Neurobiology of D1 Dopamine Receptors after Neonatal-6-OHDA Treatment: Relevance to Lesch-Nyhan Disease

  • George R. Breese
  • Robert A. Mueller
  • T. Celeste Napier
  • Gary E. Duncan
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 204)


Central administration of 6-hydroxydopamine (6-OHDA) to adult or neonatal rats destroys dopamine-containing neurons, produces a variety of behavioral deficits (Breese et al., 1973; Smith et al., 1973) and enhances behavioral responses to dopamine agonists (Ungerstedt, 1971; Schoenfeld and Uretsky, 1972; Hollister et al., 1974; 1979; Setler et al. 1978; Kilts et al. 1979). In spite of the common biochemical deficiency observed in neonatally and adult-lesioned rats, Breese et al. (1984 a,b) reported that certain behavioral responses to L-DOPA or apomorphine in adult-6-OHDA-treated rats (Breese et al., 1970) differ from those observed in rats lesioned as neonates and tested with dopamine agonists as adults (Breese et al., 1972; Smith et al., 1973). For example, neonatally 6-OHDA-lesioned rats exhibit self-mutilation behavior (SMB) after treatment with dopamine agonists which do not elicit this response in adult-6-OHDA treated rats (Breese et al., 1984b).


Dopamine Receptor Dopamine Agonist Locomotor Response Dopamine Receptor Subtype Spiperone Binding 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Arnt, J., 1985, Hyperactivity induced by stimulation of separate D1 and D2 receptors in rats with bilateral 6-OHDA lesions, Life Sci., 37:717–723.PubMedCrossRefGoogle Scholar
  2. Arnt, J., and Hyttel, J., 1984, Differential inhibition by dopamine D1 and D2 antagonists of circling behavior induced by dopamine agonists in rats with unilateral 6-hydroxydopamine lesions, Europ. J. Pharmacol., 102:349–354.CrossRefGoogle Scholar
  3. Bevan, P., 1983, Repeated apomorphine treatment causes behavioral supersensitivity and dopamine D2 receptor hyposensitivity, Neurosci. Letter, 35:185–189.CrossRefGoogle Scholar
  4. Billard, W., Ruperto, V., Crosby, G., Iorio, L.C., and Barnett, A., 1984, Characterization of the binding of 3H-SCH 23390, a selective D1 receptor antagonist ligand, in rat striatum, Life Sci., 35:1885–1893.PubMedCrossRefGoogle Scholar
  5. Breese, G.R. and Traylor, T.D. Effects of 6-hydroxydopamine on brain norepinephrine and dopamine: Evidence for selective degeneration of catecholamine neurons, 1970, J. Pharmacol. Exp. Ther., 174:413–420. .PubMedGoogle Scholar
  6. Breese, G.R., and Traylor, T.D., 1972, Developmental characteristics of brain catecholamines and tyrosine hydroxylase in the rats: Effects of 6-hydroxydopamine, Brit. J. Pharmacol., 44:210–222.Google Scholar
  7. Breese, G.R., Baumeister, A.A., McCown, T.J., Emerick, S.G., Frye, G.D. and Mueller, R.A., 1984a, Neonatal-6-hydroxydopamine: Model of susceptibility for self-mutilation in the Lesch-Nyhan Syndrome, Pharmacol. Biochem. Behav., 21:459–461.PubMedCrossRefGoogle Scholar
  8. Breese, G.R., Baumeister, A.A., McCown, T.J., Emerick, S.G., Frye, G.D., Crotty, K., and Mueller, R.A., 1984b, Behavioral differences between neonatal and adult-6-hydroxydopamine-treated rats to dopamine agonists: Relevance to neurological symptoms in clinical syndromes with reduced brain dopamine, J. Pharmacol. Exp. Ther., 231:343–354.PubMedGoogle Scholar
  9. Breese, G.R., Baumeister, A., Napier, T.C., Frye, G.D., and Mueller, R.A., 1985a, Evidence that D1 dopamine receptors contribute to the supersensitive behavioral responses induced by L-dihydroxyphenylalanine in rats treated neonatally with 6-hydroxydopamine, J. Pharmacol. Exp. Ther., 235:287–295.PubMedGoogle Scholar
  10. Breese, G.R., Cooper, B.R. and Smith, R.D., 1973, Biochemical and behavioral alterations following 6-hydroxydopamine administration into brain. In: “Frontiers in Catecholamine Research”, Usdin, E. and Snyder, S. (Eds.). Pergamon Press, pp. 701–706.Google Scholar
  11. Breese, G.R. and Mueller, R.A., 1985, SCH 23390 antagonism of a D2 dopamine agonist depends upon catecholaminergic neurons, Europ. J. Pharmacol., 113:109–114.CrossRefGoogle Scholar
  12. Breese, G.R., Mueller, R.A., and Mailman, R.B., 1979, Effects of dopaminergic agonists and antagonists on in vivo cyclic nucleotide content: Relation of guanosine 3’5’-monophosphate (cGMP) changes in cerebellum to behavior, J. Pharmacol. Exp. Ther., 209:262–270.PubMedGoogle Scholar
  13. Breese, G.R., Napier, T.C., and Mueller, R.A., 1985c, Dopamine agonist-induced locomotor activity in rats treated with 6-hydroxydopamine at differing ages: Functional supersensitivity of D1 dopamine receptors in neonatally lesioned rats, J. Pharmacol Exp. Ther., 234:447–455.PubMedGoogle Scholar
  14. Breese, G.R., McCown, T.J., Baumeister, A.A., Emerick, S.G., Frye, G.D. and Mueller, R.A., 1984c, L-DOPA induced self-biting in rats treated with 6-hydroxydopamine as neonates: Model of self-mutilation observed in Lesch-Nyhan syndrome, Fed. Proc., 43:928.Google Scholar
  15. Christensen, A.V., Arnt, J., Hyttel, J., Larson, J.J., and Svendsen, O., 1984, Pharmacological effects of a specific dopamine D1 antagonist SCH 23390 in comparison with neuroleptics, Life Sci., 34:1529–1540.PubMedCrossRefGoogle Scholar
  16. Claveria, L.E., Teychenne, P.F., Calne, D.B., Petrie, A. and Bassendine, M.F., 1975, Dopaminergic agonists in Parkinsonism, Adv. Neurol., 9:393–397.Google Scholar
  17. Cooper, B.R., Breese, G.R., Grant, L.D., and Howard, J.J., 1973, Effects of 6-hydroxydopamine treatments on active avoidance responding: Evidence for involvement of brain dopamine, J. Pharmacol. Exp. Ther., 185:358–370.PubMedGoogle Scholar
  18. Costall, B., Kelley, M.E., and Naylor, R.J., 1984, Unilateral striatal denervation: Reduced motor inhibitory effects of dopamine antagonists revealed in models of asymmetric and circling behavior, Nauyn-Schmeideberg’s Arch. Pharmacol., 326:29–35.CrossRefGoogle Scholar
  19. Costall, B., Naylor, R.J., and Neumeyer, J.L., 1975, Differences in the nature of the stereotyped behavior by apomorphine derivatives in the rat and in their actions in extrapyramidal and mesolimbic brain areas, Europ. J. Pharmacol., 31:1–16.CrossRefGoogle Scholar
  20. Creese, I., Burt, D.R., and Snyder, S.H., 1977, Dopamine receptor binding enhancement accompanies lesion-induced behavioral supersensitivity, Science, 197:596–598.PubMedCrossRefGoogle Scholar
  21. Goldstein, M., Anderson, L.T., Reuben, R. and Dancis, J., 1985, Self-mutilation in Lesch-Nyhan disease is caused by dopaminergic denervation, Lancet, 1:338–339.PubMedCrossRefGoogle Scholar
  22. Goldstein, M., Lew, T.Y., Asano, T., and Weta, K., 1980, Alterations in dopamine receptors. Effects of lesions and haloperidol treatment, Comm. Psychopharm., 4:21–25.Google Scholar
  23. Heikkila, R.E., Shapiro, B.S., and Duvoisin, R.C., 1981, The relationship between loss of dopamine nerve terminals, striatal (3H)-spiroperidol binding and rotational behavior in unilaterallly 6-hydroxydopamine-lesioned rats, Brain Res., 211:285–292.PubMedCrossRefGoogle Scholar
  24. Herrera-Marschitz, M., and Ungerstedt, U., Evidence that striatal efferents relate to different dopamine receptors, Brain Res., 323:269–278.Google Scholar
  25. Hollister, A.S., Breese, G.R., and Cooper, B.R., 1974, Comparison of tyrosine hydroxylase and dopamine-β-hydroxylase inhibition with the effects of various 6-hydroxydopamine treatments on d-amphetamine induced motor activity, Psychopharmacologia, 36:1–16.PubMedCrossRefGoogle Scholar
  26. Hollister, A.S., Breese, G.R., and Mueller, R.A., 1979, Role of monoamine neural systems in L-dihydroxyphenylalanine stimulated activity, J. Pharmacol. Exp. Ther., 208:37–43.PubMedGoogle Scholar
  27. Hornykiewicz, O., 1973, Parkinson’s disease: From brain homogenate to treatment, Fed. Proc, 32:183–190.PubMedGoogle Scholar
  28. Hyttel, J., 1978, A comparison of the effect of neuroleptic drugs on the binding of 3H-haloperidol and 3H-(Z)-flupentixol and an adenylate cyclase activity in rat striatal tissue in vitro, Prog. Neuro-Psychopharmacol., 2:329–335.CrossRefGoogle Scholar
  29. Iorio, L.C., Barnett, A., Leitz, F.H., Houser, V.P., and Korduba, A., 1983, SCH-23390, a potential benzazepine antipsychotic with unigue interactions on dopaminergic systems, J. Pharmacol. Exp. Ther., 226:462–468.PubMedGoogle Scholar
  30. Jackson, D.M., Anden, N-E. and Dahlstrom, A., 1975, A functional effect of dopamine in the nucleus accumbens and in some dopamine-rich areas of the rat brain, Psychopharmacologia, 45:139–149.PubMedCrossRefGoogle Scholar
  31. Kebabian, J.W., and Calne, D.B., 1979, Multiple receptors for dopamine, Nature (Lond)., 227:93–96.CrossRefGoogle Scholar
  32. Kelley, W.N. and Wyngaarden, T.B., 1983, Clinical syndromes associated with hypoxanthine-guanine-phosphoribosyl-transferase deficiency. In: “Metabolic Basis of Inherited Disease”, edited by Stanberry et al. New York: McGraw Hill, pp. 1115–1143.Google Scholar
  33. Kilts, C.D., Smith, D.A., Ondrusek, M.G., Mailman, R.B., Mueller, R.A., and Breese, G.R., 1979, Differential effects of “Dopaminergic agonists” on measures of dopaminergic function, Soc. Neurosci. Abst., 5:562.Google Scholar
  34. Klawans, W.L., Paulson, G.W., Ringel, S.P. and Barbeau A., 1972, Use of L-DOPA in the detection of prof L-DOPA in the detection of presymptomatic Hungtington’s chorea, N. Engl. J. Med., 286:1332–1334.PubMedCrossRefGoogle Scholar
  35. Klawans, H.L., Hitri, A., Carvey, P.M., Nausieda, P.A. and Weiner, W.J., 1979, Effect of chronic dopaminergic agonism on striatal membrane dopamine binding, Adv. Neurol., 24:217–224.Google Scholar
  36. Koller, W.C., Cortin, J.C., and Fields, J.Z., 1984, Pergolide down-regulates D2 dopamine receptors but fails to block haloperidol induced behavioral supersensitivity, Society Neurosci. Abst., 10:1136.Google Scholar
  37. Laduron, P.M., 1983, Commentary: Dopamine-sensitive adenylate cyclase as a receptor site, In: “Dopamine Receptors” (ed. C. Kaiser and T.W. Kebabian), Am. Chem. Soc. (Washington, D.C.) pp. 22–28.Google Scholar
  38. Lesch, M. and Nyhan, W.L., 1964, A familial disorder of uric acid metabolism and central nervous system function, Am. J. Med., 36:561–570.PubMedCrossRefGoogle Scholar
  39. Lloyd, K.G., Hornykiewicz, O., Davidson, L., Shannak, K., Farley, I., Goldstein, M., Shibuya, M., Kelley, W.N., and Fox, I.H., 1981, Biochemical evidence of dysfunction of brain neurotransmitters in the Lesch-Nyhan syndrome, N. Eng. J. Med., 305:1106–1111.CrossRefGoogle Scholar
  40. Mailman, R.B., Kilts, C.D., Beaumont, K., and Breese, G.R., 1981, “Supersensitivity” of dopamine systems: Comparisons between haloperidol withdrawal, intracisternal and unilateral 6-hydroxydopamine (6-OHDA) treatments, Fed Proc., 40:291.Google Scholar
  41. Mailman, R.B., Towle, A., Schulz, D.W., Lewis, M.H., Breese, G.R., DeHaven, D.H., and Krigman, M.R., 1983, Neonatal 6-OHDA treatment of rats: Changes in dopamine (DA) receptors, striatal neurochemistry and anatomy, Soc. Neurosci. Abstr., 9:932.Google Scholar
  42. Mailman, R.B., Schulz, D.W., Lewis, M.H., Staples, L. Rollema, H. and DeHaven, D.L., 1984, SCH 23390: A selective D1 dopamine antagonist with potent D-2 behavioral actions, Europ. J. Pharmacol., 101:159–160.CrossRefGoogle Scholar
  43. Molloy, A.G. and Waddington, T.L., 1984, Dopaminergic behavior stereospecifically promoted by the D1 agonist R- SK & F 38393 and selectively blocked by the D1 antagonist SCH 23390, Psychopharmacology, 82:409–410.PubMedCrossRefGoogle Scholar
  44. Neve, K.A., Altar, C.A., Wong, C.A., and Marshall, T.F., 1984, Quantitative analysis of (3H) spiroperidol binding to rat forebrain sections: Plasticity of neostriatal dopamine receptors after nigrostriatal injury, Brain Res., 302:9–18.PubMedCrossRefGoogle Scholar
  45. Onali, P., Olianas, M. and Gessa, G.L., 1985, Characterization of dopamine receptors mediating inhibition of adenylate cyclase activity in rat striatum, Mol. Pharmacol., 28:138–145.PubMedGoogle Scholar
  46. Pijnenburg, A.J.J., Honig, W.M.M., Van Der Heyden, J.A.M., and Van Rossum, J.M., 1976, Effects of chemical stimulation of the mesolimbic dopamine system upon locomotor activity, Europ. J. Pharmacol., 35:45–58.CrossRefGoogle Scholar
  47. Robinson, T.E., 1984, Behavioral sensitization: Characteristics of enduring changes in rotational behavior produced by intermittent injections of amphetamine in male and female rats, Psychopharmacology, 84:466–475.PubMedCrossRefGoogle Scholar
  48. Schoenfeld, R., and Uretsky, N., 1972, Altered response to apomorphine in 6-hydroxydopamine-treated rats, Europ. J. Pharmacol., 19:115–118.Google Scholar
  49. Seeman, P., 1980, Brain dopamine receptors, Pharmacol. Rev., 32:229–313.PubMedGoogle Scholar
  50. Setler, P.E., Sarau, H.M., Zirkle, CL., and Saunders, H.L., 1978, The central effects of a novel dopamine agonist, Europ. J. Pharmacol., 50:419–430.CrossRefGoogle Scholar
  51. Smith, R.D., Cooper, B.R., and Breese, G.R., 1973, Growth and behavioral changes in developing rats treated intracisternally with 6-hydroxydopamine: Evidence for involvement of brain dopamine, J. Pharmacol. Exp. Ther., 185:609–619.Google Scholar
  52. Staunton, D.A., Wolfe, B.B., Groves, P.M., and Molinoff, P.B., 1981, Dopamine receptor changes following destruction of the nigrostriatal pathway: Lack of a relationship to rotation behavior, Brain Res., 211:315–327.PubMedCrossRefGoogle Scholar
  53. Tsuruta, K., Frey, E.A., Grewe, C.W., Cote, T.E., Eskay, R.L., and Kebabian, T.W., 1981, Evidence that LY-141865 specifically stimulates the D2 dopamine receptor, Nature (Lond), 292:463–465.CrossRefGoogle Scholar
  54. Ungerstedt, U., 1971, Postsynaptic supersensitivity after 6-hydroxydopamine induced degeneration of the nigrostriatal dopamine system, Acta Physiol. Scand., Supplement367, pp. 69–93.Google Scholar
  55. Walaas, S.I., Aswad, D.W., and Greengard, P., 1983, A dopamine and cyclic AMP-regulated phosphoprotein enriched in dopamine-innervated brain regions, Nature, 301:69–71.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • George R. Breese
    • 1
  • Robert A. Mueller
    • 1
  • T. Celeste Napier
    • 1
  • Gary E. Duncan
    • 1
  1. 1.Biological Sciences Research Center and the Mental Health Clinical Research CenterUniversity of North Carolina School of MedicineChapel HillUSA

Personalised recommendations