Cited by 437Neurotransmitter Receptor Influence on BehaviorAnxiety, Depression, Psychometrics, Treatment, Cognitive ProcessesMemory and Neural Mechanisms

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Animal models of ‘anxiety’: Where next?

Rodgers, R J·1997·Behavioural Pharmacology

DOI 10.1097/00008877-199711000-00003

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Abstract

Numerous procedures have been developed to facilitate preclinical research on the behavioural pharmacology of anxiety and, as a result of this application, are often referred to as animal models of 'anxiety'. This is an unfortunate misnomer, not only because of the apparent inability of many tests to detect novel anxiolytics consistently, but also because the term implies that anxiety is a unitary emotion. Such difficulties have arisen largely as a consequence of test development strategies which, by emphasizing pharmacological (i.e. benzodiazepine) validation, have yielded models predictive of a specific type of anxiolytic activity. The present review argues that the refinement of existing tests as well as the development of new procedures requires urgent attention to the much neglected issue of behavioural validation. From an evolutionary perspective, normal human anxiety may be conceptualized as a repertoire of defence reactions tailored to meet different forms of threats, and disorders of anxiety as the inappropriate activation or exaggeration of these usually adaptive response patterns. In this context, consideration of the defensive reactions typically observed in our animal models reveals substantially greater commonality in the behavioural effects of benzodiazepine and 5-HT1A anxiolytics than would otherwise be apparent. Therefore, with the exception of the conventional plus-maze paradigm (discussed at some length), better correspondence is seen in tests involving unconditioned response to potential threat (e.g. social interaction, distress vocalizations and light/dark exploration) than in tests of conditioned fear reactions. Even within the latter grouping, however, greater commonality is seen in procedures based on reactions to proximal threat (e.g. freezing, startle, ultrasonic vocalizations, burying) than those involving reactions to distal threat (e.g. avoidance/flight). Significantly, very similar findings have been reported in tests specifically designed to study defensive reactions (e.g. rat and mouse defence test batteries) or which incorporate a more detailed knowledge of defence into established procedures (e.g. ethological plus-maze and defensive burying paradigms). Furthermore, recent evidence also suggests that drugs with proved clinical efficacy in panic attacks/panic disorder have reliably stronger effects on flight responses than other components of the defensive repertoire. It is concluded that a focus on defensive behaviour patterns improves test validity (predictive/face/construct), offers a more rational basis for test selection in drug development programmes, and provides a firmer theoretical framework for future methodological and therapeutic advance.

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Background
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Background
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Method
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Self-citation
A way forward for anxiolytic drug development: Testing candidate anxiolytics with anxiety-potentiated startle in healthy humans
Grillon, C., & Ernst, M. (2020) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2020.09.024 · Cited by 52
“The limited efficacy of animal models in the drug development process and the need for alternatives have long been pointed out (Griebel and Holmes, 2013; Rodgers, 1997).”
Background
The Elevated Plus-Maze Test: Differential Psychopharmacology of Anxiety-Related Behavior
Pawlak, C. R., Karrenbauer, B. D., Schneider, P., & Ho, Y. (2012) · Emotion Review · doi:10.1177/1754073911421374 · Cited by 57
“For example, in all animal models for psychiatric conditions three types of validity have been suggested, namely, predictive, face, and construct validity (e.g., Pawlak & Weyers, 2006; Rodgers, 1997; Treit, 1985; Willner, 1986; Willner & Mitchell, 2002).”
Background
The intercalated paracapsular islands as a module for integration of signals regulating anxiety in the amygdala
Palomares-Castillo, E., Hernández‐Pérez, O. R., Pérez-Carrera, D., Crespo‐Ramírez, M., Fuxé, K., & de la Mora, M. P. (2012) · Brain Research · doi:10.1016/j.brainres.2012.03.047 · Cited by 56
Free versus forced exposure to an elevated plus-maze: evidence for new behavioral interpretations during test and retest
Roy, V., Chapillon, P., Jeljeli, M., Caston, J., & Belzung, C. (2008) · Psychopharmacology · doi:10.1007/s00213-008-1378-2 · Cited by 56
“The elevated plus-maze has been extensively used in a wide range of research fields in order to examine the effects of a variety of procedures (such as lesions, early stimulation, toxic substances) on anxiety-like behaviors (Carobrez and Bertoglio 2005); it is also the standard for screening the efficiency of pharmaco…”
Measurement of Anxiety in Transgenic Mice
Weiss, S. Μ., Lightowler, S., Stanhope, K. J., Kennett, G. A., & Dourish, C. T. (2000) · Reviews in the Neurosciences · doi:10.1515/revneuro.2000.11.1.59 · Cited by 55
Use of the elevated plus-maze test with opaque or transparent walls in the detection of mouse strain differences and the anxiolytic effects of diazepam
Hagenbuch, N., Feldon, J., & Yee, B. K. (2005) · Behavioural Pharmacology · doi:10.1097/01.fbp.0000189811.77049.3e · Cited by 52
“Several dedicated reviews of the EPM did not discuss the significance of the construction of the enclosed arms (Handley and McBlane, 1993; Reibaud and Bohme, 1993; Dawson and Tricklebank, 1995; File, 2001), while others recognized its importance (Rodgers and Johnson, 1995; Hogg, 1996; Rodgers, 1997; Rodgers et al., 19…”
Background
Ethological validation and the assessment of anxiety-like behaviours: methodological comparison of classical analyses and structural approaches
Calatayud, F., Belzung, C., & Aubert, A. (2004) · Behavioural Processes · doi:10.1016/j.beproc.2004.04.002 · Cited by 55
“The notion of “natural stimulus” is quite vague since it refers to all unconditioned stimuli sustaining spontaneous responses (Rodgers, 1997).”
Background
Neural Mechanisms of Placebo Anxiolysis
Meyer, B., Yuen, K. S. L., Ertl, M., Polomac, N., Mulert, C., Büchel, C., & Kalisch, R. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.4793-14.2015 · Cited by 50
“Ethologists have long made a distinction between fear responses to imminent threats (such as the presence of a predator), which often involve flight or fight, and more sustained anxiety responses to distal or potential threats (such as the odor of a predator), often involving vigilant scanning and risk assessment (Fan…”
Background
Blockade of NMDA receptors and nitric oxide synthesis in the dorsolateral periaqueductal gray attenuates behavioral and cellular responses of rats exposed to a live predator
de Aguiar, D. C., & Guimarães, F. S. (2009) · Journal of Neuroscience Research · doi:10.1002/jnr.22082 · Cited by 51
“Because these behaviors are innate and easily evoked in the laboratory, they have been extensively used to investigate the neural substrate mediating emotional responses to threatening stimuli (Blanchard et al., 2003; Hendrie et al., 1996; Rodgers, 1997).”
Background
Diazepam Has No Beneficial Effects on Stress-Induced Behavioural and Endocrine Changes in Male Tree Shrews
van Kampen, M., Schmitt, U., Hiemke, C., & Fuchs, E. (2000) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(99)00190-2 · Cited by 51
MDMA (‘ecstasy’) exhibits an anxiogenic-like activity in social encounters between male mice
Maldonado, E., & Navarro, J. F. (2001) · Pharmacological Research · doi:10.1006/phrs.2001.0824 · Cited by 51
“In fact, such behavioural categories have been frequently used to assess the anxiety-changing properties of drugs [25, 26 ].”
Background
Critical neuropsychobiological analysis of panic attack- and anticipatory anxiety-like behaviors in rodents confronted with snakes in polygonal arenas and complex labyrinths: a comparison to the elevated plus- and T-maze behavioral tests
Coimbra, N. C., Paschoalin-Maurin, T., Bassi, G. S., Kanashiro, A., Biagioni, A. F., Felippotti, T. T., Elias-Filho, D. H., Mendes-Gomes, J., Coimbra, J. P. C., Almada, R. C., et al. (2017) · Brazilian Journal of Psychiatry · doi:10.1590/1516-4446-2015-1895 · Cited by 51
Effects of social defeat and of diazepam on behavior in a resident–intruder test in male DBA/2 mice
Lumley, L. A., Charles, R. F., Charles, R. C., et al. (2000) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(00)00382-8 · Cited by 49
Cage colour preferences and effects of home cage colour on anxiety in laboratory mice
Sherwin, C. M., & Glen, E. (2003) · Animal Behaviour · doi:10.1006/anbe.2003.2286 · Cited by 49
Behavioral profile of 3,4-methylenedioxy-methamphetamine (MDMA) in agonistic encounters between male mice
Navarro, J. F., & Maldonado, E. (1999) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/s0278-5846(98)00100-6 · Cited by 49
Behavioral Effects of Diazepam in the Murine Plus-Maze
Dalvi, A., & Rodgers, R. J. (1999) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(98)00220-2 · Cited by 48
Self-citation
Selective activation of serotoninergic dorsal raphe neurons facilitates sleep through anxiolysis
Venner, A., Broadhurst, R. Y., Sohn, L. T., Todd, W. D., & Fuller, P. M. (2019) · SLEEP · doi:10.1093/sleep/zsz231 · Cited by 56
“First, the open field test and elevated plus maze reflect different facets of emotionality [61].”
Background
Methylglyoxal can mediate behavioral and neurochemical alterations in rat brain
Hansen, F., Pandolfo, P., Galland, F., Torres, F. V., Dutra, M. F., Batassini, C., Guerra, M. C., Leite, M. C., & Gonçalves, C. (2016) · Physiology & Behavior · doi:10.1016/j.physbeh.2016.05.046 · Cited by 45
An Exploration Based Cognitive Bias Test for Mice: Effects of Handling Method and Stereotypic Behaviour
Novak, J., Bailoo, J. D., Melotti, L., Rommen, J., & Würbel, H. (2015) · PLoS ONE · doi:10.1371/journal.pone.0130718 · Cited by 46
“However, instead of using latency to approach to measure cognitive bias, mice were left to explore the maze, exploiting the conflict between the exploratory drive and neophobic tendency when faced with novel or ambiguous places [28–30].”
Background
Valerian extract characterized by high valerenic acid and low acetoxy valerenic acid contents demonstrates anxiolytic activity
Felgentreff, F., Becker, A., Meier, B. H., & Brattström, A. (2012) · Phytomedicine · doi:10.1016/j.phymed.2012.08.003 · Cited by 46
“Situational anxiety was measured in the elevated plus maze test (Rodgers 1997).”
Method
The anxiolytic-like effect of rutin in rats involves GABAA receptors in the basolateral amygdala
Hernández-León, A., González-Trujano, M. E., & Fernández‐Guasti, A. (2017) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000290 · Cited by 46
“receptors (Niehoff and Kuhar, 1983) that, when blocked, effectively prevent the anxiolytic-like (Rodgers, 1997) effects of BDZ administered systemically (Fernandez-Guasti and Saldivar, 1990; Sanders and Shekhar, 1995).”
Background
Anxiolytic properties of the antipsychotic alkaloid alstonine
Costa-Campos, L., Dassoler, S. C., Rigo, A. P., Iwu, M. M., & Elisabetsky, E. (2004) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2003.12.002 · Cited by 46
Neonatal thyroxine treatment: changes in the number of corticotropin-releasing-factor (CRF) and neuropeptide Y (NPY) containing neurons and density of tyrosine hydroxylase positive fibers (TH) in the amygdala correlate with anxiety-related behavior of wistar rats
Yilmazer‐Hanke, D., Hantsch, M., Hanke, J., Schulz, C., Faber‐Zuschratter, H., & Schwegler, H. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2003.12.004 · Cited by 45
Housing conditions affect rat responses to two types of ambiguity in a reward–reward discrimination cognitive bias task
Parker, R. M., Paul, E. S., Burman, O. H. P., Browne, W. J., & Mendl, M. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.07.048 · Cited by 44
Effects of 3,4-methylenedioxy-methamphetamine (MDMA) on anxiety in mice tested in the light-dark box
Maldonado, E., & Navarro, J. F. (2000) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/s0278-5846(99)00112-8 · Cited by 43
Sex-related effects of sleep deprivation on depressive- and anxiety-like behaviors in mice
González-Castañeda, R. E., Gálvez‐Contreras, A. Y., Martínez-Quezada, C. J., Jáuregui-Huerta, F., García‐Estrada, J., Ramos-Zúñiga, R., Luquín, S., & González-Pérez, Ó. (2015) · EXPERIMENTAL ANIMALS · doi:10.1538/expanim.15-0054 · Cited by 43
“Locomotion, evaluated in the open field test, is indicator motivation and anxiety [21, 42, 43].”
Background
Role of the amygdaloid cholecystokinin (CCK)/gastrin‐2 receptors and terminal networks in the modulation of anxiety in the rat. Effects of CCK‐4 and CCK‐8S on anxiety‐like behaviour and [3H]GABA release
de la Mora, M. P., Hernandez-Gómez, A.-M., Arizmendi‐García, Y., Jacobsen, K. X., Lara‐García, D., Flores‐Gracia, C., Crespo‐Ramírez, M., Gallegos‐Cari, A., Nuche‐Bricaire, A., & Fuxé, K. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2007.05963.x · Cited by 43
Molecular Pathways of Anxiety Revealed by Knockout Mice
Tóth, M., & Wood, S. J. (2001) · Molecular Neurobiology · doi:10.1385/mn:23:2-3:101 · Cited by 42
The effects of environmental enrichment and social isolation and their reversion on anxiety and fear conditioning
Mora-Gallegos, A., & Fornaguera, J. (2018) · Behavioural Processes · doi:10.1016/j.beproc.2018.10.022 · Cited by 42
Some Guidelines for Defining Personality Differences in Rats
Driscoll, P., Fernández‐Teruel, A., Corda, M. G., et al. (2009) · Springer eBooks · doi:10.1007/978-0-387-76727-7_20 · Cited by 42
Risk Evaluation of Endocrine-Disrupting Chemicals: Effects of Developmental Exposure to Low Doses of Bisphenol A on Behavior and Physiology in Mice ( Mus musculus )
Gioiosa, L., Palanza, P., Parmigiani, S., & vom Saal, F. S. (2015) · Dose-Response · doi:10.1177/1559325815610760 · Cited by 41
“The EPM paradigm is one of the most widely used animal tests for the study of anxiety.(41) It consists of 2 open arms and 2 closed arms that extend from a common central platform.”
Method
Where are we heading? Challenges in evidence-based severity assessment
Keubler, L. M., Hoppe, N., Potschka, H., Talbot, S. R., Vollmar, B., Zechner, D., Häger, C., & Bleich, A. (2019) · Laboratory Animals · doi:10.1177/0023677219877216 · Cited by 41

Authors: Rodgers, R. J.
Affiliations: University of Leeds (GB)
Corresponding author: Rodgers, R J
Venue: Behavioural Pharmacology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 1997-11
Volume: 8
Issue: 6
Pages: 477-496
ISSN: 0955-8810 (ISSN-L)
DOI: 10.1097/00008877-199711000-00003
OpenAlex: W2076532454
Cited by: 437
References: 0
Citations by year: 2026: 1 · 2025: 5 · 2024: 7 · 2023: 6 · 2022: 7 · 2021: 1 · 2020: 8 · 2019: 7 · 2018: 9 · 2017: 10 · 2016: 10 · 2015: 15 · 2014: 22 · 2013: 22 · 2012: 21
FWCI: 4.73
Type: journal article
Language: en
Open access: closed
Locations: Behavioural Pharmacology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords: animal models of anxiety, defensive reactions, benzodiazepines, 5-HT1A receptor agonist, defensive burying, panic disorder, threat response, test validity
MeSH terms: Animals, Anxiety, Disease Models, Animal, Humans

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Animal models of ‘anxiety’: Where next?

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