The CRF-like peptide urocortin greatly attenuates loss of extracellular striatal dopamine in rat models of Parkinson's disease by activating CRF(1) receptors.
We have recently observed that the corticotrophin releasing factor (CRF) related peptide urocortin reverses key features of nigrostriatal damage in two paradigms of Parkinson's disease. Here we have studied whether these effects are supported by a retention of striatal basal and evoked extracellular dopamine and the receptor(s) that may mediate this effect. Fourteen days following stereotaxic injections of 6-hydroxydopamine (6-OHDA) or lipopolysaccharide (LPS) and urocortin, extracellular dopamine levels in striata ipsilateral to injection sites of 6-OHDA/LPS and urocortin treated rats were comparable with sham injected rats, whilst rats given 6-OHDA/LPS and vehicle had considerably lower dopamine levels. Striatal dopamine levels in animals where urocortin injection was delayed by seven days were only modestly decreased compared to animals receiving 6-OHDA/LPS and urocortin concomitantly. Additionally, the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were also preserved in dialysates from urocortin treated rats. The effects of urocortin were entirely blocked by the non-selective CRF receptor antagonist alpha-helical CRF as well as the selective CRF(1) antagonist NBI 27914 and were not replicated by the selective CRF(2) ligand urocortin III. In the substantia nigra tissue dopamine changes mirrored those seen in striatal extracellular dopamine. Our data strongly suggest that urocortin is capable of maintaining adequate nigrostriatal function in vivo via CRF(1) receptors following. neurotoxic challenge.
Abuirmeileh
Amjad
A
Department of Pharmacology, The School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK.
Harkavyi
Alexander
A
Kingsbury
Ann
A
Lever
Rebecca
R
Whitton
Peter S
PS
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D008297:Male; D017551:Microdialysis; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054832:Urocortins / Q000494:pharmacology*; D000099052:CRF Receptor, Type 1
C101531:CRF receptor type 2; D008024:Ligands; D018696:Neuroprotective Agents; D018019:Receptors, Corticotropin-Releasing Hormone; D054832:Urocortins; D000099052:CRF Receptor, Type 1