| OCD (obsessive-compulsive disorder) is a chronic and debilitating psychiatric condition characterized by intrusive and persistent thoughts (obsessions) and repetitive behaviors (compulsions) that become ritualistic in an attempt to escape the obsessions. Currently there is a paucity of animal models with robust and spontaneous (non-drug or non-behaviorally induced) compulsive-like behaviors. This study is aimed at validating a novel robust and spontaneous genetic mouse model of OCD. The compulsive-like nest-building behavior in mice selected for high levels of nest-building behavior (BIG) has good face validity, with a behavioral phenotype that resembles hoarding behavior characteristic of OCD. In addition, male and female BIG mice displayed compulsivelike digging behavior relative to mice selected for low levels of nest-building behavior (SMALL), as assessed by the marble-burying test. Both chronic oral fluoxetine and clomipramine treatment reduced compulsive-like nest-building behavior in male BIG mice. Furthermore, chronic oral fluoxetine administration decreased nest-building behavior of BIG mice in a dose-dependent manner, while desipramine, an antidepressant not effective for treating OCD, did not significantly alter this behavior. The administration of fluoxetine did not cause a decrease in general locomotor behavior. These findings suggest that the nest-building phenotype has predictive validity. In addition, chronic oral fluoxetine treatment reduced compulsive-like digging behavior in male and female BIG mice as compared to SMALL mice. Gender effects were also found in treatment response. Clomipramine did not reduce nest-building in female BIG mice in a dose-dependent manner, which is consistent with previous studies. These data are in contrast to previous studies using BIG male mice which had a significant decrease in nest-building behavior with oral clomipramine. These results are consistent with studies on humans, which have found gender differences in the treatment effects of antidepressants. Additional construct validity is implicated by the results of targeted serotonergic lesions of the raphe nuclei in male BIG mice, which reduced repetitive nest-building behavior. More research is necessary to confirm the appropriateness of this model for human OCD; however, this model is promising based on the data that support good face, predictive and construct validity. |
