SKF83959 exhibits biochemical agonism by stimulating [ 35S]GTPγS binding and phosphoinositide hydrolysis in rat and monkey brain

• Published in: Neuropharmacology 2001-05, Vol.40 (6), p.826-837
• Main Authors: Panchalingam, Sandra, Undie, Ashiwel S
• Format: Article
• Language: English
• Subjects: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine - analogs & derivatives; 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine - pharmacology; Animals; Anticonvulsants. Antiepileptics. Antiparkinson agents; benzazepine; Benzazepines - metabolism; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Cytidine Diphosphate Diglycerides - metabolism; D 1-like receptors; Dopamine - metabolism; Dopamine Agonists - pharmacology; Dopamine-sensitive phospholipase C; Dose-Response Relationship, Drug; Female; GTPγS binding; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Inositol Phosphates - metabolism; Macaca mulatta; Male; Medical sciences; Monkey; Neuropharmacology; Parkinson's disease; Pharmacology. Drug treatments; Phosphatidylinositides; Phosphatidylinositols - metabolism; phosphoinositides; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1 - agonists; Receptors, Dopamine D1 - metabolism
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/S0028-3908(01)00011-9

SKF83959, a benzazepine with high affinity for aminergic receptors, elicits behaviors such as grooming and vacuous chewing that are characteristic of dopamine D 1-like receptor stimulation in rodents. Unlike classical D 1 agonists, however, SKF83959 does not stimulate adenylyl cyclase. Knowing that some D 1-like receptors are coupled to phospholipase C-mediated signaling cascades in the brain, the present study aimed to determine whether SKF83959 exhibits an agonistic action at the biochemical level and also whether this benzazepine can modulate phosphoinositide hydrolysis in a manner that would be consistent with the behavioral effects of the drug. Similar to dopamine and the selective D 1-like agonist SKF38393, SKF83959 competitively displaced the receptor binding of [ 3H]dopamine in an agonist-like manner, significantly stimulated [ 35S]guanosine-5′- O-(3-thio)triphosphate binding, and potently enhanced phospholipase C-mediated phosphoinositide hydrolysis in rat and monkey brain tissues. SKF83959 was generally more potent than SKF38393, whereas SKF38393 consistently exhibited greater pharmacological efficacy. These findings may implicate a role for the phospholipase C signaling cascade in the agonistic behavioral and antiparkinsonian activity of SKF83959. Dopamine-sensitive phospholipase C signaling should probably be considered in subsequent formulations of mechanisms and models of dopaminergic function in the normal or diseased brain.