Apomorphine susceptibility and animal models for psychopathology: genes and environment

Many years ago we found a bimodal distribution of a number of different behaviors in our regular outbred Wistar stock. This was observed in the response to novelty, the response in a resident-intruder test as well as in the stereotypy response to the dopamine agonist apomorphine. On the basis of that, we decided to selectively breed these animals, which resulted in the the APO-SUS and APO-UNSUS lines. The APO-SUS rats show a strong, stereotyped gnawing response, whereas APO-UNSUS show only a weak gnawing response. Follow-up studies have shown that the phenotypical expression of these rats depend on genetic and early and late environmental factors. Because these rats were not selected on the basis of a specific behavioral trait, but rather on the basis of a difference in susceptibility for a specific neurotransmitter, it is not surprising that these animals show major differences in the neurochemical state of the central nervous system. In fact, in many respects they represent mirror images of each other. Moreover, these animals show clear differences in their endocrine and immunological systems. APO-SUS rats can be characterized as having a hyper-reactive hypothalamus-pituitary-adrenal axis, and a dominance of the T_H2 system. Apart from discussing the main differences between APO-SUS and APO-UNSUS rats, the review specifically focuses on the former as a potential model for schizophrenia. We have been able to show that APO-SUS rats indeed share a large number of behavioral, neurochemical, endocrinological, and immunological similarities with patients suffering from schizophrenia. Because schizophrenia is also likely to result from an interaction between genetic and early stressful life events, the APO-SUS rat might represent a promising animal model for studying this severe mental disorder.