Neonatal dopamine lesion in the rat results in enhanced adenylate cyclase activity without altering dopamine receptor binding or dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein (DARPP-32) immunoreactivity.
Newborn male Sprague-Dawley rats were treated neonatally with an intracisternal injection of 75 micrograms 6-hydroxydopamine (6-OHDA) following desipramine pretreatment in order to induce a permanent selective dopamine (DA) lesion. At 60-70 days of age a massive loss of tyrosine hydroxylase (TH) immunoreactive (IR) cells was seen in substantia nigra. The TH-IR terminal density was reduced by 92% in striatum, 77% in nucleus accumbens and by 72% in tuberculum olfactorium. Quantitative autoradiography using 3H-SCH-23390 and 3H-spiperone did not reveal any alteration of DA D1 and D2 receptor binding in the denervated regions studied. Furthermore, no change in the Bmax or Kd of 3H-SCH-23390 or 3H-spiperone in vitro binding was observed in membrane preparations of striatum following the neonatal DA lesion. Basal and DA-stimulated accumulation of cAMP was increased in striatal membrane preparations of the neonatally DA-lesioned rats. No alteration of the immunoreactivity of the D1 receptor associated phosphoprotein dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein (DARPP-32), was observed as visualized using quantitative immunohistochemistry. Thus, neonatal DA lesions seem to induce a selective functional supersensitivity reflected by an enhanced activity of D1 receptor-coupled adenylate cyclase, without any alteration in the number of affinity of D1 and D2 receptor sites. Furthermore, the appearance of DARPP-32 seems to be independent of intact DA input during development.
Luthman
J
J
Department of Histology and Neurobiology, Karolinska Institute, Stockholm, Sweden.
Lindqvist
E
E
Young
D
D
Cowburn
R
R
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001479:Basal Ganglia / Q000378:metabolism; D001552:Benzazepines / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D000242:Cyclic AMP / Q000494:pharmacology*; D003891:Desipramine / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D006892:Hydroxydopamines / Q000494:pharmacology; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016627:Oxidopamine; D010750:Phosphoproteins; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000378:metabolism*; D013134:Spiperone / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D001552:Benzazepines; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D006892:Hydroxydopamines; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D011954:Receptors, Dopamine; D013134:Spiperone; D016627:Oxidopamine; D000242:Cyclic AMP; D014446:Tyrosine 3-Monooxygenase; D000262:Adenylyl Cyclases; D003891:Desipramine; D004298:Dopamine