A robust animal model of state anxiety: fear-potentiated behaviour in the elevated plus-maze

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Abstract

Fear (i.e., decreased percentage time spent on open-arm exploration) in the elevated plus-maze can be potentiated by prior inescapable stressor exposure, but not by escapable stress. The use of fear-potentiated plus-maze behaviour has several advantages as compared to more traditional animal models of anxiety. (a) In contrast to the traditional (spontaneous) elevated plus-maze, which measures innate fear of open spaces, fear-potentiated plus-maze behaviour reflects an enhanced anxiety state (allostatic state). This “state anxiety” can be defined as an unpleasant emotional arousal in face of threatening demands or dangers. A cognitive appraisal of threat is a prerequisite for the experience of this type of emotion. (b) Depending on the stressor used (e.g., fear of shock, predator odour, swim stress, restraint, social defeat, predator stress (cat)), this enhanced anxiety state can last from 90 min to 3 weeks. Stress effects are more severe when rats are isolated in comparison to group housing. (c) Drugs can be administered in the absence of the original stressor and after stressor exposure. As a consequence, retrieval mechanisms are not affected by drug treatment. (d) Fear-potentiated plus-maze behaviour is sensitive to proven/putative anxiolytics and anxiogenics which act via mechanisms related to the benzodiazepine–gamma-aminobutyric acid receptor, but it is also sensitive to corticotropin-releasing receptor antagonists and glucocorticoid receptor antagonists and serotonin receptor agonists/antagonists complex (high predictive validity). (e) Fear-potentiated plus-maze behaviour is very robust, and experiments can easily be replicated in other labs. (f) Fear-potentiated plus-maze behaviour can be measured both in males and females. (g) Neural mechanisms involved in contextual fear conditioning, fear potentiation and state anxiety can be studied .Thus, fear-potentiated plus-maze behaviour may be a valuable measure in the understanding of neural mechanisms involved in the development of anxiety disorders and in the search for novel anxiolytics. Finally, the involvement of corticotropin-releasing factor and corticosteroid–corticotropin-releasing factor interactions in the production of fear-potentiated plus-maze behaviour are discussed.

Section snippets

Different stressors produce fear potentiation in the elevated plus-maze

In the field of anxiety, the elevated plus-maze has become one of the most popular animal models (Pellow et al., 1985). The test involves placing a naive rat (or mouse or pig) in the center of an elevated plus-maze with two open and two enclosed arms, and allowing it to freely explore Rodgers and Cole, 1993, Rodgers and Dalvi, 1997, Andersen et al., 2000. It has been suggested that the reluctance of rats to explore the open arms of the maze is caused by fear of open spaces, rather than the

Stressor controllability and fear-potentiated plus-maze behaviour

To study the effects of stressor controllability on fear-potentiated plus-maze behaviour, an experiment was set up in accordance with the methods of Weiss (1968) on the influence of psychological variables on stress-induced pathology. Three groups were used (Korte et al., 1999). The first group (no stress) of rats received no shocks (see Fig. 1). The second group of rats were trained in a two-way (shuttle box) active avoidance paradigm and were exposed to 10 controllable mild electric footshock

Duration of fear potentiation

To study the duration of fear-potentiated plus-maze behaviour in group-housed rats, they received one inescapable mild footshock (0.6 mA, a.c. for 3 s) (loss of control) (Korte et al., 1999). The next day, the rats were exposed to the prior shock compartment, but no further footshock was given (contextual conditioning). The rats were placed at the following times in the plus-maze: directly, 30 min, 60 min, 90 min, 120 min and 180 min after reexposure to former shock compartment. The control

Classical anxiolytic and anxiogenic drug effects on fear-potentiated plus-maze behaviour in female rats

Previously, we have shown that the classical benzodiazepine anxiolytic diazepam (valium) and the anxiogenic inverse benzodiazepine agonist methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), respectively, decreased and increased the enhanced anxiety state as measured in the elevated plus-maze in male rats (Korte et al., 1999). To study whether these drug effects were sex-dependent, we used the same drugs in female rats. A similar stress procedure as described in “duration of fear

Corticosteroid involvement in fear-potentiated plus-maze behaviour

To study whether glucocorticosteroids are involved in fear potentiation in the elevated plus-maze test, a similar stress procedure was used as described in Section 3. Male rats were first placed in the prior shock compartment, then injected subcutaneously with vehicle or glucocorticoid receptor antagonist RU38486 or the even more specific glucocorticoid receptor antagonist ORG34580 and 30 min thereafter placed in the elevated plus-maze.

Fig. 5 shows, as expected, that vehicle (0)-treated

CRF involvement in fear-potentiated plus-maze behaviour

In order to show that fear-potentiated plus-maze behaviour is a very robust measure and corticotropin-releasing factor (CRF) receptors are involved in this enhanced anxiety state, we replicated and extended (24 h after defeat) an experiment firstly performed in the Koob laboratory of the Scripps Research Institute at La Jolla (USA) Heinrichs et al., 1992, Koob et al., 1993, Menzaghi et al., 1994. We investigated whether the potent mixed CRF1,2 receptor antagonist d-Phe CRF-(12-41), which was

Allostasis, allostatic state and allostatic load in relation to enhanced anxiety

Allostasis refers to the integrative adaptive processes maintaining stability through change Sterling and Eyer, 1988, McEwen and Stellar, 1993, McEwen, 1998, McEwen, 2000, Goldstein and McEwen, 2002. By controlling all the mechanisms simultaneously, the brain can enforce its command and introduce experience, memories, anticipation and reevaluation of needs in anticipation of physiological requirements (Koob and Le Moal, 2001). Allostatic state, as defined by Koob and Le Moal (2001), refers to a

Seven reasons why fear-potentiated plus-maze behaviour should be used

The present review clearly shows the many advantages of the use of fear-potentiated plus-maze behaviour as a valuable measure in the understanding of neural mechanisms involved in state anxiety and in the search for novel anxiolytics.

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    In contrast to the normal elevated plus-maze, which measures innate fear of open spaces, fear-potentiated plus-maze behaviour reflects an enhanced anxiety state (allostatic state).

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    Depending on the stressor used (e.g., fear of shock; predator odour, swim stress,

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