L-DOPA-induced activation of striatal p38MAPK and CREB in neonatal dopaminergic denervated rat

Relevance to self-injurious behavior

Subbiah Sivam, Subbiah Pugazhenthi, Vidya Pugazhenthi, Heath Brown

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

The destruction of nigrostriatal dopaminergic neurons with 6-hydroxydopamine (6OHDA) during the neonatal period results in dopamine (DA) loss and susceptibility for self-injurious behavior (SIB) when challenged with L-dihydroxyphenylalanine (L-DOPA), via a supersensitive D1 receptor-mediated mechanism. However, there are no changes in D1 receptor binding or mRNA levels, suggesting a potential postreceptor signaling mechanism(s). Here, we examined whether L-DOPA-induced SIB is associated with altered MAPK signaling (p38MAPK, ERK1/2, and JNK) and their nuclear target, CREB. Neonatal dopaminergic lesioned animals were challenged, as adults, with L-DOPA, observed for SIB for 6 hr, and then sacrificed. The data were grouped as follows: control, lesioned rats without SIB (SIB-), and lesioned rats that were positive for SIB (SIB+). HPLC analysis of striatal extracts revealed a more significant loss of DA and an increase of serotonin in the SIB+ than in the SIB- group. The striatal levels of TH protein were severely decreased, but D1 receptor levels were unaltered in the lesioned groups. These results confirm and extend previous studies indicating that SIB is associated with a near-total loss of DA and TH, an increase in serotonin, and no change in D1 receptor levels. The present studies further revealed that the levels of active phosphorylated forms of p38MAPK and CREB were significantly higher in the SIB+ group than in the SIB- group in the striatum, but not in cortex or olfactory tubercle. The results indicate an induction of striatal p38MAPK and an activation of its nuclear target, CREB, as additional mechanisms in the genesis of L-DOPA-induced SIB.

Original languageEnglish
Pages (from-to)339-349
Number of pages11
JournalJournal of Neuroscience Research
Volume86
Issue number2
DOIs
StatePublished - Feb 1 2008

Fingerprint

Corpus Striatum
Self-Injurious Behavior
Dihydroxyphenylalanine
Dopamine
Serotonin
Oxidopamine
Dopaminergic Neurons

Keywords

  • 6-hydroxydopamine
  • CREB
  • Dopamine
  • L-DOPA
  • p38MAPK
  • Self-injurious behavior

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

L-DOPA-induced activation of striatal p38MAPK and CREB in neonatal dopaminergic denervated rat : Relevance to self-injurious behavior. / Sivam, Subbiah; Pugazhenthi, Subbiah; Pugazhenthi, Vidya; Brown, Heath.

In: Journal of Neuroscience Research, Vol. 86, No. 2, 01.02.2008, p. 339-349.

Research output: Contribution to journalArticle

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abstract = "The destruction of nigrostriatal dopaminergic neurons with 6-hydroxydopamine (6OHDA) during the neonatal period results in dopamine (DA) loss and susceptibility for self-injurious behavior (SIB) when challenged with L-dihydroxyphenylalanine (L-DOPA), via a supersensitive D1 receptor-mediated mechanism. However, there are no changes in D1 receptor binding or mRNA levels, suggesting a potential postreceptor signaling mechanism(s). Here, we examined whether L-DOPA-induced SIB is associated with altered MAPK signaling (p38MAPK, ERK1/2, and JNK) and their nuclear target, CREB. Neonatal dopaminergic lesioned animals were challenged, as adults, with L-DOPA, observed for SIB for 6 hr, and then sacrificed. The data were grouped as follows: control, lesioned rats without SIB (SIB-), and lesioned rats that were positive for SIB (SIB+). HPLC analysis of striatal extracts revealed a more significant loss of DA and an increase of serotonin in the SIB+ than in the SIB- group. The striatal levels of TH protein were severely decreased, but D1 receptor levels were unaltered in the lesioned groups. These results confirm and extend previous studies indicating that SIB is associated with a near-total loss of DA and TH, an increase in serotonin, and no change in D1 receptor levels. The present studies further revealed that the levels of active phosphorylated forms of p38MAPK and CREB were significantly higher in the SIB+ group than in the SIB- group in the striatum, but not in cortex or olfactory tubercle. The results indicate an induction of striatal p38MAPK and an activation of its nuclear target, CREB, as additional mechanisms in the genesis of L-DOPA-induced SIB.",
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AB - The destruction of nigrostriatal dopaminergic neurons with 6-hydroxydopamine (6OHDA) during the neonatal period results in dopamine (DA) loss and susceptibility for self-injurious behavior (SIB) when challenged with L-dihydroxyphenylalanine (L-DOPA), via a supersensitive D1 receptor-mediated mechanism. However, there are no changes in D1 receptor binding or mRNA levels, suggesting a potential postreceptor signaling mechanism(s). Here, we examined whether L-DOPA-induced SIB is associated with altered MAPK signaling (p38MAPK, ERK1/2, and JNK) and their nuclear target, CREB. Neonatal dopaminergic lesioned animals were challenged, as adults, with L-DOPA, observed for SIB for 6 hr, and then sacrificed. The data were grouped as follows: control, lesioned rats without SIB (SIB-), and lesioned rats that were positive for SIB (SIB+). HPLC analysis of striatal extracts revealed a more significant loss of DA and an increase of serotonin in the SIB+ than in the SIB- group. The striatal levels of TH protein were severely decreased, but D1 receptor levels were unaltered in the lesioned groups. These results confirm and extend previous studies indicating that SIB is associated with a near-total loss of DA and TH, an increase in serotonin, and no change in D1 receptor levels. The present studies further revealed that the levels of active phosphorylated forms of p38MAPK and CREB were significantly higher in the SIB+ group than in the SIB- group in the striatum, but not in cortex or olfactory tubercle. The results indicate an induction of striatal p38MAPK and an activation of its nuclear target, CREB, as additional mechanisms in the genesis of L-DOPA-induced SIB.

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