D1 Dopamine receptor-mediated substance P depletion in the striatonigral neurons of rats subjected to neonatal dopaminergic denervation: implications for self-injurious behavior

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Abstract

The present study examined the influences of dopamine (DA) receptor stimulation on enkephalin (Met5-enkephalin; ME) and tachykinin (substance P; SP) systems of basal ganglia of Sprague-Dawley rats, lesioned as neonates with 6-hydroxydopamine (6-OHDA). It has been proposed that the neonatal 6-OHDA-lesioned rat could serve as a model for the DA deficiency and self-injurious behavior (SIB) observed in the childhood neurological disorder, Lesch-Nyhan syndrome. In agreement with earlier work, the present study found that the neonatal 6-OHDA treatment at 3 days of age, reduced DA and caused an increase in ME and a decrease in SP content in the striatum and substantia nigra, when tested as adults. Administration of the DA precursor, l-dihydroxyphenylalanine (l-DOPA), to lesioned animals, induced SIB; increased DA and DOPAC levels; produced a greater decrease (-64%) in SP levels in the striatum and substantia nigra than was observed with lesion alone (-28%). The l-DOPA-induced decrease in SP levels and the SIB observed in the lesioned animals were blocked by pretreatment with the D1 receptor antagonist, SCH-23390. Moreover, administration of the D1 receptor agonist, SKF-38393, but not the D2 agonist, LY-171555, to lesioned animals mimicked the l-DOPA responses in all respects, except that the agonists did not alter DA or DOPAC levels. None of the DA agonists or antagonists treatments affected lesion-induced increase in ME levels in the striatum. These results indicate for the first time, that SIB precipitated by DA agonists in neonatal dopaminergic denervated animals, is associated with a marked and selective decrease in SP in the striatonigral SP neurons. This process has two components: (a) a retarded development of the SP system due to neonatal dopaminergic denervation; and (b) a depletion of the remaining SP, presumably by enhanced release due to D1 DA receptor-mediated activation of striatonigral SP neurons.

Original languageEnglish
Pages (from-to)119-130
Number of pages12
JournalBrain Research
Volume500
Issue number1-2
DOIs
StatePublished - Oct 23 1989

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Self-Injurious Behavior
Dopamine D1 Receptors
Denervation
Substance P
Oxidopamine
Dopamine
Dihydroxyphenylalanine
Neurons
3,4-Dihydroxyphenylacetic Acid
Enkephalins
Dopamine Agonists
Substantia Nigra
4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrzolo(3,4-g)quinoline
Lesch-Nyhan Syndrome
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
Tachykinins
Dopamine Antagonists
Dopamine Receptors
Basal Ganglia
Nervous System Diseases

Keywords

  • 6-Hydroxydopamine
  • Dopamine deficiency
  • High-performance liquid chromatography
  • l-Dihydroxyphenylalanine
  • Lesch-Nyhan syndrome
  • LY-171555
  • Met-enkephalin
  • Radioimmunoassay
  • SCH-23390
  • Self-injurious behavior
  • SKF-38393
  • Striatum
  • Substance P
  • Substantia nigra

ASJC Scopus subject areas

  • Developmental Biology
  • Molecular Biology
  • Clinical Neurology
  • Neuroscience(all)

Cite this

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title = "D1 Dopamine receptor-mediated substance P depletion in the striatonigral neurons of rats subjected to neonatal dopaminergic denervation: implications for self-injurious behavior",
abstract = "The present study examined the influences of dopamine (DA) receptor stimulation on enkephalin (Met5-enkephalin; ME) and tachykinin (substance P; SP) systems of basal ganglia of Sprague-Dawley rats, lesioned as neonates with 6-hydroxydopamine (6-OHDA). It has been proposed that the neonatal 6-OHDA-lesioned rat could serve as a model for the DA deficiency and self-injurious behavior (SIB) observed in the childhood neurological disorder, Lesch-Nyhan syndrome. In agreement with earlier work, the present study found that the neonatal 6-OHDA treatment at 3 days of age, reduced DA and caused an increase in ME and a decrease in SP content in the striatum and substantia nigra, when tested as adults. Administration of the DA precursor, l-dihydroxyphenylalanine (l-DOPA), to lesioned animals, induced SIB; increased DA and DOPAC levels; produced a greater decrease (-64{\%}) in SP levels in the striatum and substantia nigra than was observed with lesion alone (-28{\%}). The l-DOPA-induced decrease in SP levels and the SIB observed in the lesioned animals were blocked by pretreatment with the D1 receptor antagonist, SCH-23390. Moreover, administration of the D1 receptor agonist, SKF-38393, but not the D2 agonist, LY-171555, to lesioned animals mimicked the l-DOPA responses in all respects, except that the agonists did not alter DA or DOPAC levels. None of the DA agonists or antagonists treatments affected lesion-induced increase in ME levels in the striatum. These results indicate for the first time, that SIB precipitated by DA agonists in neonatal dopaminergic denervated animals, is associated with a marked and selective decrease in SP in the striatonigral SP neurons. This process has two components: (a) a retarded development of the SP system due to neonatal dopaminergic denervation; and (b) a depletion of the remaining SP, presumably by enhanced release due to D1 DA receptor-mediated activation of striatonigral SP neurons.",
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author = "Subbiah Sivam",
year = "1989",
month = "10",
day = "23",
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pages = "119--130",
journal = "Brain Research",
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number = "1-2",

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T1 - D1 Dopamine receptor-mediated substance P depletion in the striatonigral neurons of rats subjected to neonatal dopaminergic denervation

T2 - implications for self-injurious behavior

AU - Sivam, Subbiah

PY - 1989/10/23

Y1 - 1989/10/23

N2 - The present study examined the influences of dopamine (DA) receptor stimulation on enkephalin (Met5-enkephalin; ME) and tachykinin (substance P; SP) systems of basal ganglia of Sprague-Dawley rats, lesioned as neonates with 6-hydroxydopamine (6-OHDA). It has been proposed that the neonatal 6-OHDA-lesioned rat could serve as a model for the DA deficiency and self-injurious behavior (SIB) observed in the childhood neurological disorder, Lesch-Nyhan syndrome. In agreement with earlier work, the present study found that the neonatal 6-OHDA treatment at 3 days of age, reduced DA and caused an increase in ME and a decrease in SP content in the striatum and substantia nigra, when tested as adults. Administration of the DA precursor, l-dihydroxyphenylalanine (l-DOPA), to lesioned animals, induced SIB; increased DA and DOPAC levels; produced a greater decrease (-64%) in SP levels in the striatum and substantia nigra than was observed with lesion alone (-28%). The l-DOPA-induced decrease in SP levels and the SIB observed in the lesioned animals were blocked by pretreatment with the D1 receptor antagonist, SCH-23390. Moreover, administration of the D1 receptor agonist, SKF-38393, but not the D2 agonist, LY-171555, to lesioned animals mimicked the l-DOPA responses in all respects, except that the agonists did not alter DA or DOPAC levels. None of the DA agonists or antagonists treatments affected lesion-induced increase in ME levels in the striatum. These results indicate for the first time, that SIB precipitated by DA agonists in neonatal dopaminergic denervated animals, is associated with a marked and selective decrease in SP in the striatonigral SP neurons. This process has two components: (a) a retarded development of the SP system due to neonatal dopaminergic denervation; and (b) a depletion of the remaining SP, presumably by enhanced release due to D1 DA receptor-mediated activation of striatonigral SP neurons.

AB - The present study examined the influences of dopamine (DA) receptor stimulation on enkephalin (Met5-enkephalin; ME) and tachykinin (substance P; SP) systems of basal ganglia of Sprague-Dawley rats, lesioned as neonates with 6-hydroxydopamine (6-OHDA). It has been proposed that the neonatal 6-OHDA-lesioned rat could serve as a model for the DA deficiency and self-injurious behavior (SIB) observed in the childhood neurological disorder, Lesch-Nyhan syndrome. In agreement with earlier work, the present study found that the neonatal 6-OHDA treatment at 3 days of age, reduced DA and caused an increase in ME and a decrease in SP content in the striatum and substantia nigra, when tested as adults. Administration of the DA precursor, l-dihydroxyphenylalanine (l-DOPA), to lesioned animals, induced SIB; increased DA and DOPAC levels; produced a greater decrease (-64%) in SP levels in the striatum and substantia nigra than was observed with lesion alone (-28%). The l-DOPA-induced decrease in SP levels and the SIB observed in the lesioned animals were blocked by pretreatment with the D1 receptor antagonist, SCH-23390. Moreover, administration of the D1 receptor agonist, SKF-38393, but not the D2 agonist, LY-171555, to lesioned animals mimicked the l-DOPA responses in all respects, except that the agonists did not alter DA or DOPAC levels. None of the DA agonists or antagonists treatments affected lesion-induced increase in ME levels in the striatum. These results indicate for the first time, that SIB precipitated by DA agonists in neonatal dopaminergic denervated animals, is associated with a marked and selective decrease in SP in the striatonigral SP neurons. This process has two components: (a) a retarded development of the SP system due to neonatal dopaminergic denervation; and (b) a depletion of the remaining SP, presumably by enhanced release due to D1 DA receptor-mediated activation of striatonigral SP neurons.

KW - 6-Hydroxydopamine

KW - Dopamine deficiency

KW - High-performance liquid chromatography

KW - l-Dihydroxyphenylalanine

KW - Lesch-Nyhan syndrome

KW - LY-171555

KW - Met-enkephalin

KW - Radioimmunoassay

KW - SCH-23390

KW - Self-injurious behavior

KW - SKF-38393

KW - Striatum

KW - Substance P

KW - Substantia nigra

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DO - 10.1016/0006-8993(89)90305-3

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