Abstract
Rationale
There is a persistent pressing need for valid animal models of cognitive and mnemonic disruptions (such as seen in Alzheimer’s disease and other dementias) usable for preclinical research.
Objectives
We have set out to test the validity of administration of biperiden, an M1-acetylcholine receptor antagonist with central selectivity, as a potential tool for generating a fast screening model of cognitive impairment, in outbred Wistar rats.
Methods
We used several variants of the Morris water maze task: (1) reversal learning, to assess cognitive flexibility, with probe trials testing memory retention; (2) delayed matching to position (DMP), to evaluate working memory; and (3) “counter-balanced acquisition,” to test for possible anomalies in acquisition learning. We also included a visible platform paradigm to reveal possible sensorimotor and motivational deficits.
Results
A significant effect of biperiden on memory acquisition and retention was found in the counter-balanced acquisition and probe trials of the counter-balanced acquisition and reversal tasks. Strikingly, a less pronounced deficit was observed in the DMP. No effects were revealed in the reversal learning task.
Conclusions
Based on our results, we do not recommend biperiden as a reliable tool for modeling cognitive impairment.
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Notes
While we had also data for the distance required to reach the platform, it correlated strongly with escape latency, r(870) = .94, 95% CI = [.94, .95], p < .001, so we show results only for escape latency for simplicity.
b refers to regression coefficient
Abbreviations
- Ach:
-
Acetylcholine
- AChR:
-
Acetylcholine receptors
- AD:
-
Alzheimer’s disease
- BBB:
-
Blood-brain barrier
- BIP:
-
Biperiden
- C:
-
Control group
- CA:
-
Counter-balanced acquisition
- cAMP:
-
Cyclic adenosine monophosphate
- CNS:
-
Central nervous system
- DMP:
-
Delayed matching to position
- DMSO:
-
Dimethyl-sulfoxide
- GABA:
-
Gamma-amino-butyric acid
- GPCRs:
-
G-Protein coupled receptors
- i.p.:
-
Intraperitoneally
- ITI:
-
Inter-trial interval
- mAChR:
-
Muscarinic acetylcholine receptors
- MWM:
-
Morris water maze
- NSP:
-
Non-spatial pretraining
- s.c.:
-
Subcutaneously
- SCOP:
-
Scopolamine
- VP:
-
Visible platform
References
AHFS DI Essentials (2017, 1 4) Biperiden Hydrochloride. Retrieved from Drugs.com: https://www.drugs.com/monograph/biperiden-hydrochloride.html. Accessed 5 Oct 2017
Asth L, Lobão-Soares B, André E, Soares VP, Gavioli EC (2012) The elevated T-maze task as an animal model to simultaneously investigate the effects of drugs on long-term memory and anxiety in mice. Brain Res Bull 87:526–533. https://doi.org/10.1016/j.brainresbull.2012.02.008
Bell LA, Bell KA, McQuiston AR (2013) Synaptic muscarinic response types in hippocampal CA1 interneurons depend on different levels of presynaptic activity and different muscarinic receptor subtypes. Neuropharmacology 73:160–173. https://doi.org/10.1016/j.neuropharm.2013.05.026
Borghans LGJM, Blokland A, Sambeth A (2017) Effects of biperiden and acute tryptophan depletion and their combination on verbal word memory and EEG. Psychopharmacology 234:1135–1143. https://doi.org/10.1007/s00213-017-4549-1
Button KS, Ioannidis JPA, Mokrysz C, Nosek BA, Flint J, Robinson ESJ, Munafò MR (2013) Power failure: why small sample size undermines the reliability of neuroscience. Nat Rev Neurosci 14:365–376. https://doi.org/10.1038/nrn3475
Carruthers SP, Gurvich CT, Rossell SL (2015) The muscarinic system, cognition and schizophrenia. Neurosci Biobehav Rev 55:393–402. https://doi.org/10.1016/j.neubiorev.2015.05.011
Czéh B, Stuchlik A, Wesierska M, Cimadevilla JM, Pokorný J, Seress L, Bures J (2001) Effect of neonatal dentate gyrus lesion on allothetic and idiothetic navigation in rats. Neurobiol Learn Mem 75:190–213. https://doi.org/10.1006/nlme.2000.3975
Deiana S, Platt B, Riedel G (2011) The cholinergic system and spatial learning. Behav Brain Res 221:389–411. https://doi.org/10.1016/j.bbr.2010.11.036
Foster DJ, Choi DL, Jeffrey Conn P, Rook JM (2014) Activation of M1 and M4 muscarinic receptors as potential treatments for Alzheimer’s disease and schizophrenia. Neuropsychiatr Dis Treat 10:183–191. https://doi.org/10.2147/NDT.S55104
Gelman A, Hill J (2006) Data analysis using regression and multilevel/hierarchical models Analytical Methods for Social Research. Cambridge University Press, Cambridge. https://doi.org/10.1017/CBO9780511790942
Gieling E, Wehkamp W, Willigenburg R, Nordquist RE, Ganderup NC, van der Staay FJ (2013) Performance of conventional pigs and Göttingen miniature pigs in a spatial holeboard task: effects of the putative muscarinic cognition impairer biperiden. Behav Brain Funct 9:4. https://doi.org/10.1186/1744-9081-9-4
Hut RA, Van der Zee EA (2011) The cholinergic system, circadian rhythmicity, and time memory. Behav Brain Res 221:466–480. https://doi.org/10.1016/j.bbr.2010.11.039
Jiang S, Li Y, Zhang C, Zhao Y, Bu G, Xu H, Zhang YW (2014) M1 muscarinic acetylcholine receptor in Alzheimer’s disease. Neurosci Bull 30:295–307. https://doi.org/10.1007/s12264-013-1406-z
Kimura Y, Ohue M, Kitaura T, Kihira K (1999) Amnesic effects of the anticholinergic drugs, trihexyphenidyl and biperiden: differences in binding properties to the brain muscarinic receptor. Brain Res 834:6–12. https://doi.org/10.1016/S0006-8993(99)01526-7
Klinkenberg I, Blokland A (2011) A comparison of scopolamine and biperiden as a rodent model for cholinergic cognitive impairment. Psychopharmacology 215:549–566. https://doi.org/10.1007/s00213-011-2171-1
Kremin T, Gerber D, Giocomo LM et al (2006) Muscarinic suppression in stratum radiatum of CA1 shows dependence on presynaptic M1 receptors and is not dependent on effects at GABAB receptors. Neurobiol Learn Mem 85:153–163. https://doi.org/10.1016/j.nlm.2005.09.005
Laczó J, Markova H, Lobellova V, Gazova I, Parizkova M, Cerman J, Nekovarova T, Vales K, Klovrzova S, Harrison J, Windisch M, Vlcek K, Svoboda J, Hort J, Stuchlik A (2017) Scopolamine disrupts place navigation in rats and humans: a translational validation of the hidden goal task in the Morris water maze and a real maze for humans. Psychopharmacology 234:535–547. https://doi.org/10.1007/s00213-016-4488-2
Leslie FM, Mojica CY, Reynaga DD (2013) Nicotinic receptors in addiction pathways. Mol Pharmacol 83:753–758. https://doi.org/10.1124/mol.112.083659
Malikowska N, Sałat K, Podkowa A (2017) Comparison of pro-amnesic efficacy of scopolamine, biperiden, and phencyclidine by using passive avoidance task in CD-1 mice. J Pharmacol Toxicol Methods 86:76–80. https://doi.org/10.1016/j.vascn.2017.04.006
Muller JF, Mascagni F, Zaric V, Mcdonald AJ (2013) Muscarinic cholinergic receptor M1 in the rat basolateral amygdala: ultrastructural localization and synaptic relationships to cholinergic axons. J Comp Neurol 521:1743–1759. https://doi.org/10.1002/cne.23254
Myers TM, Galbicka G, Sipos ML, Varadi S, Oubre JL, Clark MG (2002) Effects of anticholinergics on serial-probe recognition accuracy of rhesus macaques (Macaca mulatta). Pharmacol Biochem Behav 73:829–834. https://doi.org/10.1016/S0091-3057(02)00909-7
Petrasek T, Prokopova I, Bahnik S, Schonig K, Berger S, Vales K, Tews B, Schwab ME, Bartsch D, Stuchlik A (2014) Nogo-A downregulation impairs place avoidance in the Carousel maze but not spatial memory in the Morris water maze. Neurobiol Learn Mem 107:42–49. https://doi.org/10.1016/j.nlm.2013.10.015
Petrasek T, Skurlova M, Maleninska K et al (2016) A rat model of Alzheimer’s disease based on Abeta42and pro-oxidative substances exhibits cognitive deficit and alterations in glutamatergic and cholinergic neurotransmitter systems. Front Aging Neurosci 8. https://doi.org/10.3389/fnagi.2016.00083
Pittaras EC, Faure A, Leray X, Moraitopoulou E, Cressant A, Rabat AA, Meunier C, Fossier P, Granon S (2016) Neuronal nicotinic receptors are crucial for tuning of E/I balance in prelimbic cortex and for decision-making processes. Front Psychiatry 7. https://doi.org/10.3389/fpsyt.2016.00171
Prado VF, Janickova H, Al-Onaizi MA, Prado MAM (2017) Cholinergic circuits in cognitive flexibility. Neuroscience 345:130–141. https://doi.org/10.1016/j.neuroscience.2016.09.013
Quené H, Van Den Bergh H (2004) On multi-level modeling of data from repeated measures designs: a tutorial. Speech Comm 43:103–121. https://doi.org/10.1016/j.specom.2004.02.004
R Core Team (2016) R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna
Robinson L, Harbaran D, Riedel G (2004) Visual acuity in the water maze: sensitivity to muscarinic receptor blockade in rats and mice. Behav Brain Res 151:277–286. https://doi.org/10.1016/j.bbr.2003.09.001
Robinson L, Platt B, Riedel G (2011) Involvement of the cholinergic system in conditioning and perceptual memory. Behav Brain Res 221:443–465. https://doi.org/10.1016/j.bbr.2011.01.055
Sambeth A, Riedel WJ, Klinkenberg I, Kähkönen S, Blokland A (2015) Biperiden selectively induces memory impairment in healthy volunteers: no interaction with citalopram. Psychopharmacology 232:1887–1897. https://doi.org/10.1007/s00213-014-3822-9
Schliebs R, Arendt T (2011) The cholinergic system in aging and neuronal degeneration. Behav Brain Res 221:555–563. https://doi.org/10.1016/j.bbr.2010.11.058
Steele RJ, Morris RGM (1999) Delay-dependent impairment of a matching-to-place task with chronic and intrahippocampal infusion of the NMDA-antagonist D-AP5. Hippocampus 9:118–136. https://doi.org/10.1002/(SICI)1098-1063(1999)9:2<118::AID-HIPO4>3.0.CO;2-8
Svoboda J, Popelikova A, Stuchlik A (2017) Drugs interfering with muscarinic acetylcholine receptors and their effects on place navigation. Front Psychiatry 8. https://doi.org/10.3389/fpsyt.2017.00215
Szczodry O, van der Staay FJ, Arndt SS (2014) Modelling Alzheimer-like cognitive deficits in rats using biperiden as putative cognition impairer. Behav Brain Res 274:307–311. https://doi.org/10.1016/j.bbr.2014.08.036
Talpos JC, Aerts N, Fellini L, Steckler T (2014) A touch-screen based paired-associates learning (PAL) task for the rat may provide a translatable pharmacological model of human cognitive impairment. Pharmacol Biochem Behav 122:97–106. https://doi.org/10.1016/j.pbb.2014.03.014
Vales K, Stuchlik A (2005) Central muscarinic blockade interferes with retrieval and reacquisition of active allothetic place avoidance despite spatial pretraining. Behav Brain Res 161:238–244. https://doi.org/10.1016/j.bbr.2005.02.012
VanPatten S, Al-Abed Y (2017) The challenges of modulating the ‘rest and digest’ system: acetylcholine receptors as drug targets. Drug Discov Today 22:97–104. https://doi.org/10.1016/j.drudis.2016.09.011
Vingerhoets C, Bakker G, van Dijk J, Bloemen OJN, Wang Y, Chan RCK, Booij J, van Amelsvoort TAMJ (2017) The effect of the muscarinic M1receptor antagonist biperiden on cognition in medication free subjects with psychosis. Eur Neuropsychopharmacol 27:854–864. https://doi.org/10.1016/j.euroneuro.2017.06.014
von Linstow Roloff E, Harbaran D, Micheau J et al (2007) Dissociation of cholinergic function in spatial and procedural learning in rats. Neuroscience 146:875–889. https://doi.org/10.1016/j.neuroscience.2007.02.038
Wezenberg E, Verkes RJ, Sabbe BGC, Ruigt GSF, Hulstijn W (2005) Modulation of memory and visuospatial processes by biperiden and rivastigmine in elderly healthy subjects. Psychopharmacology 181:582–594. https://doi.org/10.1007/s00213-005-0083-7
Witkin JM, Overshiner C, Li X, Catlow JT, Wishart GN, Schober DA, Heinz BA, Nikolayev A, Tolstikov VV, Anderson WH, Higgs RE, Kuo MS, Felder CC (2014) M1 and M2 muscarinic receptor subtypes regulate antidepressant-like effects of the rapidly acting antidepressant scopolamine. J Pharmacol Exp Ther 351:448–456. https://doi.org/10.1124/jpet.114.216804
Acknowledgements
We thank Michaela Radostna, Barbara Stuchlikova, Vladimira Markova, Antonin Zahalka, and Jindrich Kalvoda for the technical support and assistance.
Funding
This work was supported by GACR grant 17-04047S. Institutional support for IPHYS was provided by RVO: 67985823.
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Popelíková, A., Bahník, Š., Lobellová, V. et al. Mnemonic and behavioral effects of biperiden, an M1-selective antagonist, in the rat. Psychopharmacology 235, 2013–2025 (2018). https://doi.org/10.1007/s00213-018-4899-3
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DOI: https://doi.org/10.1007/s00213-018-4899-3