Elevated plus maze

The elevated plus maze (EPM) is a rodent model of anxiety that is used as a screening test for putative anxiolytic compounds and as a general research tool in neurobiological anxiety research.

The test setting consists of a plus-shaped apparatus with two open and two enclosed arms, each with an open roof, elevated 40–70 cm from the floor. The model is based on rodents' aversion of open spaces. This aversion leads to the behavior termed thigmotaxis, which involves avoidance of open areas by confining movements to enclosed spaces or to the edges of a bounded space. In EPM this translates into a restriction of movement to the enclosed arms   ).

Anxiety reduction in the plus-maze is indicated by an increase in the proportion of time spent in the open arms (time in open arms/total time in open or closed arms), and an increase in the proportion of entries into the open arms (entries into open arms/total entries into open or closed arms). Total number of arm entries and number of closed-arm entries are usually employed as measures of general activity (see.

While EPM is the most commonly employed behavioral animal anxiety model, there are several issues concerning the validity of the model. Classical clinical anxiolytics, such as benzodiazepines (e.g., Valium), do reduce measures of anxiety in EPM. However, more novel compounds, such as 5-HT1A agonists (e.g., Buspar) give mixed results. Selective serotonin reuptake inhibitors and tricyclic antidepressants, which are commonly employed in clinical settings to treat anxiety disorders, also do not lead to a stable anxiolytic effect on EPM. This raises the possibility that EPM is a suitable model for testing GABA-related compounds, such as benzodiazepines or direct GABAA agonists, but not for other drugs. Despite this, the model is commonly employed for screening putative anxiolytics and for general research into the brain mechanisms of anxiety, because of the ease of employment and the vast number of studies already in the literature.

Books

 * Doremus, T. L., Varlinskaya, E. I., & Spear, L. P. (2004). Age-related differences in elevated plus maze behavior between adolescent and adult rats. New York, NY: New York Academy of Sciences.
 * Reibaud, M., & Bohme, G. A. (1993). Evaluation of putative anxiolytics in the elevated plus-maze test. San Diego, CA: Academic Press.

Papers

 * Aguiar, M. S., & Brandao, M. L. (1996). Effects of microinjections of the neuropeptide substance P in the dorsal periaqueductal gray on the behavior of rats in the plus-maze test: Physiology & Behavior Vol 60(4) Oct 1996, 1183-1186.
 * Albrechet-Souza, L., Oliveira, A. R., De Luca, M. C. Z., Tomazini, F. M., Santos, N. R., & Brandao, M. L. (2005). A comparative study with two types of elevated plus-maze (transparent vs. opaque walls) on the anxiolytic effects of midazolam, one-trial tolerance and fear-induced analgesia: Progress in Neuro-Psychopharmacology & Biological Psychiatry Vol 29(4) May 2005, 571-579.
 * Andrade, M. M. M., Tome, M. F., Santiago, E. S., Lucia-Santos, A., & de Andrade, T. G. C. S. (2003). Longitudinal study of daily variation of rats' behavior in the elevated plus-maze: Physiology & Behavior Vol 78(1) Jan 2003, 125-133.
 * Andreatini, R., & Bacellar, L. F. S. (2000). Animal models: Trait or state measure? The test-retest reliability of the elevated plus-maze and behavioral despair: Progress in Neuro-Psychopharmacology & Biological Psychiatry Vol 24(4) May 2000, 549-560.
 * Anseloni, V. Z., & Brandao, M. L. (1997). Ethopharmacological analysis of behaviour of rats using variations of the elevated plus-maze: Behavioural Pharmacology Vol 8(6-7) Nov 1997, 533-540.
 * Appenrodt, E., Kroning, G., & Schwarzberg, H. (1999). Increased plasma ACTH in rats exposed to the elevated plus-maze is independent of the pineal gland: Psychoneuroendocrinology Vol 24(8) Nov 1999, 833-838.
 * Beijamini, V., & Guimaraes, F. S. (2006). Activation of neurons containing the enzyme nitric oxide synthase following exposure to an elevated plus maze: Brain Research Bulletin Vol 69(4) Apr 2006, 347-355.
 * Bertoglio, L. J., & Carobrez, A. P. (2002). Prior maze experience required to alter midazolam effects in rats submitted to the elevated plus-maze: Pharmacology, Biochemistry and Behavior Vol 72(1-2) May 2002, 449-455.
 * Bertoglio, L. J., & Carobrez, A. P. (2003). Anxiolytic-like effects of NMDA/glycine-B receptor ligands are abolished during the elevated plus-maze trial 2 in rats: Psychopharmacology Vol 170(4) Dec 2003, 335-342.
 * Biala, G., & Kruk, M. (2008). Calcium channel antagonists suppress cross-tolerance to the anxiogenic effects of D-amphetamine and nicotine in the mouse elevated plus maze test: Progress in Neuro-Psychopharmacology & Biological Psychiatry Vol 32(1) Jan 2008, 54-61.
 * Biala, G., & Kruk, M. (2008). Cannabinoid receptor ligands suppress memory-related effects of nicotine in the elevated plus maze test in mice: Behavioural Brain Research Vol 192(2) Oct 2008, 198-202.
 * Blundell, J., & Adamec, R. (2006). Elevated pCREB in the PAG after exposure to the elevated plus maze in rats previously exposed to a cat: Behavioural Brain Research Vol 175(2) Dec 2006, 285-295.
 * Borta, A., & Schwarting, R. K. W. (2005). Inhibitory avoidance, pain reactivity, and plus-maze behavior in Wistar rats with high versus low rearing activity: Physiology & Behavior Vol 84(3) Mar 2005, 387-396.
 * Botelho, S., Estanislau, C., & Morato, S. (2007). Effects of under- and overcrowding on exploratory behavior in the elevated plus-maze: Behavioural Processes Vol 74(3) Mar 2007, 357-362.
 * Bush, D. E. A., & Vaccarino, F. J. (2007). Individual differences in elevated plus-maze exploration predicted progressive-ratio cocaine self-administration break points in Wistar rats: Psychopharmacology Vol 194(2) Oct 2007, 211-219.
 * Cao, B. J., & Rodgers, R. J. (1996). Different behavioural profiles of the R(+)- and S(-)-enantiomers of 8-hydroxy-2-(di-n-propylamino)tetralin in the murine elevated plus-maze: Behavioural Pharmacology Vol 7(8) Dec 1996, 810-819.
 * Cao, B. J., & Rodgers, R. J. (1997). Anxiolytic-like profile of p-MPPI, a novel 5HT-sub(1A ) receptor antagonist, in the murine elevated plus-maze: Psychopharmacology Vol 129(4) Feb 1997, 365-371.
 * Cao, B. J., & Rodgers, R. J. (1997). Influence of 5-HT-sub(1A ) receptor antagonism on plus-maze behaviour in mice. I. Pindolol enantiomers and pindobind 5-HT-sub(1A): Pharmacology, Biochemistry and Behavior Vol 58(2) Oct 1997, 583-591.
 * Cao, B. J., & Rodgers, R. J. (1997). Influence of 5-HT-sub(1A ) receptor antagonism on plus-maze behaviour in mice. II. WAY 100635, SDZ 216-525 and NAN-190: Pharmacology, Biochemistry and Behavior Vol 58(2) Oct 1997, 593-603.
 * Cao, B. J., & Rodgers, R. J. (1998). Comparative effects of novel 5-HT-sub(1A ) receptor ligands, LY293284, LY315712 and LY297996, on plus-maze anxiety in mice: Psychopharmacology Vol 139(3) Oct 1998, 185-194.
 * Carobrez, A. P., & Bertoglio, L. J. (2005). Ethological and temporal analyses of anxiety-like behavior: The elevated plus-maze model 20 years on: Neuroscience & Biobehavioral Reviews Vol 29(8) Dec 2005, 1193-1205.
 * Carrasco, M. C., Vicens, P., Vidal, J., & Redolat, R. (2006). Effects of co-administration of bupropion and nicotinic agonists on the elevated plus-maze test in mice: Progress in Neuro-Psychopharmacology & Biological Psychiatry Vol 30(3) May 2006, 455-462.
 * Carvalho, R. C., Patti, C. C., Takatsu-Colemana, A. L., Kameda, S. R., Souza, C. F., Garcez-do-Carmo, L., et al. (2006). Effects of reserpine on the plus-maze discriminative avoidance task: Dissociation between memory and motor impairments: Brain Research Vol 1122(2) Nov 2006, 179-183.
 * Chung, B. K., & Yoon, B. S. (1996). Effects of medial and lateral septal lesions on expression of anxiety in an elevated plus-maze in rats: Korean Journal of Biological & Physiological Psychology Vol 8(1) 1996, 39-48.
 * Clenet, F., Hascoet, M., Fillion, G., Galons, H., & Bourin, M. (2005). Role of GABA-ergic and serotonergic systems in the anxiolytic-like mechanism of action of a 5-HT-moduline antagonist in the mouse elevated plus maze: Behavioural Brain Research Vol 158(2) Mar 2005, 339-348.
 * Cole, J. C., & Rodgers, R. J. (1993). An ethological analysis of the effects of chlordiazepoxide and bretazenil (Ro 16-6028) in the murine elevated plus-maze: Behavioural Pharmacology Vol 4(6) Dec 1993, 573-580.
 * Collinson, N., & Dawson, G. R. (1997). On the elevated plus-maze the anxiolytic-like effects of the 5-HT-sub(1a ) agonist, 8-OH-DPAT, but not the anxiogenic-like effects of the 5-HT-sub(1A ) partial agonist, buspirone, are blocked by the 5-HT-sub(1A ) antagonist, WAY 100635: Psychopharmacology Vol 132(1) Jul 1997, 35-43.
 * Coussons-Read, M. E., & Crnic, L. S. (1996). Behavioral assessment of the Ts65Dn nouse, a model for Down syndrome: Altered behavior in the elevated plus maze and open field: Behavior Genetics Vol 26(1) Jan 1996, 7-13.
 * Da Cunha, I. C., Jose, R. F., Pereira, L. O., Pimenta, J. A., de Souza, I. A. O., Reiser, R., et al. (2005). The role of nitric oxide in the emotional learning of rats in the plus-maze: Physiology & Behavior Vol 84(3) Mar 2005, 351-358.
 * Dal-Col, M. L. C., Pereira, L. O., Rosa, V. P., Calixto, A. V., Carobrez, A. P., & Faria, M. S. (2003). Lack of midazolam-induced anxiolysis in the plus-maze Trial 2 is dependent on the length of Trial 1: Pharmacology, Biochemistry and Behavior Vol 74(2) Jan 2003, 395-400.
 * Dawson, G. R., Crawford, S. P., Collinson, N., Iversen, S. D., & et al. (1995). Evidence that the anxiolytic-like effects of chlordiazepoxide on the elevated plus maze are confounded by increases in locomotor activity: Psychopharmacology Vol 118(3) Apr 1995, 316-323.
 * de Almeida, R. N., Motta, S. C., de Brito Faturi, C., Catallani, B., & Leite, J. R. (2004). Anxiolytic-like effects of rose oil inhalation on the elevated plus-maze test in rats: Pharmacology, Biochemistry and Behavior Vol 77(2) Feb 2004, 361-364.
 * De Mello Cruz, A. P., Pinheiro, G., Alves, S. H., Ferreira, G., Mendes, M., Faria, L., et al. (2005). Behavioral effects of systemically administered MK-212 are prevented by ritanserin microinfusion into the basolateral amygdala of rats exposed to the elevated plus-maze: Psychopharmacology Vol 182(3) Nov 2005, 345-354.
 * De-Mello, N., & Carobrez, A. P. (2002). Elevated T-maze as an animal model of memory: Effects of scopolamine: Behavioural Pharmacology Vol 13(2) Mar 2002, 139-148.
 * Doremus, T. L., Varlinskaya, E. I., & Spear, L. P. (2006). Factor analysis of elevated plus-maze behavior in adolescent and adult rats: Pharmacology, Biochemistry and Behavior Vol 83(4) Apr 2006, 570-577.
 * Ducottet, C., & Belzung, C. (2004). Behaviour in the elevated plus-maze predicts coping after subchronic mild stress in mice: Physiology & Behavior Vol 81(3) May 2004, 417-426.
 * Elfline, G. S., Branda, E. M., Babich, M., & Quock, R. M. (2004). Antagonism by NOS inhibition of the behavioral effects of benzodiazepine and GABA-sub(A) receptor agonists in the mouse elevated plus-maze: Neuropsychopharmacology Vol 29(8) Aug 2004, 1419-1425.
 * Elliott, B. M., Faraday, M. M., Phillips, J. M., & Grunberg, N. E. (2004). Effects of nicotine on elevated plus maze and locomotor activity in male and female adolescent and adult rats: Pharmacology, Biochemistry and Behavior Vol 77(1) Jan 2004, 21-28.
 * Espejo, E. F. (1997). Effects of weekly or daily exposure to the elevated plus-maze in male mice: Behavioural Brain Research Vol 87(2) Sep 1997, 233-238.
 * Espejo, E. F. (1997). Structure of the mouse behaviour on the elevated plus-maze test of anxiety: Behavioural Brain Research Vol 86(1) Jun 1997, 105-112.
 * Estanislau, C., & Morato, S. (2006). Behavior ontogeny in the elevated plus-maze: prenatal stress effects: International Journal of Developmental Neuroscience Vol 24(4) Jun 2006, 255-262.
 * Ferguson, S. A., & Gray, E. P. (2005). Aging effects on elevated plus maze behavior in spontaneously hypertensive, Wistar-Kyoto and Sprague-Dawley male and female rats: Physiology & Behavior Vol 85(5) Aug 2005, 621-628.
 * Fernandes, C., & File, S. E. (1996). The influence of open arm ledges and maze experience in the elevated plus-maze: Pharmacology, Biochemistry and Behavior Vol 54(1) May 1996, 31-40.
 * Ferris, P., Seward, E., & Dawson, G. R. (2001). Interactions between LY354740, a Group II metabotropic agonist and the GABA-sub(A)-benzodiazepine receptor complex in the rat elevated plus-maze: Journal of Psychopharmacology Vol 15(2) 2001, 76-82.
 * File, S. E., Zangrossi, H., & Andrews, N. (1993). Social interaction and elevated plus-maze tests: Changes in release and uptake of 5-HT and GABA: Neuropharmacology Vol 32(3) Mar 1993, 217-221.
 * File, S. E., Zangrossi, H., Viana, M., & Graeff, F. G. (1993). Trial 2 in the elevated plus-maze: A different form of fear? : Psychopharmacology Vol 111(4) Jul 1993, 491-494.
 * Francolin-Silva, A. L., Hernandes, A. d. S., Fukuda, M. T. H., Valadares, C. T., & Almeida, S. S. (2006). Anxiolytic-like effects of short-term postnatal protein malnutrition in the elevated plus-maze test: Behavioural Brain Research Vol 173(2) Sep 2006, 310-314.
 * Frussa-Filho, R., & de A. Ribeiro, R. (2002). One-trial tolerance to the effects of chlordiazepoxide in the elevated plus-maze is not due to acquisition of a phobic avoidance of open arms during initial exposure: Life Sciences Vol 71(5) Jun 2002, 519-525.
 * Garcia, A. M. B., Cardenas, F. P., & Morato, S. (2005). Effect of different illumination levels on rat behavior in the elevated plus-maze: Physiology & Behavior Vol 85(3) Jun 2005, 265-270.
 * Garcia, A. M. B., Martinez, R., Brandao, M. L., & Morato, S. (2005). Effects of apomorphine on rat behavior in the elevated plus-maze: Physiology & Behavior Vol 85(4) Jul 2005, 440-447.
 * Gonzalez, L. E., & File, S. E. (1997). A five minute experience in the elevated plus-maze alters the state of the benzodiazepine receptor in the dorsal raphe nucleus: Journal of Neuroscience Vol 17(4) Feb 1997, 1505-1511.
 * Griebel, G., Moreau, J.-L., Jenck, F., Martin, J. R., & et al. (1993). Some critical determinants of the behaviour of rats in the elevated plus-maze: Behavioural Processes Vol 29(1-2) Apr 1993, 37-47.


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 * Rodgers, R. J., Evans, P. M., & Murphy, A. (2005). Anxiogenic profile of AM-251, a selective cannabinoid CB1 receptor antagonist, in plus-maze-naive and plus-maze-experienced mice: Behavioural Pharmacology Vol 16(5-6) Sep 2005, 405-413.
 * Rodgers, R. J., Haller, J., Halasz, J., & Mikics, E. (2003). 'One-trial sensitization' to the anxiolytic-like effects of cannabinoid receptor antagonist SR141716A in the mouse elevated plus-maze: European Journal of Neuroscience Vol 17(6) Mar 2003, 1279-1286.
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 * Rojas-Ortiz, Y. A., Rundle-Gonzalez, V., Rivera-Ramos, I., & Jorge, J. C. (2006). Modulation of elevated plus maze behavior after chronic exposure to the anabolic steroid 17alpha -methyltestosterone in adult mice: Hormones and Behavior Vol 49(1) Jan 2006, 123-128.
 * Rostami, P., Hajizadeh-Moghaddam, A., & Zarrindast, M.-R. (2006). The effects of histaminergic agents in the ventral hippocampus of rats in the plus-maze test of anxiety-like behaviours: Physiology & Behavior Vol 87(5) May 2006, 891-896.
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 * Sala-Roca, J., Marti-Carbonell, M. A., Garau, A., Darbra, S., & Balada, F. (2002). Effects of dysthyroidism in plus maze and social interaction tests: Pharmacology, Biochemistry and Behavior Vol 72(3) Jun 2002, 643-650.
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 * Tambour, S., Didone, V., Tirelli, E., & Quertemont, E. (2005). Dissociation between the locomotor and anxiolytic effects of acetaldehyde in the elevated plus-maze: Evidence that acetaldehyde is not involved in the anxiolytic effects of ethanol in mice: European Neuropsychopharmacology Vol 15(6) Dec 2005, 655-662.
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