrine and activation by the alpha-antagonist piperoxane. Brain Res 112:413–419PubMedCrossRefGoogle Scholar
  9. Cedarbaum JM, Aghajanian GK (1977) Catecholamine receptors on locus coeruleus neurons: pharmacological characterization. Eur J Pharmacol 44:375–385PubMedCrossRefGoogle Scholar
  10. Cedarbaum JM, Aghajanian GK (1978) Afferent projections to the rat locus coeruleus as determined by a retrograde tracing technique. J Comp Neurol 178:1–16PubMedCrossRefGoogle Scholar
  11. Charney DS, Riordan CE, Kleber HD, Murburg M, Braverman P, Sternberg DE, Heninger GR, Redmond DE Jr (1982) Clonidine and naltrexone. Arch Gen Psychiatry 39:1327–1332PubMedGoogle Scholar
  12. Charney DS, Sternberg DE, Kleber HD, Heninger GR, Redmond DE Jr (1981) The clinical use of clonidine in abrupt withdrawal from methadone. Arch Gen Psychiatry 38:1273–1277PubMedGoogle Scholar
  13. Crawley JN, Laverty R, Roth RH (1979) Clonidine reversal of increased norepinephrine metabolite levels during morphine withdrawal. Eur J Pharmacol 57:247–250PubMedCrossRefGoogle Scholar
  14. DiStefano PS, Brown OM (1985) Biochemical correlates of morphine withdrawal. 2. Effects of clonidine. J Pharmacol Exp Ther 233:339–344PubMedGoogle Scholar
  15. Elam M, Thoren P, Svensson TH (1986) Locus coeruleus neurons and sympathetic nerves: activation by visceral afferents. Brain Res 375:117–125PubMedCrossRefGoogle Scholar
  16. Elsworth JD, Roth RH, Redmond DE Jr (1983) Relative importance of 3-methoxy-4-hydroxyphenylglycol and 3,4-dihydroxyphenylglycol as norepinephrine metabolites in rat, monkey, and humans. J Neurochem 41(3):786–793PubMedGoogle Scholar
  17. Fallon JH, Koziella DA, Moore RY (1978) Catecholamine innervation of the basal forebrain. II. Amygdala, suprarhinal cortex and entorhinal cortex. J Comp Neurol 180:533–544PubMedCrossRefGoogle Scholar
  18. Fielding S, Wilker J, Hynes M, Szewczak M, Novick WJ Jr, Lal H (1978) A comparison of clonidine with morphine for antinociceptive and anti-withdrawal actions. J Pharmacol Exp Ther 207:899–905PubMedGoogle Scholar
  19. Franz DN, Hare BD, McCloseky KL (1982) Spinal sympathetic neurons: possible sites of opiate withdrawal suppression by clonidine. Science 215:1643–1645PubMedGoogle Scholar
  20. Freedman JE, Aghajanian GK (1985) Opiate and alpha-2-adrenoceptor responses of rat amygdaloid neurons: co-localization and interactions during withdrawal. J Neurosci 5(11):3016–3024PubMedGoogle Scholar
  21. Gianutsos G, Hynes MD, Lal H (1976) Enhancement of morphine withdrawal and apomorphine-induced aggression by clonidine. Psychopharmacol Commun 2:165–171PubMedGoogle Scholar
  22. Gold MS, Redmond DE, Kleber HD (1978) Clonidine in opiate withdrawal. Lancet II:599–602CrossRefGoogle Scholar
  23. Gold MS, Pottash AC, Sweeney DR, Kleber HD (1980) Opiate withdrawal using clonidine. JAMA 243:343–346PubMedCrossRefGoogle Scholar
  24. Graham AW, Aghajanian GK (1971) Effects of amphetamine on single cell activity in a catecholamine nucleus, the locus coeruleus. Nature 234:100PubMedCrossRefGoogle Scholar
  25. Keppel G (1982) Design and analysis; a researchers handbook. Englewood, Cliffs, N.J., Prentice HallGoogle Scholar
  26. Korf J, Bunney BS, Aghajanian GK (1974) Noradrenergic neurons: morphine inhibition of spontaneous activity. Eur J Pharmacol 25:165–169PubMedCrossRefGoogle Scholar
  27. Lagowska J, Calvino B, Ben-Ari Y (1978) Intra-amygdaloid applications of naloxone elicits severe withdrawal signs in morphine dependent rats. Neurosci Lett 8:241–245CrossRefGoogle Scholar
  28. Laverty R, Roth RH (1980) Clonidine reverses the increased norepinephrine turnover during morphine withdrawal in rats. Brain Res 182:482–485PubMedCrossRefGoogle Scholar
  29. Marwaha J, Kehne JH, Commissaris RL, Lakoski J, Shaw W, Davis M (1983) Spinal clonidine inhibits neural firing in locus coeruleus. Brain Res 276:379–382PubMedCrossRefGoogle Scholar
  30. Nakaki T, Chang PCJ, Tokunaga Y, Kato R (1981) Alpha-2-adrenoceptors modulating diarrhea in morphine-dependent rats. J Pharm Pharmacol 33:397–399PubMedGoogle Scholar
  31. Paxinos G, Watson C (1982) The rat brain in stereotaxic coordinates. Academic Press, Sydney, New York, LondonGoogle Scholar
  32. Redmond DE Jr (1981) Clonidine and the primate locus coeruleus: evidence suggesting anxiolytic and anti-withdrawal effects. In: Lal H, Fielding S (eds) Psychopharmacology of clonidine. Liss, New York, pp 147–163Google Scholar
  33. Redmond DE Jr, Huang YH (1982) The primate locus coeruleus and effects of clonidine on opiate withdrawal. J Clin Psychiatry 43:6 (sect. 2) 25–29PubMedGoogle Scholar
  34. Roth RH, Elsworth JD, Redmond DE Jr (1982) Clonidine suppression of noradrenergic hyperactivity during morphine withdrawal by clonidine: biochemical studies in rodents and primates. J Clin Psychiatry 43:6, 42–46PubMedGoogle Scholar
  35. Sparber SG, Meyer DR (1978) Clonidine antagonizes naloxone-induced suppression of conditioned behavior and body weight loss in morphine-dependent rats. Pharmacol Biochem Behav 9:319–325PubMedCrossRefGoogle Scholar
  36. Siegel S (1956) Nonparametric statistics. McGraw-Hill, New YorkGoogle Scholar
  37. Simantov R, Kuhar MJ, Uhl GR, Snyder SH (1977) Opioid peptide enkephalin: immunohistological mapping in rat central nervous system. Proc Natl Acad Sci USA 74:2167–2171PubMedCrossRefGoogle Scholar
  38. Svensson T, Bunney BS, Aghajanian GK (1975) Inhibition of both noradrenergic and serotonergic neurons in brain by the alpha-2-adrenergic agoinist clonidine. Brain Res 92:291PubMedCrossRefGoogle Scholar
  39. Tseng LF, Loh HH, Way EL (1975) Effects of clonidine on morphine withdrawal signs in the rat. Eur J Pharmacol 30:93–99PubMedCrossRefGoogle Scholar
  40. Uhde TW, Redmond DE Jr, Kleber HD (1980) Clonidine supresses the opiate abstinence syndrome without clonidine-withdrawal symptoms: a blind inpatient study. Psychiatry Res 2:37–47PubMedCrossRefGoogle Scholar
  41. Ungerstedt U (1971) Stereotaxic mapping of the monoamine pathways in the rat brain. Acta Physiol Scand [Suppl] 367:1–48Google Scholar
  42. U'Prichard DC, Reisine TD, Mason ST, Fibiger HC, Yamamura HI (1980) Modulation of rat brain alpha- and beta-adrenergic receptor populations by lesion of the dorsal noradrenergic bundle. Brain Res 187:143–154PubMedCrossRefGoogle Scholar
  43. Van der Laan JW (1983) Is the clonidine potentiation of jumping in precipitated morphine withdrawal mediated by alpha-1-receptors? Naunyn-Schmiedeberg's Arch Pharmacol 322S:R86Google Scholar
  44. Van der Laan JW (1985) Effects of alpha-2-agonists on morphine withdrawal behaviour: potentiation of jumping mediated by alpha-2-receptors. Naunyn-Schmiedeberg's Arch Pharmacol 329:293–298CrossRefGoogle Scholar
  45. Washton AM, Resnick RB (1980) Clonidine for opiate detoxification: outpatient clinical trial. Am J Psychiatry 137:1121–1122PubMedGoogle Scholar
  46. Wolf G (1971) Elementary histology for neuropsychologists. In: Myers RD (ed) Methods in psychobiology, vol 1. Academic Press, London New York, pp 281–300Google Scholar
  47. Young WS III, Kuhar MJ (1980) Noradrenergic alpha-1 and alpha-2 receptors: light microscope autoradiographic localization. Proc Natl Acad Sci USA 77:1696–1700PubMedCrossRefGoogle Scholar
  48. Zebrowska-Lupina I, Przegalinski E, Sloniec M, Kleinrok Z (1977) Clonidine induced Locomotor hyperativity in rats. Naunyn-Schmiedeberg's Arch Pharmacol 297:227–231CrossRefGoogle Scholar
  49. Zigun JR, Bannon MJ, Roth RH (1981) Comparison of two alpha-noradrenergic agonists (clonidine and guanfacine) on norepinephrine turnover in the cortex of rats during morphine abstinence. Eur J Pharmacol 70:565–570PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1988

Authors and Affiliations

  • J. R. Taylor
    • 1
  • J. D. Elsworth
    • 1
  • E. J. Garcia
    • 1
  • S. J. Grant
    • 1
  • R. H. Roth
    • 1
  • D. E. RedmondJr
    • 1
  1. 1.Neurobehavior Laboratory and Departments of Psychiatry and PharmacologyYale University School of MedicineNew HavenUSA

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