Memantine, an uncompetitive N-methyl-D-aspartate receptor antagonist, and the cholinesterase inhibitor, donepezil, are approved in most countries for treating moderate-to-severe Alzheimer's disease (AD). These drugs have different molecular targets; thus, it is expected that the effects of combined treatment would be synergistic. Some reports do show memantine/donepezil synergy in ameliorating cognition in AD model animals, but their combined effects on behavioral and psychological symptoms of dementia (BPSD)-like behaviors have not been addressed. Here, we investigate combined memantine/donepezil effects on cognitive impairment and BPSD-like behaviors in olfactory bulbectomized (OBX) mice. Interestingly, combined administration synergistically improved both depressive-like behaviors and impaired social interaction in OBX mice, whereas only weak synergistic effects on cognitive performance were seen. To address mechanisms underlying these effects, we used in vivo microdialysis study and observed impaired nicotine-induced serotonin (5-HT) release in OBX mouse hippocampus. Combined memantine/donepezil administration, but not single administration of either, significantly antagonized the decrease in nicotine-induced 5-HT release seen in OBX mouse hippocampus. Furthermore, decreased autophosphorylation of calcium/calmodulin dependent protein kinase II (CaMKII) was rescued in hippocampal CA1 and dentate gyrus of OBX mice by combined memantine/donepezil administration. These results suggest that improvement of BPSD-like behaviors by the co-administration of both drugs is in part mediated by enhanced 5-HT release and CaMKII activity in OBX mouse hippocampus.

1.
Sato N, Morishita R: The roles of lipid and glucose metabolism in modulation of β-amyloid, tau, and neurodegeneration in the pathogenesis of Alzheimer disease. Front Aging Neurosci 2015;7:199.
2.
Steinberg M, Shao H, Zandi P, Lyketsos CG, Welsh-Bohmer KA, Norton MC, Breitner JC, Steffens DC, et al: Point and 5-year period prevalence of neuropsychiatric symptoms in dementia: the Cache County Study. Int J Geriatr Psychiatry 2008;23:170-177.
3.
Stoppe G, Brandt CA, Staedt JH: Behavioural problems associated with dementia: the role of newer antipsychotics. Drugs Aging 1999;14:41-54.
4.
Nagaratnam N, Lewis-Jones M, Scott D, Palazzi L: Behavioral and psychiatric manifestations in dementia patients in a community: caregiver burden and outcome. Alzheimer Dis Assoc Disord 1998;12:330-334.
5.
Steele C, Rovner B, Chase GA, Folstein M: Psychiatric symptoms and nursing home placement of patients with Alzheimer's disease. Am J Psychiatry 1990;147:1049-1051.
6.
Francis PT, Palmer AM, Snape M, Wilcock GK: The cholinergic hypothesis of Alzheimer's disease: a review of progress. J Neurol Neurosurg Psychiatry 1999;66:137-147.
7.
Geldmacher DS: Donepezil (Aricept) for treatment of Alzheimer's disease and other dementing conditions. Expert Rev Neurother 2004;4:5-16.
8.
Monaghan DT, Jane DE: Pharmacology of NMDA receptors; in Van Dongen AM (ed): Biology of the NMDA Receptor (Frontiers in Neuroscience). Boca Raton, CRC Press, 2009, pp 257-282.
9.
Sani G, Serra G, Kotzalidis GD, Romano S, Tamorri SM, Manfredi G, Caloro M, Telesforo CL, Caltagirone SS, Panaccione I, Simonetti A, Demontis F, Serra G, Girardi P: The role of memantine in the treatment of psychiatric disorders other than the dementias: a review of current preclinical and clinical evidence. CNS Drugs 2012;26:663-690.
10.
Lopez OL, Becker JT, Wahed AS, Saxton J, Sweet RA, Wolk DA, Klunk W, Dekosky ST: Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease. J Neurol Neurosurg Psychiatry 2009;80:600-607.
11.
Shua-Haim J, Smith J, Picard F, et al: Steady-state pharmacokinetics of rivastigmine in patients with mild to moderate Alzheimer's disease not affected by co-administration of memantine: an open-label, crossover, single-centre study. Clin Drug Investig 2008;28:361-374.
12.
Yao C, Raoufinia A, Gold M, et al: Steady-state pharmacokinetics of galantamine are not affected by addition of memantine in healthy subjects. J Clin Pharmacol 2005;45:519-528.
13.
Bahar-Fuchs A, Chételat G, Villemagne VL, Moss S, Pike K, Masters CL, Rowe C, Savage G: Olfactory deficits and amyloid-β burden in Alzheimer's disease, mild cognitive impairment, and healthy aging: a PiB PET study. J Alzheimers Dis 2010;22:1081-1087.
14.
Albers MW, Tabert MH, Devanand DP: Olfactory dysfunction as a predictor of neurodegenerative disease. Curr Neurol Neurosci Rep 2006;6:379-386.
15.
Aleksandrova IY, Kuvichkin VV, Kashparov IA, Medvinskaya NI, Nesterova IV, Lunin SM, Samokhin AN, Bobkova NV: Increased level of beta-amyloid in the brain of bulbectomized mice. Biochemistry (Mosc) 2004;69:176-180.
16.
Hozumi S, Nakagawasai O, Tan-No K, Niijima F, Yamadera F, Murata A, Arai Y, Yasuhara H, Tadano T: Characteristics of changes in cholinergic function and impairment of learning and memory-related behavior induced by olfactory bulbectomy. Behav Brain Res 2003;138:9-15.
17.
Wesson DW, Levy E, Nixon RA, Wilson DA: Olfactory dysfunction correlates with amyloid-beta burden in an Alzheimer's disease mouse model. J Neurosci 2010;30:505-514.
18.
Yabuki Y, Shinoda Y, Izumi H, Ikuno T, Shioda N, Fukunaga K: Dehydroepiandrosterone administration improves memory deficits following transient brain ischemia through sigma-1 receptor stimulation. Brain Res 2015;1622:102-113.
19.
Yabuki Y, Ohizumi Y, Yokosuka A, Mimaki Y, Fukunaga K: Nobiletin treatment improves motor and cognitive deficits seen in MPTP-induced Parkinson model mice. Neuroscience 2014;259:126-141.
20.
Tremolizzo L, Doueiri MS, Dong E, Grayson DR, Davis J, Pinna G, Tueting P, Rodriguez-Menendez V, et al: Valproate corrects the schizophrenia-like epigenetic behavioral modifications induced by methionine in mice. Biol Psychiatry 2005;57:500-509.
21.
Porsolt RD, Bertin A, Jalfre M: Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 1977;229:327-336.
22.
Kheirbek MA, Drew LJ, Burghardt NS, Costantini DO, Tannenholz L, Ahmari SE, Zeng H, Fenton AA, Hen R: Differential control of learning and anxiety along the dorsoventral axis of the dentate gyrus. Neuron 2013;77:955-968.
23.
Yabuki Y, Nakagawasai O, Moriguchi S, Shioda N, Onogi H, Tan-No K, Tadano T, Fukunaga K: Decreased CaMKII and PKC activities in specific brain regions are associated with cognitive impairment in neonatal ventral hippocampus-lesioned rats. Neuroscience 2013;234:103-115.
24.
Fukunaga K, Goto S, Miyamoto E: Immunohistochemical localization of Ca2+/calmodulin-dependent protein kinase II in rat brain and various tissues. J Neurochem 1988;51:1070-1078.
25.
Borre Y, Bosman E, Lemstra S, Westphal KG, Olivier B, Oosting RS: Memantine partly rescues behavioral and cognitive deficits in an animal model of neurodegeneration. Neuropharmacology 2012;62:2010-2017.
26.
Yamada M, Hayashida M, Zhao Q, Shibahara N, Tanaka K, Miyata T, Matsumoto K: Ameliorative effects of yokukansan on learning and memory deficits in olfactory bulbectomized mice. J Ethnopharmacol 2011;135:737-746.
27.
Yamamoto Y, Fukunaga K: Donepezil rescues the medical septum cholinergic neurons via nicotinic Ach receptor stimulation in olfactory bulbectomized mice. Adv Alzheimers Dis 2013;2:161-170.
28.
De Deurwaerdère P, Di Giovanni G: Serotonergic modulation of the activity of mesencephalic dopaminergic systems: therapeutic implications. Prog Neurobiol 2016;pii:S0301-0082(15)30096-4.
29.
Locca JF, Büla CJ, Zumbach S, Bugnon O: Pharmacological treatment of behavioral and psychological symptoms of dementia (BPSD) in nursing homes: development of practice recommendations in a Swiss canton. J Am Med Dir Assoc 2008;9:439-448.
30.
Muramatsu RS, Litzinger MH, Fisher E, Takeshita J: Alternative formulations, delivery methods, and administration options for psychotropic medications in elderly patients with behavioral and psychological symptoms of dementia. Am J Geriatr Pharmacother 2010;8:98-114.
31.
Islam MR, Moriguchi S, Tagashira H, Fukunaga K: Rivastigmine restores 5-HT1A receptor levels in the hippocampus of olfactory bulbectomized mice. Adv Alzheimers Dis 2014;3:128-136.
32.
Han F, Nakano T, Yamamoto Y, Shioda N, Lu YM, Fukunaga K: Improvement of depressive behaviors by nefiracetam is associated with activation of CaM kinases in olfactory bulbectomized mice. Brain Res 2009;1265:205-214.
33.
Moriguchi S, Sakagami H, Yabuki Y, Sasaki Y, Izumi H, Zhang C, Han F, Fukunaga K: Stimulation of sigma-1 receptor ameliorates depressive-like behaviors in CaMKIV null mice. Mol Neurobiol 2015;52:1210-1222.
34.
Almeida RC, Souza DG, Soletti RC, López MG, Rodrigues AL, Gabilan NH: Involvement of PKA, MAPK/ERK and CaMKII, but not PKC in the acute antidepressant-like effect of memantine in mice. Neurosci Lett 2006;395:93-97.
35.
Martinez-Coria H, Green K, Banerjee PK, LaFerla FM: Combination of Memantine and Donepezil Reverses Cognitive Deficits in Transgenic Mice with Both Amyloid-Beta Plaques and Neurofibrillary Tangles. Istanbul, 22nd Congress of the European College of Neuropsychopharmacology (ECNP), 2009.
36.
Neumeister KL, Riepe MW: Synergistic effects of antidementia drugs on spatial learning and recall in the APP23 transgenic mouse model of Alzheimer's disease. J Alzheimers Dis 2012;30:245-251.
37.
Parsons CG, Stöffler A, Danysz W: Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system - too little activation is bad, too much is even worse. Neuropharmacology 2007;53:699-723.
38.
Parsons CG, Danysz W, Dekundy A, Pulte I: Memantine and cholinesterase inhibitors: complementary mechanisms in the treatment of Alzheimer's disease. Neurotox Res 2013;24:358-369.
39.
Palmer AM, Gershon S: Is the neuronal basis of Alzheimer's disease cholinergic or glutamatergic? FASEB J 1990;4:2745-2752.
40.
Danysz W, Parsons CG, Mobius HJ, Stoffler A, Quack G: Neuroprotective and symptomatological action of memantine relevant for Alzheimer's disease - a unified glutamatergic hypothesis on the mechanism of action. Neurotox Res 2000;2:85-97.
41.
Davidsson P, Blennow K, Andreasen N, Eriksson B, Minthon L, Hesse C: Differential increase in cerebrospinal fluid-acetylcholinesterase after treatment with acetylcholinesterase inhibitors in patients with Alzheimer's disease. Neurosci Lett 2001;300:157-160.
42.
Han F, Shioda N, Moriguchi S, Qin ZH, Fukunaga K: The vanadium (IV) compound rescues septo-hippocampal cholinergic neurons from neurodegeneration in olfactory bulbectomized mice. Neuroscience 2008;151:671-679.
43.
Shioda N, Yamamoto Y, Han F, Moriguchi S, Yamaguchi Y, Hino M, Fukunaga K: A novel cognitive enhancer, ZSET1446/ST101, promotes hippocampal neurogenesis and ameliorates depressive behavior in olfactory bulbectomized mice. J Pharmacol Exp Ther 2010;333:43-50.
44.
Ihalainen J, Sarajärvi T, Rasmusson D, Kemppainen S, Keski-Rahkonen P, Lehtonen M, Banerjee PK, Semba K, Tanila H: Effects of memantine and donepezil on cortical and hippocampal acetylcholine levels and object recognition memory in rats. Neuropharmacology 2011;61:891-899.
45.
Aletrino MA, Vogels OJ, Van Domburg PH, Ten Donkelaar HJ: Cell loss in the nucleus raphes dorsalis in Alzheimer's disease. Neurobiol Aging 1992;13:461-468.
46.
Arai H, Kosaka K, Iizuka R: Changes of biogenic amines and their metabolites in postmortem brains from patients with Alzheimer-type dementia. J Neurochem 1984;43:388-393.
47.
Rodríguez JJ, Noristani HN, Verkhratsky A: The serotonergic system in ageing and Alzheimer's disease. Prog Neurobiol 2012;99:15-41.
48.
Holmes C, Arranz MJ, Powell JF, Collier DA, Lovestone S: 5-HT2A and 5-HT2C receptor polymorphisms and psychopathology in late onset Alzheimer's disease. Hum Mol Genet 1998;7:1507-1509.
49.
Islam MR, Moriguchi S, Tagashira H, Fukunaga K: Rivastigmine improves hippocampal neurogenesis and depression-like behaviors via 5-HT1A receptor stimulation in olfactory bulbectomized mice. Neuroscience 2014;272:116-130.
50.
Muraoka S, Kamei K, Muneoka K, Takigawa M: Chronic imipramine administration amplifies the serotonin2A receptor-induced intracellular Ca2+ mobilization in C6 glioma cells through a calmodulin-dependent pathway. J Neurochem 1998;71:1709-1718.
51.
Polter AM, Li X: Glycogen synthase kinase-3 is an intermediate modulator of serotonin neurotransmission. Front Mol Neurosci 2011;4:31.
52.
Cirrito JR, Disabato BM, Restivo JL, Verges DK, Goebel WD, Sathyan A, Hayreh D, D'Angelo G, Benzinger T, Yoon H, Kim J, Morris JC, Mintun MA, Sheline YI: Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans. Proc Natl Acad Sci U S A 2011;108:14968-14973.
53.
Moyano S, Del Río J, Frechilla D: Role of hippocampal CaMKII in serotonin 5-HT(1A) receptor-mediated learning deficit in rats. Neuropsychopharmacology 2004;29:2216-2224.
54.
Yamasaki N, Maekawa M, Kobayashi K, Kajii Y, Maeda J, Soma M, Takao K, Tanda K, Ohira K, Toyama K, Kanzaki K, Fukunaga K, Sudo Y, Ichinose H, Ikeda M, Iwata N, Ozaki N, Suzuki H, Higuchi M, Suhara T, Yuasa S, Miyakawa T: Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders. Mol Brain 2008;1:6.
55.
Kemppainen N, Laine M, Laakso MP, Kaasinen V, Någren K, Vahlberg T, Kurki T, Rinne JO: Hippocampal dopamine D2 receptors correlate with memory functions in Alzheimer's disease. Eur J Neurosci 2003;18:149-154.
56.
Tanaka Y, Meguro K, Yamaguchi S, Ishii H, Watanuki S, Funaki Y, Yamaguchi K, Yamadori A, Iwata R, Itoh M: Decreased striatal D2 receptor density associated with severe behavioral abnormality in Alzheimer's disease. Ann Nucl Med 2003;17:567-573.
57.
Periclou AP, Ventura D, Sherman T: Lack of pharmacokinetic or pharmacodynamic interaction between memantine and donepezil. Ann Pharmacother 2004;38:1389-1394.
58.
Choi SH, Park KW, Na DL, Han HJ, Kim EJ, Shim YS, Lee JH; Expect Study Group: Tolerability and efficacy of memantine add-on therapy to rivastigmine transdermal patches in mild to moderate Alzheimer's disease: a multicenter, randomized, open-label, parallel-group study. Curr Med Res Opin 2011;27:1375-1383.
59.
Dantoine T, Auriacombe S, Sarazin M, Becker H, Pere JJ, Bourdeix I: Rivastigmine monotherapy and combination therapy with memantine in patients with moderately severe Alzheimer's disease who failed to benefit from previous cholinesterase inhibitor treatment. Int J Clin Pract 2006;60:110-118.
60.
Cummings JL, Schneider E, Tariot PN, Graham SM; Memantine MEM-MD-02 Study Group: Behavioral effects of memantine in Alzheimer disease patients receiving donepezil treatment. Neurology 2006;67:57-63.
61.
Lopez OL, Becker JT, Wahed AS, Saxton J, Sweet RA, Wolk DA, Klunk W, Dekosky ST: Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease. J Neurol Neurosurg Psychiatry 2009;80:600-607.
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