title: The 5-hydroxytryptamine4 receptor agonists prucalopride and PRX-03140 increase acetylcholine and histamine levels in the rat prefrontal cortex and the power of stimulated hippocampal θ oscillations.
abstract: 5-Hydroxytryptamine (5-HT)(4) receptor agonists reportedly stimulate brain acetylcholine (ACh) release, a property that might provide a new pharmacological approach for treating cognitive deficits associated with Alzheimer's disease. The purpose of this study was to compare the binding affinities, functional activities, and effects on neuropharmacological responses associated with cognition of two highly selective 5-HT(4) receptor agonists, prucalopride and 6,7-dihydro-4-hydroxy-7-isopropyl-6-oxo-N-[3-(piperidin-1-yl)propyl]thieno[2,3-b]pyridine-5-carboxamide (PRX-03140). In vitro, prucalopride and PRX-03140 bound to native rat brain 5-HT(4) receptors with K(i) values of 30 nM and 110 nM, respectively, and increased cAMP production in human embryonic kidney-293 cells expressing recombinant rat 5-HT(4) receptors. In vivo receptor occupancy studies established that prucalopride and PRX-03140 were able to penetrate the brain and bound to 5-HT(4) receptors in rat brain, achieving 50% receptor occupancy at free brain exposures of 330 nM and 130 nM, respectively. Rat microdialysis studies revealed that prucalopride maximally increased ACh and histamine levels in the prefrontal cortex at 5 and 10 mg/kg, whereas PRX-03140 significantly increased cortical histamine levels at 50 mg/kg, failing to affect ACh release at doses lower than 150 mg/kg. In combination studies, donepezil-induced increases in cortical ACh levels were potentiated by prucalopride and PRX-03140. Electrophysiological studies in rats demonstrated that both compounds increased the power of brainstem-stimulated hippocampal θ oscillations at 5.6 mg/kg. These findings show for the first time that the 5-HT(4) receptor agonists prucalopride and PRX-03140 can increase cortical ACh and histamine levels, augment donepezil-induced ACh increases, and increase stimulated-hippocampal θ power, all neuropharmacological parameters consistent with potential positive effects on cognitive processes.
authors.affiliation: Neuroscience Research Unit, Pfizer Global Research and Development, Eastern Point Rd., Groton, CT 06340, USA. david.e.johnson@pfizer.com
authors.forename: David E
authors.initials: DE
authors.lastname: Johnson
authors.forename: Elena
authors.initials: E
authors.lastname: Drummond
authors.forename: Sarah
authors.initials: S
authors.lastname: Grimwood
authors.forename: Aarti
authors.initials: A
authors.lastname: Sawant-Basak
authors.forename: Emily
authors.initials: E
authors.lastname: Miller
authors.forename: Elaine
authors.initials: E
authors.lastname: Tseng
authors.forename: Laura L
authors.initials: LL
authors.lastname: McDowell
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Vanase-Frawley
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Fisher
authors.forename: David M
authors.initials: DM
authors.lastname: Rubitski
authors.forename: Kim J
authors.initials: KJ
authors.lastname: Stutzman-Engwall
authors.forename: Robin T
authors.initials: RT
authors.lastname: Nelson
authors.forename: Weldon E
authors.initials: WE
authors.lastname: Horner
authors.forename: Roxanne R
authors.initials: RR
authors.lastname: Gorczyca
authors.forename: Mihaly
authors.initials: M
authors.lastname: Hajos
authors.forename: Chester J
authors.initials: CJ
authors.lastname: Siok
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D019540:Area Under Curve; D001572:Benzofurans / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004569:Electroencephalography; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006632:Histamine / Q000378:metabolism*; D006801:Humans; D008297:Male; D017551:Microdialysis; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism; D012701:Serotonin / Q000737:chemistry / Q000378:metabolism; D058828:Serotonin 5-HT4 Receptor Agonists / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: C525011:6,7-dihydro-4-hydroxy-7-isopropyl-6-oxo-N-(3-(piperidin-1-yl)propyl)thieno(2,3-b)pyridine-5-carboxamide; D001572:Benzofurans; D011728:Pyridones; D058828:Serotonin 5-HT4 Receptor Agonists; D013876:Thiophenes; C406662:prucalopride; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin; D006632:Histamine; D000109:Acetylcholine