PT  - JOURNAL ARTICLE
AU  - David E. Johnson
AU  - Elena Drummond
AU  - Sarah Grimwood
AU  - Aarti Sawant-Basak
AU  - Emily Miller
AU  - Elaine Tseng
AU  - Laura L. McDowell
AU  - Michelle A. Vanase-Frawley
AU  - Katherine E. Fisher
AU  - David M. Rubitski
AU  - Kim J. Stutzman-Engwall
AU  - Robin T. Nelson
AU  - Weldon E. Horner
AU  - Roxanne R. Gorczyca
AU  - Mihaly Hajos
AU  - Chester J. Siok
TI  - The 5-Hydroxytryptamine<sub>4</sub> Receptor Agonists Prucalopride and PRX-03140 Increase Acetylcholine and Histamine Levels in the Rat Prefrontal Cortex and the Power of Stimulated Hippocampal θ Oscillations
AID  - 10.1124/jpet.112.192351
DP  - 2012 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 681--691
VI  - 341
IP  - 3
4099  - http://jpet.aspetjournals.org/content/341/3/681.short
4100  - http://jpet.aspetjournals.org/content/341/3/681.full
SO  - J Pharmacol Exp Ther2012 Jun 01; 341
AB  - 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-HT4 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-HT4 receptors with Ki values of 30 nM and 110 nM, respectively, and increased cAMP production in human embryonic kidney-293 cells expressing recombinant rat 5-HT4 receptors. In vivo receptor occupancy studies established that prucalopride and PRX-03140 were able to penetrate the brain and bound to 5-HT4 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-HT4 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.