Principles and Role in Psychopharmacology

The EPM stands as one of the most popular in vivo animal tests currently in use not only to drug discovery/ development, but also to investigate the neurobiological mechanisms underlying ► anxiety. According to Fig. 3, over forty percent of EPM current use, estimates the emotionality of rodents submitted to previous genetical, biochemical and/or behavioral manipulations. Moreover, the EPM is an excellent example of task based on the study of unconditioned or spontaneous behavior. Its popularity, with around 4,300 published papers so far (Fig. 1), is likely due to its obvious and numerous advantages, namely: economy, rapidity, simplicity of design and bidirectional drug sensitivity, couple with the fact that it does not require lengthy training procedures or the use of food/water deprivation or electric shock (Pellow et al. 1985; Lister 1990; Rodgers et al. 1997; Carobrez and Bertoglio 2005).

The behavioral measures routinely scored during the 5-min EPM session are the frequency of open- and enclosed-arms entries and the amount of time spent on the open- and enclosed-arms. These data are used to calculate the percentage of open-arms entries {%OAE; [open entries/(open+enclosed entries)] x 100} and the percentage of time spent in open-arms {%OAT; [open time/(open+enclosed time)] x 100}. As illustrated in Fig. 2, there is a clear enclosed-arm preference. Under the influence of an anxiogenic-like drug, a further reduction in the open-arms exploration is observed. After being administered with anxiolytics, however, the animal displays significantly more open-arms exploration. In this context, it is worth mentioning that the efficacy of the EPM test in discriminating anxioselective compounds has been increased with the adoption of more ethologically-based analysis, i.e., the measurement of some acts and postures such as stretched-attend, head-dipping and grooming (Cruz et al. 1994). For instance, the frequency of stretched-attend postures towards the open-arms (Fig. 2c,g) can be used as an index of ► risk assessment, a close behavioral dimension related to anxiety (Rodgers et al. 1997; Carobrez and Bertoglio 2005). The anxiose-lective discriminative property confers to the EPM test the predictive validity required to screen putative compounds and/or to identify alternative pharmacological interventions in anxiety field.

Elevated Plus Maze. Fig. 1. Published papers using the elevated-plus maze test in each year, according to the search performed on the PubMed site (http://www.ncbi.nlm.nih.gov/ pubmed) in November 2009. e=estimated value based on the mean number of published paper per month in 2009.

Methodological Variables

The main organismic variables of interest in the EPM test are species, strain, age, gender and estrus cycle/lactation, all of which have proven to interfere with its behavioral baseline level (Rodgers and Cole 1994). Furthermore, the different social role in the rodent group can be an important source of variation among dominant/subordinate males and females. As a consequence, either ► false-negative or ► false-positive results can occur if these important caveats are not taken into account. For instance, in spite of having similar defensive responses, mice and rats show a different level of general exploratory activity in the EPM test (mice been more active than rats). Anxiety scores also tend to change with age, apparently reflecting distinct brain development and/or the behavioral repertoire of the species.

Some procedural variables have also been shown to impact on the EPM baseline level. They include housing conditions, ► circadian rhythm, illumination level, time of testing, apparatus construction, definition of behavioral measures, prior handling/stress, and prior test experience. Together with organismic variables, these are the main sources of inter-laboratory variability in the use of the EPM (Carobrez and Bertoglio 2005). Based on the fact that behavioral responses and pharmacological effects observed in the EPM are under the influence of these

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Anxiety and Depression 101

Anxiety and Depression 101

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