Muscarinic acetylcholine receptors (mAChRs) have been found to regulate many diverse functions, ranging from motivation and feeding to spatial navigation, an important and widely studied type of cognitive behavior. Systemic administration of non-selective antagonists of mAChRs, such as scopolamine or atropine, have been found to have adverse effects on a vast majority of place navigation tasks. However, many of these results may be potentially confounded by disruptions of functions other than spatial learning and memory. Although studies with selective antimuscarinics point to mutually opposite effects of M1 and M2 receptors, their particular contribution to spatial cognition is still poorly understood, partly due to a lack of truly selective agents. Furthermore, constitutive knock-outs do not always support results from selective antagonists. For modeling impaired spatial cognition, the scopolamine-induced amnesia model still maintains some limited validity, but there is an apparent need for more targeted approaches such as local intracerebral administration of antagonists, as well as novel techniques such as optogenetics focused on cholinergic neurons and chemogenetics aimed at cells expressing metabotropic mAChRs.

Institute of Physiology of the Czech Academy of Sciences Prague Czechia

Zobrazit více v PubMed

VanPatten S, Al-Abed Y. The challenges of modulating the ‘rest and digest’ system: acetylcholine receptors as drug targets. Drug Discov Today (2016) 22(1):97–104.10.1016/j.drudis.2016.09.011 PubMed DOI

Hut RA, Van der Zee EA. The cholinergic system, circadian rhythmicity, and time memory. Behav Brain Res (2011) 221:466–80.10.1016/j.bbr.2010.11.039 PubMed DOI

Leslie FM, Mojica CY, Reynaga DD. Nicotinic receptors in addiction pathways. Mol Pharmacol (2013) 83:753–8.10.1124/mol.112.083659 PubMed DOI

Prado VF, Janickova H, Al-Onaizi MA, Prado MAM. Cholinergic circuits in cognitive flexibility. Neuroscience (2017) 345:130–41.10.1016/j.neuroscience.2016.09.013 PubMed DOI

Robinson L, Platt B, Riedel G. Involvement of the cholinergic system in conditioning and perceptual memory. Behav Brain Res (2011) 221:443–65.10.1016/j.bbr.2011.01.055 PubMed DOI

Deiana S, Platt B, Riedel G. The cholinergic system and spatial learning. Behav Brain Res (2011) 221:389–411.10.1016/j.bbr.2010.11.036 PubMed DOI

Schliebs R, Arendt T. The cholinergic system in aging and neuronal degeneration. Behav Brain Res (2011) 221:555–63.10.1016/j.bbr.2010.11.058 PubMed DOI

Jiang S, Li Y, Zhang C, Zhao Y, Bu G, Xu H, et al. M1 muscarinic acetylcholine receptor in Alzheimer’s disease. Neurosci Bull (2014) 30:295–307.10.1007/s12264-013-1406-z PubMed DOI PMC

Pittaras E, Faure A, Leray X, Moraitopoulou E, Cressant A, Rabat A, et al. Neuronal nicotinic receptors are crucial for tuning of E/I balance in prelimbic cortex and for decision-making processes. Front Psychiatry (2016) 7:171.10.3389/fpsyt.2016.00171 PubMed DOI PMC

Carruthers SP, Gurvich CT, Rossell SL. The muscarinic system, cognition and schizophrenia. Neurosci Biobehav Rev (2015) 55:393–402.10.1016/j.neubiorev.2015.05.011 PubMed DOI

Witkin JM, Overshiner C, Li X, Catlow JT, Wishart GN, Schober DA, et al. M1 and m2 muscarinic receptor subtypes regulate antidepressant-like effects of the rapidly acting antidepressant scopolamine. J Pharmacol Exp Ther (2014) 351:448–56.10.1124/jpet.114.216804 PubMed DOI

Malca Garcia GR, Hennig L, Shelukhina IV, Kudryavtsev DS, Bussmann RW, Tsetlin VI, et al. Curare alkaloids: constituents of a Matis dart poison. J Nat Prod (2015) 78:2537–44.10.1021/acs.jnatprod.5b00457 PubMed DOI

Role LW, Berg DK. Nicotinic receptors in the development and modulation of CNS synapses. Neuron (1996) 16:1077–85.10.1016/S0896-6273(00)80134-8 PubMed DOI

Albuquerque EX, Pereira EFR, Alkondon M, Rogers SW. Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev (2009) 89:73–120.10.1152/physrev.00015.2008 PubMed DOI PMC

He Q, Johnston J, Zeitlinger J, City K, City K. Heteromeric α7β2 nicotinic acetylcholine receptors in the brain. Trends Pharmacol Sci (2015) 33:395–401.10.1038/nbt.3121.ChIP-nexus DOI

Sadahiro M, Sajo M, Morishita H. Nicotinic regulation of experience-dependent plasticity in visual cortex. J Physiol Paris (2016) 110:29–36.10.1016/j.jphysparis.2016.11.003 PubMed DOI PMC

Tomankova H, Valuskova P, Varejkova E, Rotkova J, Benes J, Myslivecek J. The M 2 muscarinic receptors are essential for signaling in the heart left ventricle during restraint stress in mice. Stress (2015) 3890:208–20.10.3109/10253890.2015.1007345 PubMed DOI

De Sarno P, Shestopal SA, King TD, Zmijewska A, Song L, Jope RS. Muscarinic receptor activation protects cells from apoptotic effects of DNA damage, oxidative stress, and mitochondrial inhibition. J Biol Chem (2003) 278:11086–93.10.1074/jbc.M212157200 PubMed DOI PMC

Dale PR, Cernecka H, Schmidt M, Dowling MR, Charlton SJ, Pieper MP, et al. The pharmacological rationale for combining muscarinic receptor antagonists and beta-adrenoceptor agonists in the treatment of airway and bladder disease. Curr Opin Pharmacol (2014) 16:31–42.10.1016/j.coph.2014.03.003 PubMed DOI PMC

Muise ED, Gandotra N, Tackett JJ, Bamdad MC, Cowles RA. Distribution of muscarinic acetylcholine receptor subtypes in the murine small intestine. Life Sci (2017) 169:6–10.10.1016/j.lfs.2016.10.030 PubMed DOI

Picciotto MR, Higley MJ, Mineur YS. Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron (2012) 76:116–29.10.1016/j.neuron.2012.08.036 PubMed DOI PMC

Zhang W, Basile AS, Gomeza J, Volpicelli LA, Levey AI, Wess J. Characterization of central inhibitory muscarinic autoreceptors by the use of muscarinic acetylcholine receptor knock-out mice. J Neurosci (2002) 22:1709–17. PubMed PMC

Pergolizzi JV, Philip BK, Leslie JB, Taylor R, Raffa RB. Perspectives on transdermal scopolamine for the treatment of postoperative nausea and vomiting. J Clin Anesth (2012) 24:334–45.10.1016/j.jclinane.2011.07.019 PubMed DOI

Sambeth A, Riedel WJ, Klinkenberg I, Kähkönen S, Blokland A. Biperiden selectively induces memory impairment in healthy volunteers: no interaction with citalopram. Psychopharmacology (Berl) (2015) 232:1887–97.10.1007/s00213-014-3822-9 PubMed DOI

Laurino A, Matucci R, Vistoli G, Raimondi L. 3-iodothyronamine (T1AM), a novel antagonist of muscarinic receptors. Eur J Pharmacol (2016) 793:35–42.10.1016/j.ejphar.2016.10.027 PubMed DOI

Digby GJ, Shirey JK, Conn PJ. Allosteric activators of muscarinic receptors as novel approaches for treatment of CNS disorders. Mol Biosyst (2010) 6:1345–54.10.1039/c002938f PubMed DOI PMC

Foster DJ, Choi DL, Jeffrey Conn P, Rook JM. Activation of M1 and M4 muscarinic receptors as potential treatments for Alzheimer’s disease and schizophrenia. Neuropsychiatr Dis Treat (2014) 10:183–91.10.2147/NDT.S55104 PubMed DOI PMC

Ragozzino ME, Artis S, Singh A, Twose TM, Beck JE, Messer WS. The selective M1 muscarinic cholinergic agonist CDD-0102A enhances working memory and cognitive flexibility. J Pharmacol Exp Ther (2012) 340:588–94.10.1124/jpet.111.187625 PubMed DOI PMC

Malomouzh AI, Mukhtarov MR, Nikolsky EE, Vyskočil F. Muscarinic M1 acetylcholine receptors regulate the non-quantal release of acetylcholine in the rat neuromuscular junction via NO-dependent mechanism. J Neurochem (2007) 102:2110–7.10.1111/j.1471-4159.2007.04696.x PubMed DOI

Desmarais JE, Beauclair L, Margolese HC. Anticholinergics in the era of atypical antipsychotics: short-term or long-term treatment? J Psychopharmacol (2012) 26:1167–74.10.1177/0269881112447988 PubMed DOI

Ogino S, Miyamoto S, Miyake N, Yamaguchi N. Benefits and limits of anticholinergic use in schizophrenia: focusing on its effect on cognitive function. Psychiatry Clin Neurosci (2014) 68:37–49.10.1111/pcn.12088 PubMed DOI

Vinogradov S, Fisher M, Warm H, Holland C, Kirshner MA, Pollock BG. The cognitive cost of anticholinergic burden: decreased response to cognitive training in schizophrenia. Am J Psychiatry (2009) 166:1055–62.10.1176/appi.ajp.2009.09010017 PubMed DOI PMC

Veselinović T, Vernaleken I, Janouschek H, Kellermann T, Paulzen M, Cumming P, et al. Effects of anticholinergic challenge on psychopathology and cognition in drug-free patients with schizophrenia and healthy volunteers. Psychopharmacology (Berl) (2015) 232:1607–17.10.1007/s00213-014-3794-9 PubMed DOI

Terry AV., Jr Muscarinic receptor antagonists in rats. In: Levin ED, Buccafusco JJ, editors. Animal Models of Cognitive Impairment. Boca Raton, FL: CRC Press/Taylor & Francis; (2017). Available from: http://www.ncbi.nlm.nih.gov/books/NBK2525/

Croy CH, Chan WY, Castetter AM, Watt ML, Quets AT, Felder CC. Characterization of PCS1055, a novel muscarinic M4 receptor antagonist. Eur J Pharmacol (2016) 782:70–6.10.1016/j.ejphar.2016.04.022 PubMed DOI

Jakubík J, Zimčík P, Randáková A, Fuksová K, El-Fakahany EE, Doležal V. Molecular mechanisms of methoctramine binding and selectivity at muscarinic acetylcholine receptors. Mol Pharmacol (2014) 86:180–92.10.1124/mol.114.093310 PubMed DOI

Deng H, Wang C, Su M, Fang Y. Probing biochemical mechanisms of action of muscarinic M3 receptor antagonists with label-free whole cell assays. Anal Chem (2012) 84:8232–9.10.1021/ac301495n PubMed DOI

Zhong J, Roth M. Clinical potential of aclidinium bromide in chronic obstructive pulmonary disease. Ther Clin Risk Manag (2014) 10:449–53.10.2147/TCRM.S39710 PubMed DOI PMC

Busse WW, Dahl R, Jenkins C, Cruz AA. Long-acting muscarinic antagonists: a potential add-on therapy in the treatment of asthma? Eur Respir Rev (2016) 25:54–64.10.1183/16000617.0052-2015 PubMed DOI PMC

Callegari E, Malhotra B, Bungay PJ, Webster R, Fenner KS, Kempshall S, et al. A comprehensive non-clinical evaluation of the CNS penetration potential of antimuscarinic agents for the treatment of overactive bladder. Br J Clin Pharmacol (2011) 72:235–46.10.1111/j.1365-2125.2011.03961.x PubMed DOI PMC

Peretto I, Petrillo P, Imbimbo BP. Medicinal chemistry and therapeutic potential of muscarinic M3 antagonists. Med Res Rev (2009) 29:1292–327.10.1002/med PubMed DOI

Jeon WJ, Dean B, Scarr E, Gibbons A. The role of muscarinic receptors in the pathophysiology of mood disorders: a potential novel treatment? Curr Neuropharmacol (2015) 13:739–49.10.2174/1570159X13666150612230045 PubMed DOI PMC

Espi Martinez F, Espi Forcen F, Shapov A, Martinez Moya A. Biperiden dependence: case report and literature review. Case Rep Psychiatry (2012) 2012:949256.10.1155/2012/949256 PubMed DOI PMC

Brocks DR. Anticholinergic drugs used in Parkinson’s disease: an overlooked class of drugs from a pharmacokinetic perspective. J Pharm Pharm Sci (1999) 2:39–46. PubMed

Gazova Z, Soukup O, Sepsova V, Siposova K, Drtinova L, Jost P, et al. Multi-target-directed therapeutic potential of 7-methoxytacrine-adamantylamine heterodimers in the Alzheimer’s disease treatment. Biochim Biophys Acta (2016) 1863:607–19.10.1016/j.bbadis.2016.11.020 PubMed DOI

Asth L, Lobão-Soares B, André E, Soares Vde P, Gavioli EC. 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 (2012) 87:526–33.10.1016/j.brainresbull.2012.02.008 PubMed DOI

Gieling E, Wehkamp W, Willigenburg R, Nordquist RE, Ganderup N-C, van der Staay FJ. Performance of conventional pigs and Göttingen miniature pigs in a spatial holeboard task: effects of the putative muscarinic cognition impairer Biperiden. Behav Brain Funct (2013) 9:4.10.1186/1744-9081-9-4 PubMed DOI PMC

Ishizaki J, Yokogawa K, Nakashima E, Ohkuma S, Ichimura F. Influence of ammonium chloride on the tissue distribution of anticholinergic drugs in rats. J Pharm Pharmacol (1998) 50:761–6.10.1111/j.2042-7158.1998.tb07137.x PubMed DOI

Bures J, Fenton AA, Kaminsky Y, Zinyuk L. Place cells and place navigation. Proc Natl Acad Sci U S A (1997) 94:343–50.10.1073/pnas.94.1.343 PubMed DOI PMC

D’Hooge R, De Deyn PP. Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev (2001) 36(1):60–90.10.1016/S0165-0173(01)00067-4 PubMed DOI

Morris RGM. Spatial localization does not require the presence of local cues. Learn Motiv (1981) 12:239–60.10.1016/0023-9690(81)90020-5 DOI

Sutherland RJ, Whishaw IQ, Regehr JC. Cholinergic receptor blockade impairs spatial localization by use of distal cues in the rat. J Comp Physiol Psychol (1982) 96:563–73.10.1037/h0077914 PubMed DOI

Kitanishi T, Ito HT, Hayashi Y, Shinohara Y, Mizuseki K, Hikida T. Network mechanisms of hippocampal laterality, place coding, and goal-directed navigation. J Physiol Sci (2017) 67:247–58.10.1007/s12576-016-0502-z PubMed DOI PMC

O’Keefe J, Dostrovsky J. The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat. Brain Res (1971) 34:171–5.10.1016/0006-8993(71)90358-1 PubMed DOI

McNaughton BL, Battaglia FP, Jensen O, Moser EI, Moser M-B. Path integration and the neural basis of the “cognitive map”. Nat Rev Neurosci (2006) 7:663–78.10.1038/nrn1932 PubMed DOI

Nicolelis MAL, Lebedev MA. Principles of neural ensemble physiology underlying the operation of brain-machine interfaces. Nat Rev Neurosci (2009) 10:530–40.10.1038/nrn2653 PubMed DOI

Hafting T, Fyhn M, Molden S, Moser M-B, Moser EI. Microstructure of a spatial map in the entorhinal cortex. Nature (2005) 436:801–6.10.1038/nature03721 PubMed DOI

Taube JS, Muller RU, Ranck JB, Jr. Head-direction cells recorded from the postsubiculum in freely moving rats. II. Effects of environmental manipulations. J Neurosci (1990) 10:436–47. PubMed PMC

Burgess N. Spatial memory: how egocentric and allocentric combine. Trends Cogn Sci (2006) 10:551–7.10.1016/j.tics.2006.10.005 PubMed DOI

Yan C, Wang R, Qu J, Chen G. Locating and navigation mechanism based on place-cell and grid-cell models. Cogn Neurodyn (2016) 10:353–60.10.1007/s11571-016-9384-2 PubMed DOI PMC

Fenton AA, Wesierska M, Kaminsky Y, Bures J. Both here and there: simultaneous expression of autonomous spatial memories in rats. Proc Natl Acad Sci U S A (1998) 95:11493–8.10.1073/pnas.95.19.11493 PubMed DOI PMC

Cimadevilla JM, Wesierska M, Fenton AA, Bures J. Inactivating one hippocampus impairs avoidance of a stable room-defined place during dissociation of arena cues from room cues by rotation of the arena. Proc Natl Acad Sci U S A (2001) 98:3531–6.10.1073/pnas.051628398 PubMed DOI PMC

Wesierska M, Dockery C, Fenton AA. Beyond memory, navigation, and inhibition: behavioral evidence for hippocampus-dependent cognitive coordination in the rat. J Neurosci (2005) 25:2413–9.10.1523/JNEUROSCI.3962-04.2005 PubMed DOI PMC

Kubík S, Fenton AA. Behavioral evidence that segregation and representation are dissociable hippocampal functions. J Neurosci (2005) 25:9205–12.10.1523/JNEUROSCI.1707-05.2005 PubMed DOI PMC

Klinkenberg I, Blokland A. A comparison of scopolamine and biperiden as a rodent model for cholinergic cognitive impairment. Psychopharmacology (Berl) (2011) 215:549–66.10.1007/s00213-011-2171-1 PubMed DOI PMC

Robinson L, Harbaran D, Riedel G. Visual acuity in the water maze: sensitivity to muscarinic receptor blockade in rats and mice. Behav Brain Res (2004) 151:277–86.10.1016/j.bbr.2003.09.001 PubMed DOI

Entlerova M, Lobellova V, Hatalova H, Zemanova A, Vales K, Stuchlik A. Comparison of Long-Evans and Wistar rats in sensitivity to central cholinergic blockade with scopolamine in two spatial tasks: an active place avoidance and the Morris water maze. Physiol Behav (2013) 120:11–8.10.1016/j.physbeh.2013.06.024 PubMed DOI

von Linstow Roloff E, Harbaran D, Micheau J, Platt B, Riedel G. Dissociation of cholinergic function in spatial and procedural learning in rats. Neuroscience (2007) 146:875–89.10.1016/j.neuroscience.2007.02.038 PubMed DOI

Buresova O, Krekule I, Zahalka A, Bures J. On-demand platform improves accuracy of the Morris water maze procedure. J Neurosci Methods (1985) 15:63–72.10.1016/0165-0270(85)90062-7 PubMed DOI

Spooner RI, Thomson A, Hall J, Morris RG, Salter SH. The Atlantis platform: a new design and further developments of Buresova’s on-demand platform for the water maze. Learn Mem (1994) 1:203–11. PubMed

Bertrand F, Lehmann O, Galani R, Lazarus C, Jeltsch H, Cassel JC. Effects of MDL 73005 on water-maze performances and locomotor activity in scopolamine-treated rats. Pharmacol Biochem Behav (2001) 68:647–60.10.1016/S0091-3057(01)00448-8 PubMed DOI

Brazhnik ES, Muller RU, Fox SE. Muscarinic blockade slows and degrades the location-specific firing of hippocampal pyramidal cells. J Neurosci (2003) 23:611–21. PubMed PMC

Brazhnik E, Borgnis R, Muller RU, Fox SE. The effects on place cells of local scopolamine dialysis are mimicked by a mixture of two specific muscarinic antagonists. J Neurosci (2004) 24:9313–23.10.1523/JNEUROSCI.1618-04.2004 PubMed DOI PMC

Newman EL, Gillet SN, Climer JR, Hasselmo ME. Cholinergic blockade reduces theta-gamma phase amplitude coupling and speed modulation of theta frequency consistent with behavioral effects on encoding. J Neurosci (2013) 33:19635–46.10.1523/JNEUROSCI.2586-13.2013 PubMed DOI PMC

Newman EL, Climer JR, Hasselmo ME. Grid cell spatial tuning reduced following systemic muscarinic receptor blockade. Hippocampus (2014) 24:643–55.10.1002/hipo.22253 PubMed DOI PMC

Hasselmo ME. The role of acetylcholine in learning and memory. Curr Opin Neurobiol (2006) 16:710–5.10.1016/j.conb.2006.09.002 PubMed DOI PMC

Cozzolino R, Guaraldi D, Giuliani A, Ghirardi O, Ramacci MT, Angelucci L. Effects of concomitant nicotinic and muscarinic blockade on spatial memory disturbance in rats are purely additive: evidence from the Morris water task. Physiol Behav (1994) 56:111–4.10.1016/0031-9384(94)90267-4 PubMed DOI

Riekkinen M, Riekkinen P. Dorsal hippocampal muscarinic acetylcholine and NMDA receptors disrupt water maze navigation. Neuroreport (1997) 8:645–8.10.1097/00001756-199702100-00013 PubMed DOI

Huang Z-B, Wang H, Rao X-R, Zhong G-F, Hu W-H, Sheng G-Q. Different effects of scopolamine on the retrieval of spatial memory and fear memory. Behav Brain Res (2011) 221:604–9.10.1016/j.bbr.2010.05.032 PubMed DOI

Laczó J, Markova H, Lobellova V, Gazova I, Parizkova M, Cerman J, et al. 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 (Berl) (2016) 234(4):535–47.10.1007/s00213-016-4488-2 PubMed DOI

Day LB, Schallert T. Anticholinergic effects on acquisition of place learning in the Morris water task: spatial mapping deficit or inability to inhibit nonplace strategies? Behav Neurosci (1996) 110:998–1005.10.1037/0735-7044.110.5.998 PubMed DOI

Misik J, Vanek J, Musilek K, Kassa J. Cholinergic antagonist 3-quinuclidinyl benzilate – impact on learning and memory in Wistar rats. Behav Brain Res (2014) 266:193–200.10.1016/j.bbr.2014.03.001 PubMed DOI

Kobayashi F, Yageta Y, Yamazaki T, Wakabayashi E, Inoue M, Segawa M, et al. Pharmacological effects of imidafenacin (KRP-197/ONO-8025), a new bladder selective anti-cholinergic agent, in rats. Comparison of effects on urinary bladder capacity and contraction, salivary secretion and performance in the Morris water maze task. Arzneimittelforschung (2007) 57:147–54.10.1055/s-0031-1296598 PubMed DOI

Hagan JJ, Jansen JHM, Broekkamp CLE. Blockade of spatial learning by the M1 muscarinic antagonist pirenzepine. Psychopharmacology (Berl) (1987) 93:470–6.10.1007/BF00207237 PubMed DOI

Hunter AJ, Roberts FF. The effect of pirenzepine on spatial learning in the Morris Water Maze. Pharmacol Biochem Behav (1988) 30:519–23.10.1016/0091-3057(88)90490-X PubMed DOI

Miyakawa T, Yamada M, Duttaroy A, Wess J. Hyperactivity and intact hippocampus-dependent learning in mice lacking the M1 muscarinic acetylcholine receptor. J Neurosci (2001) 21:5239–50. PubMed PMC

Bubser M, Byun N, Wood MR, Jones CK. Muscarinic receptor pharmacology and circuitry for the modulation of cognition. Handb Exp Pharmacol (2012) 208:121–66.10.1007/978-3-642-23274-9_7 PubMed DOI

Rowe WB, O’Donnell J-P, Pearson D, Rose GM, Meaney MJ, Quirion R. Long-term effects of BIBN-99, a selective muscarinic M2 receptor antagonist, on improving spatial memory performance in aged cognitively impaired rats. Behav Brain Res (2003) 145:171–8.10.1016/S0166-4328(03)00116-5 PubMed DOI

Greenlee W, Clader J, Asberom T, McCombie S, Ford J, Guzik H, et al. Muscarinic agonists and antagonists in the treatment of Alzheimer’s disease. Farmaco (2001) 56:247–50.10.1016/S0014-827X(01)01102-8 PubMed DOI

Koshimizu H, Leiter LM, Miyakawa T. M4 muscarinic receptor knockout mice display abnormal social behavior and decreased prepulse inhibition. Mol Brain (2012) 5:10.10.1186/1756-6606-5-10 PubMed DOI PMC

Pilcher JJ, Sessions GR, McBride SA. Scopolamine impairs spatial working memory in the radial maze: an analysis by error type and arm choice. Pharmacol Biochem Behav (1997) 58:449–59.10.1016/S0091-3057(97)00297-9 PubMed DOI

Myhrer T. Neurotransmitter systems involved in learning and memory in the rat: a meta-analysis based on studies of four behavioral tasks. Brain Res Brain Res Rev (2003) 41:268–87.10.1016/S0165-0173(02)00268-0 PubMed DOI

Kay C, Harper DN, Hunt M. Differential effects of MDMA and scopolamine on working versus reference memory in the radial arm maze task. Neurobiol Learn Mem (2010) 93:151–6.10.1016/j.nlm.2009.09.005 PubMed DOI

Ortega-Alvaro A, Gibert-Rahola J, Micó JA. Influence of chronic treatment with olanzapine, clozapine and scopolamine on performance of a learned 8-arm radial maze task in rats. Prog Neuropsychopharmacol Biol Psychiatry (2006) 30:104–11.10.1016/j.pnpbp.2005.08.020 PubMed DOI

Hodges DB, Lindner MD, Hogan JB, Jones KM, Markus EJ. Scopolamine induced deficits in a battery of rat cognitive tests: comparisons of sensitivity and specificity. Behav Pharmacol (2009) 20:237–51.10.1097/FBP.0b013e32832c70f5 PubMed DOI

Klinkenberg I, Blokland A. The validity of scopolamine as a pharmacological model for cognitive impairment: a review of animal behavioral studies. Neurosci Biobehav Rev (2010) 34:1307–50.10.1016/j.neubiorev.2010.04.001 PubMed DOI

Moran PM. Differential effects of scopolamine and mecamylamine on working and reference memory in the rat. Pharmacol Biochem Behav (1993) 45:533–8.10.1016/0091-3057(93)90502-K PubMed DOI

Newman LA, Gold PE. Attenuation in rats of impairments of memory by scopolamine, a muscarinic receptor antagonist, by mecamylamine, a nicotinic receptor antagonist. Psychopharmacology (Berl) (2016) 233:925–32.10.1007/s00213-015-4174-9 PubMed DOI PMC

Spowart-Manning L, van der Staay FJ. The T-maze continuous alternation task for assessing the effects of putative cognition enhancers in the mouse. Behav Brain Res (2004) 151:37–46.10.1016/j.bbr.2003.08.004 PubMed DOI

Givens B, Olton DS. Bidirectional modulation of scopolamine-induced working memory impairments by muscarinic activation of the medial septal area. Neurobiol Learn Mem (1995) 63:269–76.10.1006/nlme.1995.1031 PubMed DOI

Lalonde R. The neurobiological basis of spontaneous alternation. Neurosci Biobehav Rev (2002) 26:91–104.10.1016/S0149-7634(01)00041-0 PubMed DOI

Ukai M, Shinkai N, Kameyama T. Cholinergic receptor agonists inhibit pirenzepine-induced dysfunction of spontaneous alternation performance in the mouse. Gen Pharmacol (1995) 26:1529–32.10.1016/0306-3623(95)00038-0 PubMed DOI

Seeger T, Fedorova I, Zheng F, Miyakawa T, Koustova E, Gomeza J, et al. M2 muscarinic acetylcholine receptor knock-out mice show deficits in behavioral flexibility, working memory, and hippocampal plasticity. J Neurosci (2004) 24:10117–27.10.1523/JNEUROSCI.3581-04.2004 PubMed DOI PMC

Araya R, Noguchi T, Yuhki M, Kitamura N, Higuchi M, Saido TC, et al. Loss of M5 muscarinic acetylcholine receptors leads to cerebrovascular and neuronal abnormalities and cognitive deficits in mice. Neurobiol Dis (2006) 24:334–44.10.1016/j.nbd.2006.07.010 PubMed DOI

Deacon RMJ, Rawlins JNP. T-maze alternation in the rodent. Nat Protoc (2006) 1:7–12.10.1038/nprot.2006.2 PubMed DOI

Hatalova H, Radostova D, Pistikova A, Vales K, Stuchlik A. Spatial reversal learning in chronically sensitized rats and in undrugged sensitized rats with dopamine d2-like receptor agonist quinpirole. Front Behav Neurosci (2014) 8:122.10.3389/fnbeh.2014.00122 PubMed DOI PMC

Stuchlik A, Petrasek T, Vales K. Dopamine D2 receptors and alpha1-adrenoceptors synergistically modulate locomotion and behavior of rats in a place avoidance task. Behav Brain Res (2008) 189:139–44.10.1016/j.bbr.2007.12.025 PubMed DOI

Stuchlik A, Vales K. Role of alpha1- and alpha2-adrenoceptors in the regulation of locomotion and spatial behavior in the active place avoidance task: a dose-response study. Neurosci Lett (2008) 433:235–40.10.1016/j.neulet.2008.01.013 PubMed DOI

Stuchlik A, Vales K. Systemic administration of MK-801, a non-competitive NMDA-receptor antagonist, elicits a behavioural deficit of rats in the Active Allothetic Place Avoidance (AAPA) task irrespectively of their intact spatial pretraining. Behav Brain Res (2005) 159:163–71.10.1016/j.bbr.2004.10.013 PubMed DOI

Stuchlík A, Petrásek T, Prokopová I, Holubová K, Hatalová H, Valeš K, et al. Place avoidance tasks as tools in the behavioral neuroscience of learning and memory. Physiol Res (2013) 62(Suppl 1):S1–19. PubMed

Stuchlik A, Kubik S, Vlcek K, Vales K. Spatial navigation: implications for animal models, drug development and human studies. Physiol Res (2014) 63(Suppl 1):S237–49. PubMed

Bubenikova-Valesova V, Stuchlik A, Svoboda J, Bures J, Vales K. Risperidone and ritanserin but not haloperidol block effect of dizocilpine on the active allothetic place avoidance task. Proc Natl Acad Sci U S A (2008) 105:1061–6.10.1073/pnas.0711273105 PubMed DOI PMC

Bures J, Fenton AA, Kaminsky YU, Wesierska M, Zahalka A. Rodent navigation after dissociation of the allocentric and idiothetic representations of space. Neuropharmacology (1998) 37:689–99.10.1016/S0028-3908(98)00031-8 PubMed DOI

Czeh B, Stuchlik A, Wesierska M, Cimadevilla JM, Pokorny J, Seress L, et al. Effect of neonatal dentate gyrus lesion on allothetic and idiothetic navigation in rats. Neurobiol Learn Mem (2001) 75:190–213.10.1006/nlme.2000.3975 PubMed DOI

Kubik S, Stuchlik A, Fenton AA. Evidence for hippocampal role in place avoidance other than merely memory storage. Physiol Res (2006) 55:445–52. PubMed

Stuchlik A, Bures J. Relative contribution of allothetic and idiothetic navigation to place avoidance on stable and rotating arenas in darkness. Behav Brain Res (2002) 128:179–88.10.1016/S0166-4328(01)00314-X PubMed DOI

Vales K, Stuchlik A. Central muscarinic blockade interferes with retrieval and reacquisition of active allothetic place avoidance despite spatial pretraining. Behav Brain Res (2005) 161(2):238–44. PubMed

Barnes CA. Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. J Comp Physiol Psychol (1979) 93:74–104.10.1037/h0077579 PubMed DOI

Komater VA, Buckley MJ, Browman KE, Pan JB, Hancock AA, Decker MW, et al. Effects of histamine H3 receptor antagonists in two models of spatial learning. Behav Brain Res (2005) 159:295–300.10.1016/j.bbr.2004.11.008 PubMed DOI

Gawel K, Labuz K, Gibula-Bruzda E, Jenda M, Marszalek-Grabska M, Filarowska J, et al. Cholinesterase inhibitors, donepezil and rivastigmine, attenuate spatial memory and cognitive flexibility impairment induced by acute ethanol in the Barnes maze task in rats. Naunyn Schmiedebergs Arch Pharmacol (2016) 389:1059–71.10.1007/s00210-016-1269-8 PubMed DOI PMC

Van Der Staay FJ, Bouger PC. Effects of the cholinesterase inhibitors donepezil and metrifonate on scopolamine-induced impairments in the spatial cone field orientation task in rats. Behav Brain Res (2005) 156:1–10.10.1016/j.bbr.2004.05.010 PubMed DOI

Post AM, Wultsch T, Popp S, Painsipp E, Wetzstein H, Kittel-Schneider S, et al. The COGITAT holeboard system as a valuable tool to assess learning, memory and activity in mice. Behav Brain Res (2011) 220:152–8.10.1016/j.bbr.2011.01.054 PubMed DOI

Bainbridge NK, Koselke LR, Jeon J, Bailey KR, Wess J, Crawley JN, et al. Learning and memory impairments in a congenic C57BL/6 strain of mice that lacks the M2 muscarinic acetylcholine receptor subtype. Behav Brain Res (2008) 190:50–8.10.1016/j.bbr.2008.02.001 PubMed DOI PMC

Chemogenetic Tools and their Use in Studies of Neuropsychiatric Disorders

Mnemonic and behavioral effects of biperiden, an M1-selective antagonist, in the rat