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.
Subject(s)
Cyclic AMP Response Element-Binding Protein/drug effects , Dopamine Agents/pharmacology , Levodopa/pharmacology , Self-Injurious Behavior/physiopathology , p38 Mitogen-Activated Protein Kinases/drug effects , Animals , Animals, Newborn , Axotomy , Blotting, Western , Brain/drug effects , Brain/metabolism , Chromatography, High Pressure Liquid , Cyclic AMP Response Element-Binding Protein/metabolism , Dopamine/metabolism , Enzyme Activation/drug effects , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D1/metabolism , Self-Injurious Behavior/metabolism , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
The present study examined the effects of postnatal dopamine (DA) receptor stimulation on enkephalin (Met5-enkephalin; ME) and tachykinin (substance P; SP) systems of basal ganglia of rats, lesioned as neonates with 6-hydroxydopamine (6-OHDA, intracisternally) on the third postnatal day. D1 agonist, SKF-38393 or D2 agonist, LY-171555 (also known as quinpirole) was administered s.c. twice daily for 14 days, beginning 24 h after 6-OHDA administration. The animals were sacrificed at 60 days of age, and the concentrations of striatal DA, SP, and ME were determined by HPLC or radioimmunoassay. As expected, 6-OHDA induced a severe loss of DA, an increase in ME, and a decrease in SP. SKF-38393, but not, quinpirole significantly reversed the lesion-induced changes in ME and SP levels. The results indicate an important role for D1 receptors in the postnatal development of ME and SP systems in the striatum. These studies are relevant to our further understanding of potential early interventions in the progression and expression of DA deficiency states such as Parkinsonism and Lesch-Nyhan disease.
