Model for reduced brain dopamine in Lesch‐Nyhan syndrome and the mentally retarded: Neurobiology of neonatal‐6‐hydroxydopamine‐lesioned rats

Self-injurious behavior (SIB) remains a serious problem among the mentally retarded because no known pharmacological agents block this behavior. This symptom is especially severe in Lesch-Nyhan syndrome (LNS), a genetic disorder associated with HPRT deficiency. Because the prominent neurobiological deficit in LNS is a loss of dopaminergic neurons, reduction of dopamine with 6-hydroxydopamine (6-OHDA) in rats during their development is proposed as a model of the dopamine deficiency in LNS and in mentally retarded individuals with SIB who may have this neurotransmitter deficiency. In behavioral testing of this model, dopamine agonists that activate D1-dopamine receptors induced SIB in adult rats with neonatal 6-OHDA-dopamine lesions, a change not seen in rats lesioned as adults. SIB also has been observed when muscimol is microinjected into the substantia nigra reticulata (SNR) of the neonatal-6-OHDA lesioned rats. D1-dopamine antagonists, as well as NMDA antagonists, have been found to block the SIB induced by L-DOPA in these neonatally lesioned rats. In addition to the reduced dopamine, LNS patients also have an increased striatal serotonin content, as do rats neonatally lesioned with 6-OHDA. Activation of serotonergic receptors with m-chlorophenylpiperazine has increased oral activity in neonatal-6-OHDA-lesioned rats; destruction of serotonin-containing neurons has blocked this effect caused by a D1-dopamine agonist. These data suggest that serotonin and corresponding serotonin receptors contribute to dysfunctions in the neonatal-6-OHDA-lesioned model. This work provides background support for the hypothesis that neonatal reduction of dopamine results in increased vulnerability to SIB as a result of adaptation within a neural circuit in the brain involving D1-dopamine receptors, the SNR, and glutamate-and serotonin-containing neurons. Functional mapping in neonatally lesioned rats using 14C-2-deoxyglucose (2-DG) uptake and Fos-like immunoreactivity (Fos-L1) has implicated the SNR, entopeduncular nucleus, globus pallidus, and subthalamic nucleus in the action of a D1-dopamine agonist. In addition, a generalized increase in Fos-L1, but not 2-DG uptake, is also induced in the striatum by a D1-dopamine agonist. The action of CGS-19755 and MK-801, NMDA antagonists, on the accumulation of Fos-L1 in the striatum induced by a D1-dopamine agonist also has been examined. Whereas CGS-19755 blocked the increase in striatal Fos-L1 induced by the D1-dopamine agonist, MK-801 did not. Because both drugs block SIB in the rat model, these findings suggest that the glutamatergic neuronal system that contributes to SIB is not associated with the striatum. The research being undertaken with the model of neonatal dopa-mine reduction may suggest new therapeutic approaches to the SIB observed in developmental disorders of unknown etiology, as well as the SIB associated with LNS. © 1995 Wiley-Liss, Inc.

[1]  D. Joel,et al.  The organization of the basal ganglia-thalamocortical circuits: Open interconnected rather than closed segregated , 1994, Neuroscience.

[2]  A M Graybiel,et al.  The basal ganglia and adaptive motor control. , 1994, Science.

[3]  S. Butcher,et al.  Differential effects of competitive (CGS19755) and non-competitive (MK 801) NMDA receptor antagonists upon local cerebral blood flow and local cerebral glucose utilisation in the rat , 1994, Brain Research.

[4]  Micaela Morelli,et al.  Modulatory functions of neurotransmitters in the striatum: ACh/dopamine/NMDA interactions , 1994, Trends in Neurosciences.

[5]  T. Friedmann,et al.  Dopamine deficiency in a genetic mouse model of Lesch-Nyhan disease , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[6]  K. Perry,et al.  Age-dependence of a 6-hydroxydopamine lesion on SKF 38393- and m-chlorophenylpiperazine-induced oral activity responses of rats. , 1993, Brain research. Developmental brain research.

[7]  N. Neff,et al.  GM1 ganglioside improves dopaminergic markers of rat mesencephalic cultures treated with MPP+ , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[8]  T. Engber,et al.  N-methyl-d-aspartate receptor blockade differentially modifies regional cerebral metabolic responses to D1 and D2 dopamine agonists in rats with a unilateral 6-hydroxydopamine lesion , 1993, Neuroscience.

[9]  J. Lile,et al.  GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. , 1993, Science.

[10]  G. Breese,et al.  Evidence for involvement of brain dopamine and other mechanisms in the behavioral action of the N-methyl-D-aspartic acid antagonist MK-801 in control and 6-hydroxydopamine-lesioned rats. , 1993, The Journal of pharmacology and experimental therapeutics.

[11]  T. Hökfelt,et al.  Differential expression of acidic and basic FGF in the rat substantia nigra during development. , 1992, Neuroreport.

[12]  H. Jinnah,et al.  Functional analysis of brain dopamine systems in a genetic mouse model of Lesch-Nyhan syndrome. , 1992, The Journal of pharmacology and experimental therapeutics.

[13]  G. Breese,et al.  Comparison of the D1-dopamine agonists SKF-38393 and A-68930 in neonatal 6-hydroxydopamine-lesioned rats: behavioral effects and induction of c-fos-like immunoreactivity. , 1992, The Journal of pharmacology and experimental therapeutics.

[14]  K. Perry,et al.  Supersensitization of the oral response to SKF 38393 in neonatal 6-OHDA-lesioned rats is mediated through a serotonin system. , 1992, The Journal of pharmacology and experimental therapeutics.

[15]  L. Wallace,et al.  AMPA/kainic acid glutamate receptor antagonism in the zona incerta dorsal to the subthalamic nucleus inhibits amphetamine-induced stereotypy but not locomotor activity , 1992, Brain Research.

[16]  F. Gage,et al.  Amphetamine-induced behavioral phenotype in a hypoxanthine-guanine phosphoribosyltransferase-deficient mouse model of Lesch-Nyhan syndrome. , 1991, Behavioral neuroscience.

[17]  L. Noble,et al.  MK‐801 and ketamine induce heat shock protein HSP72 in injured neurons in posterior cingulate and retrosplenial cortex , 1991, Annals of neurology.

[18]  L. Wallace,et al.  Activation of AMPA/kainic acid glutamate receptors in the zona incerta stimulates locomotor activity , 1991, Brain Research.

[19]  J. Ferkany,et al.  Effects of competitive N-methyl-d-aspartate antagonists on midbrain dopamine neurons: An electrophysiological and behavioral comparison to phencyclidine , 1991, Neuropharmacology.

[20]  R. Kostrzewa,et al.  Supersensitized D1 receptors mediate enhanced oral activity after neonatal 6-OHDA , 1991, Pharmacology Biochemistry and Behavior.

[21]  G. Yancopoulos,et al.  BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra , 1991, Nature.

[22]  C. Gerfen,et al.  D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. , 1990, Science.

[23]  G. Breese,et al.  A dopamine deficiency model of Lesch-Nyhan disease—the neonatal-6-OHDA-lesioned rat , 1990, Brain Research Bulletin.

[24]  F. Gage,et al.  Animal models of Lesch-Nyhan syndrome , 1990, Brain Research Bulletin.

[25]  T. Engber,et al.  Responses of substantia nigra pars reticulata neurons to GABA and SKF 38393 in 6-hydroxydopamine-lesioned rats are differentially affected by continuous and intermittent levodopa administration , 1990, Brain Research.

[26]  A. Graybiel.  Neurotransmitters and neuromodulators in the basal ganglia , 1990, Trends in Neurosciences.

[27]  G. Breese,et al.  Long-term D1-dopamine receptor sensitization in neonatal 6-OHDA-lesioned rats is blocked by an NMDA antagonist , 1990, Brain Research.

[28]  G. Fagg,et al.  Excitatory amino acid receptors in the brain: membrane binding and receptor autoradiographic approaches. , 1990, Trends in pharmacological sciences.

[29]  G. Breese,et al.  Pharmacological evaluation of SCH-12679: evidence for an in vivo antagonism of D1-dopamine receptors. , 1990, The Journal of pharmacology and experimental therapeutics.

[30]  S. Dunnett,et al.  Monoamine deficiency in a transgenic (Hprt− ) mouse model of Lesch-Nyhan syndrome , 1989, Brain Research.

[31]  R. Miller,et al.  Ifenprodil is a novel type of N-methyl-D-aspartate receptor antagonist: interaction with polyamines. , 1989, Molecular pharmacology.

[32]  T. Joh,et al.  Serotonergic innervation of the rat caudate following a neonatal 6-hydroxydopamine lesion: An anatomical, biochemical and pharmacological study , 1989, Pharmacology Biochemistry and Behavior.

[33]  J. Olney.  Excitatory amino acids and neuropsychiatrie disorders , 1989, Biological Psychiatry.

[34]  R. Dingledine,et al.  Selectivity of quinoxalines and kynurenines as antagonists of the glycine site on N-methyl-D-aspartate receptors. , 1989, Molecular pharmacology.

[35]  J. Olney,et al.  Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. , 1989, Science.

[36]  R. Mueller,et al.  Clozapine antagonism of D-1 and D-2 dopamine receptor-mediated behaviors. , 1989, European journal of pharmacology.

[37]  G. Breese,et al.  Priming of D1-dopamine receptor responses: long-lasting behavioral supersensitivity to a D1-dopamine agonist following repeated administration to neonatal 6-OHDA-lesioned rats , 1989, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[38]  M. Brecher,et al.  Phencyclidine and violence: clinical and legal issues. , 1988, Journal of clinical psychopharmacology.

[39]  R. Mcquade,et al.  Pharmacological profile of SCH39166: a dopamine D1 selective benzonaphthazepine with potential antipsychotic activity. , 1988, The Journal of pharmacology and experimental therapeutics.

[40]  S. Finger,et al.  Behavioral and neurochemical evaluation of a transgenic mouse model of Lesch-Nyhan syndrome , 1988, Journal of the Neurological Sciences.

[41]  T. Curran,et al.  Expression of c-fos protein in brain: metabolic mapping at the cellular level. , 1988, Science.

[42]  J. Jankovic,et al.  Lesch‐nyhan syndrome: A study of motor behavior and cerebrospinal fluid neurotransmitters , 1988, Annals of neurology.

[43]  G. Wooten,et al.  Selective D1 and D2 dopamine agonists differentially alter basal ganglia glucose utilization in rats with unilateral 6-hydroxydopamine substantia nigra lesions , 1987, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[44]  M. Monk,et al.  HPRT-deficient (Lesch–Nyhan) mouse embryos derived from germline colonization by cultured cells , 1987, Nature.

[45]  A. Bradley,et al.  A potential animal model for Lesch–Nyhan syndrome through introduction of HPRT mutations into mice , 1987, Nature.

[46]  G. Wooten,et al.  The effects ofl-DOPA on regional cerebral glucose utilization in rats with unilateral lesions of the substantia nigra , 1986, Brain Research.

[47]  G. Frye,et al.  Involvement of the midbrain reticular formation in self-injurious behavior, stereotyped behavior, and analgesia induced by intranigral microinjection of muscimol , 1986, Brain Research.

[48]  A. M. Snyder,et al.  Sprouting of serotoninergic afferents into striatum after dopamine‐depleting lesions in infant rats: A retrograde transport and immunocytochemical study , 1986, The Journal of comparative neurology.

[49]  G. Breese,et al.  Evidence that D-1 dopamine receptors contribute to the supersensitive behavioral responses induced by L-dihydroxyphenylalanine in rats treated neonatally with 6-hydroxydopamine. , 1985, The Journal of pharmacology and experimental therapeutics.

[50]  J. Penney,et al.  γ‐Aminobutyric Acid and Benzodiazepine Receptor Changes Induced by Unilateral 6‐Hydroxydopamine Lesions of the Medial Forebrain Bundle , 1985, Journal of neurochemistry.

[51]  M. Johnston,et al.  Lesch‐Nyhan syndrome , 1985, Neurology.

[52]  J. Walters,et al.  A physiological role for dopamine as modulator of GABA effects in substantia nigra: supersensitivity in 6-hydroxydopamine-lesioned rats. , 1984, European journal of pharmacology.

[53]  G. Breese,et al.  Neonatal-6-hydroxydopamine treatment: Model of susceptibility for self-mutilation in the lesch-nyhan syndrome , 1984, Pharmacology Biochemistry and Behavior.

[54]  J. Rojahn.  Self-injurious behavior in institutionalized, severely/profoundly retarded adults—Prevalence data and staff agreement , 1984 .

[55]  A. M. Snyder,et al.  Apparent sprouting of striatal serotonergic terminals after dopamine-depleting brain lesions in neonatal rats , 1984, Brain Research.

[56]  K A Frey,et al.  Changes in [3H]muscimol binding in substantia nigra, entopeduncular nucleus, globus pallidus, and thalamus after striatal lesions as demonstrated by quantitative receptor autoradiography , 1983, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[57]  K. Shannak,et al.  Biochemical evidence of dysfunction of brain neurotransmitters in the Lesch-Nyhan syndrome. , 1981, The New England journal of medicine.

[58]  J. A. Ricardo,et al.  Efferent connections of the subthalamic region in the rat. II. The zona incerta , 1981, Brain Research.

[59]  R. Élie,et al.  Comparison of SCH-12679 and Thioridazine in Aggressive Mental Retardates , 1980, Canadian journal of psychiatry. Revue canadienne de psychiatrie.

[60]  J. Waddington,et al.  Denervation supersensitivity in the striatonigral GABA pathway , 1978, Nature.

[61]  R. Mailman,et al.  Behavioral and prolactin responses to 5-hydroxytrytophan in rats treated during development with 5,7-dihydroxytryptamine , 1978, Brain Research.

[62]  H. Sarau,et al.  The central effects of a novel dopamine agonist. , 1978, European journal of pharmacology.

[63]  B. Cooper,et al.  An inhibitory role for brain serotonin-containing systems in the locomotor effects of d-amphetamine. , 1976, The Journal of pharmacology and experimental therapeutics.

[64]  M. Olkinuora,et al.  CLOZAPINE AND AGRANULOCYTOSIS , 1975, The Lancet.

[65]  B. Cooper,et al.  EVIDENCE FOR INVOLVEMENT OF 5‐HYDROXYTRYPTAMINE IN THE ACTIONS OF AMPHETAMINE , 1974, British journal of pharmacology.

[66]  B. Cooper,et al.  Growth and behavioral changes in developing rats treated intracisternally with 6-hydroxydopamine: evidence for involvement of brain dopamine. , 1973, The Journal of pharmacology and experimental therapeutics.

[67]  W. Nyhan.  Clinical features of the Lesch-Nyhan syndrome. , 1972, Archives of internal medicine.

[68]  G. Breese,et al.  Developmental characteristics of brain catecholamines and tyrosine hydroxylase in the rat: effects of 6‐hydroxydopamine , 1972, British journal of pharmacology.

[69]  G. Breese,et al.  Effect of 6-hydroxydopamine on brain norepinephrine and dopamine evidence for selective degeneration of catecholamine neurons. , 1970, The Journal of pharmacology and experimental therapeutics.

[70]  B. Hennen,et al.  The Lesch‐Nyhan Syndrome: Self‐Destructive Biting, Mental Retardation, Neurological Disorder and Hyperuricaemia , 1967, Developmental medicine and child neurology.

[71]  W. Nyhan,et al.  A FAMILIAL DISORDER OF URIC ACID METABOLISM AND CENTRAL NERVOUS SYSTEM FUNCTION. , 1964, The American journal of medicine.

[72]  K. Perry,et al.  Supersensitization of the oral response to SKF 38393 in neonatal 6-hydroxydopamine-lesioned rats is eliminated by neonatal 5,7-dihydroxytryptamine treatment. , 1994, The Journal of pharmacology and experimental therapeutics.

[73]  C. Cotman,et al.  The excitatory amino acid receptors: their classes, pharmacology, and distinct properties in the function of the central nervous system. , 1989, Annual review of pharmacology and toxicology.

[74]  S. Schroeder,et al.  The Neurochemical Basis of Symptoms in the Lesch-Nyhan Syndrome , 1987 .

[75]  G. Breese,et al.  Neurobiology of D1 dopamine receptors after neonatal-6-OHDA treatment: relevance to Lesch-Nyhan disease. , 1986, Advances in experimental medicine and biology.

[76]  K. Jones,et al.  Serotonergic approaches to the modification of behavior in the Lesch-Nyhan Syndrome. , 1980, Applied research in mental retardation.

[77]  G. Breese,et al.  Role of monoamine neural systems in L-dihydroxyphenylalanine-stimulated activity. , 1979, The Journal of pharmacology and experimental therapeutics.