Experimental models of depression: their validation and application to the study of compounds with potential antidepressant activity

Experimental models of depression: their validation and application to the study of compounds with potential antidepressant activity 2 INDEX Experimental models of depression: their validation and application to the study of compounds with potential antidepressant activity Experimental models of depression: their validation and application to the study of compounds with potential antidepressant activity 4 I. ANIMAL MODELS FOR THE STUDY OF ANTIDEPRESSANT ACTIVITY Experimental models of depression: their validation and application to the study of compounds with potential antidepressant activity 5 Introduction Experimental models of depression are essential, both for screening new antidepressant medications and for studying the mechanisms underlying the effects of antidepressant treatments. Among the most widely utilized models are the behavioral despair test [90] and the helplessness syndrome [74, 98], that are based on the decreased performance or reactivity of animals exposed to unavoidable, uncontrollable stressors. The behavioral despair test, also known as the forced swim test, is based on the observation that rats immersed in cold water in a cylinder without the possibility of escape become immobile after an initial struggling phase. Immobility has been equated to a despair reaction, and when, 24h later, rats are placed back in the water cylinder they remain immobile for a significantly longer time than naive animals. The administration of 1-3 doses of different antidepressants during the 24h interval tends to significantly shorten the period of immobility [90, 89]. However, the response to this short-term treatment could depend on mechanisms that are different from the ones that determine the 2-4 week delay in the clinical response to antidepressants, or from the processes of neuronal plasticity mediating imipramine activity in a different experimental protocol [64]. The classic learned helplessness model evaluates the behavioral response of an animal to a sensory stimulus previously associated to stress. This model has a variable score, of 30 to 85%, in terms of the percentage of rats which become hyporeactive after the training phase [30, 74, 98], and some authors use adrenalectomized rats in order to obtain a consistently high percentage of hyporeactive rats [30]. Chronic mild stress [107, 106] is a naturalistic model of hostile environment which models anhedonia, another major symptom of depression defined as diminished interest in environmental stimuli, or diminished reinforcing effects of environmental stimuli [110]. In the chronic mild stress model, the repeated exposure of rats (maintained in a condition of partial food deprivation) to a variety of mild stressors has …