Some animal models of depression, including the majority of the more recently introduced models, are better characterized as models of predisposition to depression. In the first part of this paper, we show that the basis for such a model could be either a procedure that increases the ease with which an analogue of major depression may be evoked, or a presentation analogous to dysthymia (chronic mild depression). We then consider how the concepts of predictive, face, and construct validity apply to such models. Next, we review the validity of the available models of predisposition to depression, which derive from genetics, genomics, developmental manipulations, and brain lesioning. Finally, we compare the performance of the different models, using a novel scoring system that formalizes the evaluation of animal models against each of the three sets of validation criteria.

The importance of T cell Ag specificity and Th1 vs Th2 phenotype in synovial inflammation remains controversial. Using OVA-specific TCR transgenic T cells from DO11.10 mice, we demonstrate that mice receiving Th1, but not Th2, cells display a transient arthritis following immunization that is characterized by synovial hyperplasia, cellular infiltration, and cartilage erosion. OVA-specific T cells also accumulated in inflamed joints, suggesting that they could exert their inflammatory effect locally in the joint or in the draining lymph node. Importantly, this pathology was accompanied by a breakdown in self-tolerance, as evidenced by the induction of collagen-specific T and B cell responses. This model directly demonstrates a pivotal role for Th1 cells of an irrelevant specificity in the development of inflammatory arthritis. Furthermore, the ability to track these cells in vivo will make feasible studies revealing the dynamic role of T cells in arthritis.

Taken together, these results demonstrate that the novel 5-HT2C receptor agonist WAY-163909 produces rapid onset antidepressant-like effects in animal models and may be a novel treatment for depression.

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