Novel animal models of affective disorders.

Is there an appropriate animal model for human affective disorders? The traditional difficulties in accepting animal models for psychopathology stem from the argument that there is no evidence for concluding that what occurs in the brain of the animal is equivalent to what occurs in the brain of a human. However, if one models any or some core aspects of affective disorder, this model can become an invaluable tool in the analysis of the multitude of causes, genetic, environmental, or pharmacological, that can bring about symptoms homologous to those of patients with affective disorders. Animal models can also allow the study of the mechanisms of specific behaviors, their pathophysiology, and can aid in developing and predicting therapeutic responses to pharmacologic agents. Although animals exhibit complex and varied social and emotional behaviors for which well-validated and standardized measures exist, an understanding that a precise replica of human affective disorders cannot be expected in a single animal model is crucial. Instead, a good animal model of a human disorder should fulfill as many of the four main criteria as possible: (1) strong behavioral similarities, (2) common cause, (3) similar pathophysiology, and (4) common treatment. An animal model fulfilling any or most of these criteria can be used to elucidate the mechanisms of the specific aspect of the model that is homologous to the human disorder. A wide range of animal models of affective disorders, primarily depression, has been developed to date. They include models in which "depressive behavior" is the result of genetic selection or manipulation, environmental stressors during development or in adulthood, or pharmacologic treatments. The assessment of these animal models is based either on behavioral tests measuring traits that are homologous to symptoms of the human disorder they model, or behavioral tests responsive to appropriate pharmacologic treatments. The goal of this review is to focus on relatively recent developments of selected models, to aid in understanding their strengths and weaknesses, and to help those choosing the difficult task of developing novel animal models of affective disorders. The ideal animal model of affective disorders of the future would be an endogenous, genetic model that reiterates the essential, core aspects of the human disease and responds to the standard regimens of therapy. Because complex diseases have been approached from the genetic startpoint by using rodent models, a genetic model of affective disorder would open up possibilities for genetic analysis of polygenic traits that seem to underlie these disorders.

6-OHDA denervation substantially decreases DCC mRNA levels in rat substantia nigra compacta.

The function of deleted in colorectal cancer (DCC) protein, a member of the immunoglobulin superfamily of cell adhesion molecules, in the adult CNS is unknown. Recently the transcript encoding DCC has been shown to be expressed in a variety of rat brain regions, including the substantia nigra pars compacta and the striatum, which encompasses the nigrostriatal dopaminergic system. In the present study DCC mRNA expression in substantia nigra, striatum, dentate gyrus and piriform cortex was investigated in adult rats using in situ hybridization histochemistry following unilateral injections of 6-hydroxydopamine (6-OHDA) in the median forebrain bundle. DCC mRNA levels were greatly reduced in the substantia nigra ipsilateral to the 6-OHDA lesion compared to those on the contralateral side while there was no apparent effect on DCC mRNA levels in the other regions analysed. These data indicate expression of DCC mRNA in dopamine neurones of the substantia nigra pars compacta and support a role for DCC in the adult CNS, with potential involvement in the function of central dopamine neurones.

Differential expression of DCC mRNA in adult rat forebrain.

DCC is a member of the immunoglobulin superfamily of cell adhesion molecules, whose role in the function of the adult nervous system is unknown. DCC mRNA expression was studied in adult rat dorsal hippocampal sections using in situ hybridization histochemistry. High levels of DCC transcript were detected in hippocampus and medial habenula, whereas lower mRNA expression was found in cerebral cortex, hypothalamus and thalamus. The higher relative expression of DCC mRNA in hippocampus, compared with the remainder of the brain was confirmed using RT-PCR analysis. These data confirm the presence of DCC mRNA in adult rat brain and indicate that DCC mRNA is differentially expressed between forebrain regions, suggesting a role for DCC in the function of the adult rat central nervous system.

5-HT2B receptor mRNA in guinea pig superior cervical ganglion.

Primers for 5-HT2A, 5-HT2B and 5-HT2C receptor mRNAs were used in reverse transcriptase-linked polymerase chain reactions (RT-PCR) to determine the presence of these transcripts in the guinea pig superior cervical ganglion. This was done to help identify an as yet unknown 5-HT2-like receptor which, in addition to 5-HT2A receptors, mediates a slow depolarization of this preparation. PCR products corresponding to 5-HT2A and 5-HT2B, but not 5-HT2C, receptor mRNA could readily be detected. Subsequent sequence analysis of these products confirmed that the 5-HT2A band corresponded to part of the guinea pig 5-HT2A receptor and the 5-HT2B band probably represents a portion of the guinea pig 5-HT2B receptor. The latter sequence shares greater homology with an equivalent region of the human than the rat 5-HT2B receptor.