Animal models for the study of dopaminergic mechanisms of behavioral responses to stress, addiction and cognitive performance

Analysis of behavior in rodents submitted to stressors.

The candidate will be involved in the use of animal models for the study of depression to reproduce some known aspects of depression. They can therefore be used:

1) as a tool to investigate aspects of the neurobiology and pathophysiology of depression; 2) as experimental models for the study of the mechanisms of action of antidepressant drugs; and 3) as a screening test to clarify the antidepressant activity.

Models of acute stress:

FORCED SWIM TEST (FTS) and TAIL SUSPENSION TEST (TST): these are the most used tests for the screening of new compounds with potential antidepressant activity. In the FST (Porsolt et al., 1977) a mouse or rat is placed inside a cylinder filled with water from which they cannot escape. After an initial period in which it tries to swim and climb, the animal tends to stay afloat and/or to assume an immobile posture. In TST, immobility is measured while mice are suspended by the tail. Both tests were considered as an expression of "desperate behavior" (Cryan et al., 2005; Lucki et al., 2001). Thus the immobility measured during the test clearly indicates the degree of stress of the tested animal, a longer duration of immobility indicates a greater degree of stress ("despair").

LEARNED HELPLESSNESS: as a result of an uncontrollable and inevitable stress such as exposure to electric shocks, the animals enter a state of "impotence" so that, when they are re-exposed to the same shock with the possibility of being able to escape easily, the animals delay in the escape or even do not even try to escape (Seligman et al., 1975).

Models of chronic stress:

CHRONIC MILD STRESS (CMS): is probably the best animal model of depression. The purpose of this model is to determine a chronic-depressive state that develops gradually over time in response to stress. The CMS provides for the exposure of animals for a few weeks to a series of unforeseeable and minor stressors such as: periods of deprivation of water and food, small temperature reductions, changes in cage mates and other similar individual manipulations (Willner, 2005; Willner et al., 1992). All of this leads to alterations in most animal behaviors (some however are resistant to stress) including anhedonia and apathy. These behavioral changes, along with endocrine and neural alterations, follow those found in individuals with major depression and, as in the clinical setting, are reversed by chronic, but not acute, treatment with antidepressants (Willner et al., 1987; Willner, 1997). Furthermore, it has been shown that exposure to intense chronic stress produces reductions in sucrose consumption (Katz, 1982), a behavior that emphasizes the establishment of an anoedonic behavior linked to prolonged stress exposure.

SOCIAL DEFEAT STRESS (SDS): social defeat stress is a chronic and recurring factor in the life of all animal species. During the stress period the male mouse is introduced, like an intruder, in a new territory where there are other males of the same species. The mouse will be attacked and defeated by the animals already present inside the cage. Behavioral changes in the subject caused by the SDS, such as impaired social interaction or lack of interest, present similarities with human depression (Blanchard et al., 2001; Krishnan et al., 2007).