Dopamine receptor-mediated regulation of striatal cholinergic activity: positron emission tomography studies with norchloro[18F]fluoroepibatidine.
Large numbers of in vitro studies and microdialysis studies suggest that dopaminergic regulation of striatal acetylcholine (ACh) output is via inhibitory dopamine D2 receptors and stimulatory dopamine D1 receptors. Questions remain as to the relative predominance of dopamine D2 versus D1 receptor modulation of striatal ACh output under physiological conditions. Using positron emission tomography, we first demonstrate that norchloro[18F]fluoroepibatidine ([18F]NFEP), a selective nicotinic ACh receptor (nAChR) ligand, was sensitive to changes of striatal ACh concentration. We then examined the effect of quinpirole (D2 agonist), raclopride (D2 antagonist), SKF38393 (D1 agonist), and SCH23390 (D1 antagonist) on striatal binding of [18F]NFEP in the baboon. Pretreatment with quinpirole increased the striatum (ST) to cerebellum (CB) ratio by 26+/-6%, whereas pretreatment with raclopride decreased the ST/CB ratio by 22+/-2%. The ratio of the distribution volume of [18F]NFEP in striatum to that in cerebellum, which corresponds to (Bmax/K(D)) + 1 (index for nAChR availability), also showed a significant increase (29 and 20%; n = 2) and decrease (20+/-3%; n = 3) after pretreatment with quinpirole and raclopride, respectively. However, both the D1 agonist and antagonist had no significant effect. This suggests that under physiological conditions the predominant influence of endogenous dopamine on striatal ACh output is dopamine D2, not D1, receptor-mediated.
Ding
Y S
YS
Chemistry Department, Brookhaven National Laboratory, Upton, New York 11973-5000, USA. ding@bnl.gov
Logan
J
J
Bermel
R
R
Garza
V
V
Rice
O
O
Fowler
J S
JS
Volkow
N D
ND
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000109:Acetylcholine / Q000502:physiology*; D000818:Animals; D001549:Benzamides; D001552:Benzazepines / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003342:Corpus Striatum / Q000737:chemistry / Q000000981:diagnostic imaging / Q000502:physiology*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D005260:Female; D005462:Fluorine Radioisotopes; D010215:Papio; D010830:Physostigmine / Q000494:pharmacology; D011725:Pyridines; D020891:Raclopride / Q000494:pharmacology; D011869:Radioligand Assay; D019275:Radiopharmaceuticals; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D014055:Tomography, Emission-Computed
D001549:Benzamides; D001552:Benzazepines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002800:Cholinesterase Inhibitors; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D005462:Fluorine Radioisotopes; D011725:Pyridines; D019275:Radiopharmaceuticals; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C115362:fluoronorchloroepibatidine; D020891:Raclopride; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D010830:Physostigmine; D000109:Acetylcholine