L-DOPA-induced activation of striatal p38MAPK and CREB in neonatal dopaminergic denervated rat: relevance to self-injurious behavior.
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.
Sivam
Subbiah P
SP
Department of Pharmacology and Toxicology, Indiana University School of Medicine-Northwest, Gary, IN 46408, USA. ssivam@iun.edu
Pugazhenthi
Subbiah
S
Pugazhenthi
Vidya
V
Brown
Heath
H
D000818:Animals; D000831:Animals, Newborn; D019771:Axotomy; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D007980:Levodopa / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D016728:Self-Injurious Behavior / Q000378:metabolism / Q000503:physiopathology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D015259:Dopamine Agents; D017447:Receptors, Dopamine D1; D007980:Levodopa; D048051:p38 Mitogen-Activated Protein Kinases; D004298:Dopamine