Development of D1 and D2 dopamine receptors and associated second messenger systems in fetal striatal transplants.
Stereotactic implantation of fetal brain regional anlage into adult host brain ("brain transplantation") appears to be an increasingly viable strategy for therapy of neurodegenerative diseases. We have studied implantation of fetal striatum into adult striatum, previously lesioned by neurotoxic amino acid injection, as a model for transplantation therapy of Huntington's disease. The beginning of behavioral recovery to apomorphine is not apparent until 6.5 months after implantation. By 4 months after implantation cerebral blood flow through the implants appears equal to that in the intact contralateral striatum. At this time, cerebral glucose utilization is reduced in the implants but increases following apomorphine treatment. The development of D1 and D2 dopamine (DA) receptors is markedly deficient in the striatal grafts at both 4 and 6.5 months after implantation. Very little D2 radioligand binding was observed in the grafts at either time point; D1 receptors appeared in a patchy fashion by 6.5 months at densities approaching normal striatum. In situ hybridization of D2 dopamine receptor mRNA demonstrated robust hybridization signal in normal striatum and accumbens but no signal in 6.5-month-old striatal grafts. Adenylate cyclase (AC) activity, examined with high-affinity [3H]forskolin binding, also appeared in patches similar to D1 receptors at 6.5 months. In contrast, protein kinase C activity, labeled with [3H]phorbol ester, was very apparent in the grafts at both time points. Higher and generally homogenous densities of muscarinic cholinergic receptors, assessed with [3H]QNB binding, develop in the grafts, but there appear to be few functioning cholinergic terminals, as measured by [3H]hemicholinium binding.(ABSTRACT TRUNCATED AT 250 WORDS)
Helm
G A
GA
Department of Neurological Surgery, University of Virginia School of Medicine, Charlottesville 22908.
Robertson
M W
MW
Jallo
G I
GI
Simmons
N
N
Bennett
J P
JP
D000109:Acetylcholine / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal; D002560:Cerebrovascular Circulation; D003342:Corpus Striatum / Q000098:blood supply / Q000196:embryology* / Q000378:metabolism; D005260:Female; D016332:Fetal Tissue Transplantation; D009693:Nucleic Acid Hybridization; D012313:RNA; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000235:genetics / Q000378:metabolism*; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D015290:Second Messenger Systems
D012333:RNA, Messenger; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D012313:RNA; D000262:Adenylyl Cyclases; D001058:Apomorphine; D000109:Acetylcholine