Available online at www.sciencedirect.com Behavioural Brain Research 187 (2008) 455–461 Research report Prucalopride and donepezil act synergistically to reverse scopolamine-induced memory deficit in C57Bl/6j mice M. Cachard-Chastel a,d , S. Devers e , S. Sicsic b,d , M. Langlois b,d , F. Lezoualc’h c,d , A.M. Gardier a,d,* , C. Belzung e a University of Paris-Sud, EA3544, Fac. Pharmacie, F92296 Chˆ atenay-Malabry Cedex, France b Laboratoire de Reconnaissance Mol´ eculaire et Synth` ese, BIOCIS UMR C 8076, Facult´ e de Pharmacie, Universit´ e Paris-Sud, 92296 Chˆ atenay-Malabry Cedex, France c Signalisation et Physiopathologie Cardiaque, Inserm U-769, Facult´ e de Pharmacie, Universit´ e Paris-Sud, 92296 Chˆ atenay-Malabry Cedex, France d IFR-141, Facult´ e de Pharmacie, Universit´ e Paris-Sud, 5 Rue J.-B. Cl´ ement, 92296 Ch ˆ atenay-Malabry Cedex, France e Universit´ e Fran¸ cois Rabelais de Tours, EA3248, Fac. Sciences etTechniques, ParcGrandmont, 37200 Tours, France Received 15 August 2007; received in revised form 9 October 2007; accepted 10 October 2007 Available online 18 October 2007 Abstract It is known that 5-HT 4 receptor agonists increase sAPP levels in the cortex and hippocampus of mice as well as in a model of Alzheimer’s disease (AD). As sAPP is thought to have pro-mnesic properties, we assessed whether its increase induces cognitive improvement in a spatial memory task and whether it reverses a scopolamine-induced memory deficit. Mice treated or not treated with scopolamine were trained in the Morris water maze for 3 days. Before the probe test, they received an injection of either a 5-HT 4 receptor agonist (prucalopride or RS 67333), or an acetylcholinesterase inhibitor (donepezil), or both drugs. As expected, scopolamine decreased performance, an effect that was not reversed by the drugs tested when injected alone. However, prucalopride (5 mg kg -1 , s.c.) acted synergistically with donepezil (0.75 mg kg -1 , s.c.) to counteract completely scopolamine-induced amnesia. Western blot analysis of tissue homogenates in the cortex and hippocampus shows that sAPP levels did not differ between saline- and scopolamine-treated mice. Furthermore, a region-dependent drug action was observed since the scopolamine-treated mice display a tendency to increase sAPP levels in the hippocampus after donepezil or in the cortex after prucalopride. Our results suggest that a combined treatment with a 5-HT 4 receptor agonist with an acetylcholinesterase inhibitor has beneficial effects on memory in mice. Moreover, it seems to enhance sAPP levels in two brain regions highly affected in AD. Thus, a drug polytherapy could be interesting not only to enhance cognitive performance and decrease drawbacks but also to get the best action in each brain region. © 2007 Elsevier B.V. All rights reserved. Keywords: Serotonin 5-HT 4 receptor agonist; Amyloid precursor protein; Alzheimer’s disease; Acetylcholine esterase inhibitor 1. Introduction Alzheimer’s disease (AD) is a progressive neurodegenera- tive disorder characterized by the appearance of senile plaques mainly composed of amyloid beta protein (A), and by the development of neurofibrillary tangles in patients’ brain [1]. AD patients have cognitive deficits, impaired long-term poten- tiation (LTP) and learning and memory [2], and a consistent * Corresponding author at: University of Paris-Sud, EA3544, Fac. Pharmacie, F92296 Chˆ atenay-Malabry Cedex, France. Tel.: +33 1 46 83 54 16; fax: +33 1 46 83 53 55. E-mail address: alain.gardier@u-psud.fr (A.M. Gardier). deficit in cholinergic neurotransmission also. Several acetyl- choline esterase inhibitors such as donepezil are available in the market for the treatment of patients with mild-to-severe AD. However, beneficial effects on memory and cognition of this treatment can only be maintained for up to 36 months [3]. Com- pounds like donepezil do not stop the AD and are symptomatic treatments, which only delay patient’s loss of autonomy. Autoradiographic studies using 5-hydroxytryptamine 4 (5- HT 4 ) receptor antagonists such as [ 125 I]SB207710 and [ 3 H]GR113808 in rat, mouse, guinea pig or post-mortem human brain showed that the 5-HT 4 receptor is present at a high den- sity in the limbic system including the hippocampus and frontal cortex [4,5], suggesting a role of this subtype of 5-HT receptors 0166-4328/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2007.10.008