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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“A remarkable shift towards more natural models having greater ethological relevance has occurred recently (Hendrie et al. 1996; Rodgers 1997).”
Background
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Rodgers, R. J. (2010) · Elsevier eBooks · doi:10.1016/b978-0-08-045396-5.00002-6 · Cited by 23
Self-citation
Comparison of the predictive validity of the mirror chamber and elevated plus maze tests in mice
Paterson, N. E., Iwunze, M., Davis, S. F., Malekiani, S. A., & Hanania, T. (2010) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2010.02.005 · Cited by 18
Agonistic Onset Marks Emotional Changes and Dispersal Propensity in Wild House Mouse Males (Mus domesticus).
Rusu, A. S., & Krackow, S. (2005) · Journal of comparative psychology · doi:10.1037/0735-7036.119.1.58 · Cited by 16
“We used an open-field test (OFT) as a standard procedure for measuring normal, nonpathological anxiety and exploratory behavior of rodents (Belzung, 1999; Belzung & Griebel, 2001; Choleris, Thomas, Kavaliers, & Prato, 2001; Ramos & Mormede, 1998; Rodgers, 1997).”
Method
How Animal Models Inform Child and Adolescent Psychiatry
Stevens, H. E., & Vaccarino, F. M. (2015) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2015.01.019 · Cited by 18
The effects of varied extinction procedures on contingent cue-induced reinstatement in Sprague-Dawley rats
Buffalari, D. M., Feltenstein, M. W., & See, R. E. (2013) · Psychopharmacology · doi:10.1007/s00213-013-3156-z · Cited by 16
“Previous studies have demonstrated differences in these two paradigms, suggesting that they may measure different components of anxiety (Rodgers 1997).”
Carbon monoxide neurotoxicity: transient inhibition of avoidance response and delayed microglia reaction in the absence of neuronal death
Brunssen, S., Morgan, D. L., Parham, F. M., et al. (2003) · Toxicology · doi:10.1016/j.tox.2003.08.003 · Cited by 16
Blockade of NMDA or NO in the dorsal premammillary nucleus attenuates defensive behaviors
de Aguiar, D. C., & Guimarães, F. S. (2011) · Physiology & Behavior · doi:10.1016/j.physbeh.2011.02.034 · Cited by 15
Effects of fluoxetine and PCPA on isolation-induced morphine self-administration and startle reactivity
Raz, S., & Berger, B. D. (2010) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2010.04.007 · Cited by 13
“Startle response is a common behavioral test for assessment of emotional reactivity in rodents, and is often used to assess the effects of anti-anxiety drugs (Bourin et al., 2007; Grillon, 2002; Grillon, 2008; Rodgers, 1997).”
Higher detection sensitivity of anxiolytic effects of diazepam by ledge-free open arm with opaque walled closed arm elevated plus maze in male rats
Horii, Y., & Kawaguchi, M. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2015.07.059 · Cited by 15
D-cycloserine enhances memory consolidation in the plus-maze retest paradigm.
Rodgers, R. J., Harvest, H., Hassall, C., & Kaddour, L. A. (2011) · Behavioral Neuroscience · doi:10.1037/a0022343 · Cited by 17
“The elevated plus-maze (EPM) is currently the most popular of all rodent tests for anxiety and, for some 25 years, has been used both as a screening tool for novel anxiolytics and as a means to research the underlying neurobiology of emotion (Carobrez & Bertoglio, 2005; Hogg, 1996; Rodgers, 1997; Rodgers, 2010; Walf &…”
MethodSelf-citation
Relationship between 22-kHz calls and testosterone in male rats
Inagaki, H., & Mori, Y. (2013) · Hormones and Behavior · doi:10.1016/j.yhbeh.2013.11.003 · Cited by 15
Validation of a behavioral recording automated system in the elevated plus-maze test
Torres, C., & Arrieta, M. D. E. (2002) · Life Sciences · doi:10.1016/s0024-3205(02)01476-5 · Cited by 15
More haste, considerably less speed
Rodgers, R. J. (2007) · Journal of Psychopharmacology · doi:10.1177/0269881107074493 · Cited by 14
Self-citation
Cat odour exposure decreases exploratory activity and alters neuropeptide gene expression in CCK2 receptor deficient mice, but not in their wild-type littermates
Areda, T., Raud, S., Philips, M., Innos, J., Matsui, T., Kõks, S., Vasar, E., Karis, A., & Asser, T. (2006) · Behavioural Brain Research · doi:10.1016/j.bbr.2006.01.010 · Cited by 15
Developing Novel Anxiolytics: Improving Preclinical Detection and Clinical Assessment
Steckler, T., Stein, M. B., & Holmes, A. (2008) · Elsevier eBooks · doi:10.1016/b978-0-12-373861-5.00005-9 · Cited by 19
TP003 is a non-selective benzodiazepine site agonist that induces anxiolysis via α2GABAA receptors
Neumann, E., Ralvenius, W. T., Acuña, M. A., Rudolph, U., & Zeilhofer, H. U. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.09.026 · Cited by 14
“Many investigators distinguish unconditioned anxiety, which has been tested here, from conditioned fear response (Rodgers, 1997; Blanchard et al., 2003; Brandão et al., 2015).”
Activation and blockade of dorsal hippocampal Serotonin6 receptors regulate anxiety-like behaviors in a unilateral 6-hydroxydopamine rat model of Parkinson’s disease
Liu, K. C., Guo, Y., Zhang, J., Chen, L., Liu, Y. W., Lv, S. X., Xie, W., Wang, H. S., Zhang, Y. M., & Zhang, L. (2019) · Neurological Research · doi:10.1080/01616412.2019.1611204 · Cited by 14
“arms and entries into open arms are indicative of anxiety-like behavior, while the frequency of closed arm entries represents locomotor activity [26].”
Background
In pursuit of biomarkers for predicting susceptibility to activity‐based anorexia in adolescent female rats
Milton, L. K., Patton, T., O’Keeffe, M. A., Oldfield, B. J., & Foldi, C. J. (2022) · International Journal of Eating Disorders · doi:10.1002/eat.23705 · Cited by 14
“making, from which animals engage in high levels of risk assessment [58].”
Background
An Experimental Study to Evaluate the Effect of Memantine in Animal Models of Anxiety in Swiss Albino Mice
Bagewadi, H. G. (2015) · JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH · doi:10.7860/jcdr/2015/13233.6287 · Cited by 13
Chapter 2.5 Unconditioned models of fear and anxiety
Litvin, Y., Pentkowski, N. S., Pobbe, R. L. H., Blanchard, D. C., & Blanchard, R. J. (2008) · Handbook of behavioral neuroscience · doi:10.1016/s1569-7339(07)00006-9 · Cited by 13
Aspen shaving versus chip bedding: effects on breeding and behavior
Jackson, E., Demarest, K., Eckert, W. J., Cates‐Gatto, C., Nadav, T., Cates, L., Howard, H., & Roberts, A. J. (2014) · Laboratory Animals · doi:10.1177/0023677214553320 · Cited by 15
The NK1 receptor antagonist NKP608 lacks anxiolytic-like activity in Swiss-Webster mice exposed to the elevated plus-maze
Rodgers, R. J., Gentsch, C., Hoyer, D., Bryant, E., Green, A. J., Kolokotroni, K. Z., & Martin, J. L. (2004) · Behavioural Brain Research · doi:10.1016/j.bbr.2004.02.005 · Cited by 14
Self-citation
Environmental Familiarization in Rats: Differential Effects of Acute and Chronic Nicotine
Bevins, R. A., Koznarova, J., & Armiger, T. J. (2001) · Neurobiology of Learning and Memory · doi:10.1006/nlme.1999.3955 · Cited by 15
“, elevated plus maze) are used in animal models of anxiety (King, 1999; Rodgers, 1997).”
Method
Effects of single and simultaneous lesions of serotonergic and noradrenergic pathways on open-space and bright-space anxiety-like behavior in two animal models
Sziray, N., Kuki, Z., Nagy, K. M., Markó, B., Kompagne, H., & Lévay, G. I. (2010) · Behavioural Brain Research · doi:10.1016/j.bbr.2010.01.019 · Cited by 13
The Comparative Effects Of Chronic Consumption Of Kola Nut (Cola nitida) And Caffeine Diets On Locomotor Behaviour And Body Weights In Mice
Umoren, E. B., Osim, E., & Udoh, P. (2009) · Nigerian Journal of Physiological Sciences · doi:10.4314/njps.v24i1.46387 · Cited by 13
“This method is UMOREN et al in line with Brown et al. (1999), Archer (1973), Rodgers (1997) and Streng (1974), who used the open field apparatus to assess the locomotory and exploratory behaviour of animals in a novel environment.”
Method
Postnatal Transplantation of Interneuronal Precursor Cells Decreases Anxiety-Like Behavior in Adult Mice
Valente, M. F., Romariz, S. A. A., Calcagnotto, M. E., Ruiz, L. P., Mello, L. E., Frussa‐Filho, R., & Longo, B. M. (2013) · Cell Transplantation · doi:10.3727/096368912x657422 · Cited by 13
Behavioral, hormonal and histological stress markers of anxiety-separation in postnatal rats are reduced by prepro-thyrotropin-releasing hormone 178–199
Stahl, C. E., Redei, E. E., Wang, Y., & Borlongan, C. V. (2002) · Neuroscience Letters · doi:10.1016/s0304-3940(01)02349-7 · Cited by 13
The differential effect of the anxiolytic agent 8–OH–DPAT during lactation is independent of pup withdrawal and maternal behavior
Picazo, O., Rosenblatt, J. S., & Fernández‐Guasti, A. (2000) · Psychoneuroendocrinology · doi:10.1016/s0306-4530(00)00019-6 · Cited by 13
Anxiolytic Effects of Acute Injection of Hydro-Alcoholic Extract of Lettuce in the Elevated Plus-Maze Task in Rats
Komaki‬, A., Nasab, Z. K., Shahidi, ‬., Sarihi, A., Salehi, I., & Ghaderi, A. (2014) · Avicenna Journal of Neuro Psych Physiology · doi:10.17795/ajnpp-18695 · Cited by 12
“This test has been widely validated to measure anxiety in rodents (13, 15-25).”
Method
Evaluation of cage leaving behaviour in rats as a free choice paradigm
Bert, B., Schmidt, N. B., Voigt, J., Fink, H., & Rex, A. (2013) · Journal of Pharmacological and Toxicological Methods · doi:10.1016/j.vascn.2013.01.001 · Cited by 11
Anxiolytic effect of an extract of Salvia miltiorrhiza roots in rats
Lobina, C., Colombo, G., Gessa, G. L., Carai, M. A. M., Allegrini, P., Morazzoni, P., & Riva, A. (2017) · Journal of the Chinese Medical Association · doi:10.1016/j.jcma.2017.09.015 · Cited by 12
Maternal and Genetic Effects on Anxiety-Related Behavior of C3H/HeN, DBA/2J and NMRI Mice in a Motility-Box Following Blastocyst Transfer
Rose, C., Röhl, F., Schwegler, H., Hanke, J., & Yilmazer‐Hanke, D. (2006) · Behavior Genetics · doi:10.1007/s10519-005-9037-4 · Cited by 13
“The motility-box is a small open field suitable to study innate anxiety in freely moving animals during exploration of a novel environment using automated sampling for precise quantification of behavioral variables (Archer, 1973; Goma and Tobena, 1978; Markel et al., 1989; Rodgers, 1997 ).”
Background
Characteristics of extinction of a conditioned passive avoidance reflex in mice with different levels of anxiety
Dubrovina, N., & Tomilenko, R. А. (2007) · Neuroscience and Behavioral Physiology · doi:10.1007/s11055-007-0145-x · Cited by 12
“The greater the latent period of transfer on extinction days 9‐13, the smaller the number of glances and the greater the level of defecations reflecting a high level of anxiety [1, 4, 5, 22 ].”
BackgroundInfluential

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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