Skip to main content
Log in

Chronic neuroleptic treatment and mesolimbic dopamine denervation induce behavioural supersensitivity to opiates

  • Original Investigations
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

In the present study the functional relationship between enkephalinergic and dopaminergic neurones at the level of the nucleus accumbens was investigated. The study consisted of two experiments in which dopaminergic (DA) transmission was chronically inhibited, and the behavioural locomotor response to intra-accumbens opiate injections analysed. First, specific 6-OHDA lesion of the DA-A10 neurones (either in nucleus accumbens or ventral tegmental area) was found markedly to increase the behavioural excitatory effects induced by nucleus accumbens injection of opioid peptides or morphine. Specific lesion of the central noradrenergic neurones had no such effect. Second, chronic pharmacological blockade of DA activity either with reserpine or a neuroleptic (pipothiazine palmitate) similarly induced a strong enhancement of the behavioral response to intra-accumbens opiate injection. The results are discussed in terms of novel mechanisms underlying denervation supersensitivity, and may have important implications for the relation between dopamine dysfunction in mental illness and opiate addiction.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Atweh SF, Kuhar MJ (1977a) Autoradiographic localization of opiate receptors in rat brain. II The brain stem. Brain Res 129: 1–12

    Google Scholar 

  • Atweh SF, Kuhar MJ (1977b) Autoradiographic localization of opiate receptors in rat brain. III The telencephalon. Brain Res 134: 393–405

    Google Scholar 

  • Bozarth MA, Wise RA (1981) Intracranial self-administration of morphine into the ventral tegmental area in rats. Life Sci 28: 551–555

    Google Scholar 

  • Broekkamp CLE, Phillips AG, Cools AR (1979) Stimulant effects of enkephalin microinjection into the dopaminergic A10 area. Nature 278: 560–562

    Google Scholar 

  • Carlsson A, Rosengreen e, Bertler A, Nilsson T (1957) Effect of reserpine on the metabolism of catecholamines. In: Garattini S, Ghetti V (eds) Psychotropic drugs. Elsevier, Amsterdam, pp 363–370

    Google Scholar 

  • Goeders NE, Lane JD, Smith JE (1983) Self-administration of methionine enkephalin into the nucleus accumbens. Pharmacol Biochem Behav 20: 451–455

    Google Scholar 

  • Holzbauer M, Vogt M (1956) Depression by reserpine of the noradrenaline concentration in the hypothalamus of the cat. J Neurochem 1: 8–11

    Google Scholar 

  • Hong JS, Yang HYT, Fratta W, Costa E (1977) Determination of methionine enkephalin in discrete regions of rat brain. Brain Res 134: 383–386

    Google Scholar 

  • Hong JS, Yang HYT, Fratta W, Costa E (1978) Rat striatal methionine-enkephalin content after chronic treatment with cataleptogenic and non-cataleptogenic antischizophrenia drugs. J Pharmacol Exp Ther 205: 141–147

    Google Scholar 

  • Hong JS, Yang HYT, Gillin IC, di Guilio AM, Fratta W, Costa E (1979) Chronic treatment with haloperodol accelerates the biosynthesis of enkephalins in rat brat. Brain Res 160: 192–195

    Google Scholar 

  • Johnson RP, Sar M, Stumpf WE (1980) A topographic localization of enkephalin on the dopamine neurons of the rat substantia nigra and ventral tegmental area demonstrated by combined histofluorescence-immunohistochemistry. Brain Res 194: 566–571

    Google Scholar 

  • Joyce EM, Iversen SD (1979) The effect of morphine applied locally to mesencephalic dopamine cell bodies on spontaneous activity in the rat. Neurosci Lett 14: 207–212

    Google Scholar 

  • Kalivas PW, Widerlov E, Stanley D, Breese G, Prange AJ (1983) Enkephalin action on the mesolimbic system a dopamine-dependent and a dopamine-independent increase in locomotor activity. J Pharmacol Exp Ther 227: 227–237

    Google Scholar 

  • Kato N, Shah KR, Friesen HG, Havlicek V (1981) Effect of chronic treatment with haloperidol on serum prolactin, striatal opiate receptors and β-endorphin content in rat brain and pituitary. Prog Neuro-Psychopharmacol 5: 549–552

    Google Scholar 

  • Kelley AE, Stinus L, Iversen SD (1980) Interaction between d-ala-met-enkephalin, A10 dopaminergic neurones, and spontaneous behaviour in the rat. Behav Brain Res 1: 3–24

    Google Scholar 

  • Kostrzewa RM, Jacobowitz DM (1974) Pharmacological actions of 6-hydroxydopamine. Pharmacol Rev 26: 199–288

    Google Scholar 

  • La Motte CC Snowman A, Pert CC, Snyder SH (1978) Opiate receptor binding in rhesus monkey brain: association with limbic structures. Brain Res 155: 374–379

    Google Scholar 

  • Pert CB, Pert A, Chang JK, Fong BTW (1976) D-ala-met-enkephalinamide: a potent long-lasting synthetic pentapeptide analgesic. Science 194: 330–332

    Google Scholar 

  • Pert CB, Sivit C (1977) Neuroanatomical focus for morphine and enkephalin induced hypermotility. Nature 265: 645–647

    Google Scholar 

  • Phillips AG, Le Piane FG (1980) Reinforcing effects of morphine microinjection into the ventral tegmental area. Pharmacol Biochem Behav 12: 965–968

    Google Scholar 

  • Phillips AG, Le Piane FG, Fibiger HC (1983) Dopaminergic mediation of reward produced by direct injection of enkephalin into the ventral tegmental area. Life Sci 33: 2505–2511

    Google Scholar 

  • Pollard H, Llorens-Cortes C, Bennett JJ, Constantin J, Schwartz JC (1977a) Opiate receptors on mesolimbic dopaminergic neurons. Neurosci Lett 7: 295–299

    Google Scholar 

  • Pollard H, Llorens-Cortes C, Schwartz (1977b) Enkephalin receptors on dopaminergic neurons in rat striatum. Nature 268: 745–747

    Google Scholar 

  • Rounsaville BJ, Weissman MM, Kleber H, Wilber C (1982a) Heterogeneity of psychiatric diagnosis in treated opiate addicts. Arch Gen Psychiatry 39: 161–166

    Google Scholar 

  • Rounsaville BJ, Weissman MM, Crits-Christoph K, Wilber C, Kleber H (1982b) Diagnosis and symptoms of depression in opiate addicts. Arch Gen Psychiatry 39: 151–156

    Google Scholar 

  • Scatton B, Garret C, Glowinski J, Julou L (1975) Effect of long-acting injectable neuroleptic (the palmitic ester of pipothiazine) on dopamine metabolism in the rat striatum. In: Boissier JR, Hippuis H, Pichot P (eds) Neuropsychopharmacology. Proceedings of the IX Congress of the CINP Paris 1974, Amsterdam Exc Med, pp 472–479

  • Scatton B, Boireau A, Garret C, Glowinski J, Julou L (1977) Action of palmitic ester of pipothiazine on dopamine metabolism in the nigro-striatal, meso-limbic and meso-cortical systems. Naunyn-Schmiedeberg's Arch Pharmacol 296: 169–175

    Google Scholar 

  • Schildkraut JJ (1978) Current status of the catecholamine hypothesis of affective disorders. In: Lipton MA, DiMascio A, Killam KF (eds) Psychopharmacology: A generation of progress, Raven Press, New York, pp 1223–1234

    Google Scholar 

  • Seeman P (1981) Brain dopamine receptors. Pharmacol Rev 32: 229–313

    Google Scholar 

  • Stinus L, Koob GF, Ling N, Bloom FE, Le Moal M (1980) Locomotor activation induced by infusion of endorphins into the ventral tegmental area: evidence for opiate-dopamine interactions. Proc Natl Acad Sci (USA) 77: 2323–2327

    Google Scholar 

  • Tang F, Schwartz JP, Costa E (1983) Increase of proenkephalin mRNA and enkephalmin content of rat striatum following daily injection of haloperidol for two to three weeks. Proc Natl Acad Sci (USA) 80: 3841–3844

    Google Scholar 

  • Taquet H, Javoy-Agid F, Hamon M, Le Grand JC, Agid Y, Cesselin F (1983) Parkinson's disease affects differently met-5-enkephalin and leu-5-enkephalin in the human brain. Brain Res 280: 375–382

    Google Scholar 

  • Tarsy D, Baldessarini RJ (1973) Pharmacologically induced behavioural supersensitivity to apomorphine. Nature 245: 262–263

    Google Scholar 

  • Thal LJ, Sharpless NS, Hirschhorn ID, Horowitz SG, Makman MH (1983) Striatal met-enkephalin concentration increases following nigrostriatal denervation Biochem Pharmacol 32: 3297–3301

    Google Scholar 

  • Trujillo KA, Belluzi JD, Stein L (1983) Endorphin-catecholamine interactions in nucleus accumbens self-administration. Abstracts Soc Neurosci 9: 277

    Google Scholar 

  • Ungerstedt U (1971) Postsynaptic supersensitivity after 6-hydroxy dopamine induced degeneration of the nigro-striatal dopamine system in the rat brain. Acta Physiol Scand Suppl 367: 69–73

    Google Scholar 

  • Van Der Kooy D, Mucha RF, O'Shaughnessy M, Bucenieks P (1982) Reinforcing effects of brain microinjections of morphine revealed by conditioned place preference. Brain Res 243: 107–117

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stinus, L., Winnock, M. & Kelley, A.E. Chronic neuroleptic treatment and mesolimbic dopamine denervation induce behavioural supersensitivity to opiates. Psychopharmacology 85, 323–328 (1985). https://doi.org/10.1007/BF00428196

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00428196

Key words

Navigation