Elevated-Plus Maze

Probably the most frequently used test for unconditioned anxiety is the elevated plus maze (EPM), which was first introduced by File and coworkers (Pellow et al. 1985). The test consists of an elevated, plus-sign-shaped runway with two opposing arms being closed by walls and the other two arms being open, i.e., unprotected (Fig. 5). The animal usually is placed in the center of the EPM, 

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Bowen SE, Wiley JL, Balster RL The effects of abused inhalants on mouse behavior in an elevated plus-maze. Eur J Pharmacol 312 131-136, 1996a Bowen SE, Wiley JL, Evans EB, et al Functional observational battery comparing effects of ethanol, 1,1,1-trichloroethane, ether, and flurothyl. Neurotoxicol Ter-atol 18 577-583, 1996b... 

Elevated plus-maze Social interaction test Light/dark shuttle-box... 

Figure 19.1 The elevated plus-maze. (Top) The apparatus is arranged with two open arms, two closed arms and a central zone, raised above the ground. Animals are placed in the central zone (usually facing an open arm) and their movements scored for number of entries to the open and closed arms and the percentage time spent in the open arms. (Bottom) Chronic administration (5 days) of the anti-anxiety drug, chlordiazepoxide, increases the percentage time spent on the open arms to approximately 50% of the total. (Figure kindly provided by S. E. File)...

Rodgers, RJ and Dalvi, A (1997) Anxiety, defence and the elevated plus-maze. Neurosci. Biobehav. Rev. 21 801-810. 

Wilson, J, Watson, WP and Little, HJ (1998) CCK(B) antagonists protect against anxiety-related behaviour produce by ethanol withdrawal, measured using the elevated plus-maze. Psychopharmacology 137 121-131. 

Skrebuhhova, T., Allikmets, L. Matto, V. (1999). 5-HT2A receptors mediate the effects of antidepressants in the elevated plus-maze test but have a partial role in the forced swim test. Med. Sci. Res., 27, 277-80. 

Valerian extracts show sedative and anxiolytic effects. Whereas passionflower and chamomile have relatively specific anxiolytic effects, valerian shows more general sedative effects, but all effects occur in a dose-dependent manner (Della Logia et al. 1981 Leuschner et al. 1993). The sedative effects of valerian extract are moderate when compared to diazepam and the neuroleptic chlorpromazine (Leuschner et al. 1993). However, valepotriates reverse the anxiogenic effects of diazepam withdrawal in rats in the elevated plus maze. This effect is dose dependent, effective at 12 mg/kg but not 6 mg/kg. Interestingly, the fragrant valerian compound bornyl acetate has sedative effects in mice, but only when inhaled (Buchbauer et al. 1992). 

Sedative and anxioiytic effects A number of flavonoids have been shown to bind to benzodiazepine receptors and have anxiolytic effects (Medina et al. 1997). The anxiolytic effects of chrysin were examined in mice (Wolfman et al. 1994). Chrysin (1 mg/kg IP) reduces behavioral measures of anxiety (elevated-plus maze) in a manner similar to diazepam (0.3-0.6 mg/kg), which was reversed by pretreatment with a benzodiazepine antagonist, Ro 15-1788. The anxiolytic effect is not likely due to sedation because there is no concurrent reduction in motor activity at the doses used. Unlike diazepam, chrysin does not produce muscle relaxation at higher doses. 

Two studies have been done to date that address ginger s anxiolytic effects in an animal model (Hassenohrl et al. 1996, 1998). Unfortunately, both of these employ a combined treatment of ginger and Ginkgo biloba so they do not allow for differentiation of effects. The combination had diazepamlike effects in an animal model of anxiety (elevated-plus maze) (Hassenohrl et al. 1996). These effects were dose dependent and tripha-... 

Hasenohrl RU, Nichau CH, Frisch CH, De Souza Silva MA, Huston JP, Mattern CM, Hacker R. (1996). Anxiolytic-like effect of combined extracts of Zingiber officinale and Ginkgo biloba in the elevated plus-maze. Pharmacol Biochem Behav. 53(2) 271-5. 

Spontaneous Reduced social interaction Elevated plus maze (anxiety) Generalization to PTZ (anxiety)... 

Fig. 5 Elevated plus maze for mice. While cautiously entering the platform, the mouse displays risk assessment behavior...

One recent selectively bred rat fine is the rat model of high and low anxiety-related behavior, developed by Landgraf and colleagues (Liebsch et al. 1998). Wistar rats displaying either extremely high (HAB) or low (LAB) anxiety-related behavior on the elevated plus maze (see Sect. 2.2.2) were selected and bred over a decade (Liebsch et al. 1998). The resulting two rat fines distinctly... 

Ahmed FP, McLaughlin DP, Stanford SC, Stamford JA (2002) Maudsley reactive and non-reactive (MNRA) rats display hehavioral contrasts on exposure to an open field, the elevated plus maze or the dark-light shuttle hox. Abstract, FENS, Paris, France Ammassari-Teule A, Milhaud JM, Passino E, Restivo L, LassaUe JM (1999) Defective processing of contextual information may he involved in the poor performance of DBA/2 mice in spatial tasks. Behav Genet 29 283-289 Anisman H, Zalcman S, Shanks N, Zacharko RM (1991) Multisystem regulation of performance deficits induced hy stressors an animal model of depression. In Boulton AA, Baker GB, Martin-lverson MT (eds) Animal models in psychiatry, vol 2. Humana Press, Clifton, pp 1-59... 

Griebel G, Moreau J-L, Jenck F, Martin JR, Misslin R (1993) Some critical determinants of the behavior of rats in the elevated plus-maze. Behav Process 29 37-48 Griebel G, Sanger DJ, Perrault G (1997) Genetic differences in the mouse defense test battery. Aggress Behav 23 10-31... 

Hogg S (1996) A review of the validity and variability of the elevated plus maze as an animal model of anxiety. Pharmacol fiiochem fiehav 54 21-30... 

Parmigiani S, Palanza P, Rodgers J, Ferrari PF (1999) Selection, evolution of behavior and animal models in behavioral neuroscience. Nemosci Biobehav Rev 23 957-970 Pellow S, Chopin P, File SE, Briley M (1985) Validation of open closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14 149-167 Picciotto MR (1999) Knock-out mouse models used to study nemobiological systems. Crit Rev Neurobiol 13 103-149... 

Reul JMHM, Holsboer F (2002) Corticotropin-releasing factor receptors 1 and 2 in anxiety and depression. Curr Opin Pharmacol 2 23-33 Rodgers RJ, Cole JC (1994) The elevated plus-maze pharmacology, methodology and ethology. In Cooper SJ, Hendrie CA (eds) Ethology and psychopharmacology. John Wiley and Sons, Chichester, pp 9-44... 

Stress results in alterations in behavior and physiology that can be either adaptive or maladaptive. Although mice deficient in the calcium-stimulated adenylyl cyclase type VIII (ACS) exhibit indices of anxiety comparable with that of wildtype mice at baseline, ACS KO mice do not show normal increases in behavioral features of anxiety when subjected to repeated stress such as repetitive or post-restraint stress testing in the elevated plus maze test (Schaefer et al. 2000). Although these findings suggest a role for ACS in the modulation of anxiety, the mechanism by which ACS deficiency results in impaired stress-... 

Behavioral analyses revealed that the mice overexpressing CRH-BP exhibit increased locomotor activity in a novel environment (Burrows et al. 1998). In addition, a tendency towards decreased anxiety-related behavior was observed on the elevated plus maze, which would be in line with limited availabihty of free CRH due to enhanced binding by CRH-BP in these animals. 

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